Sheri Spunt, MD, MBA

Abstract

PURPOSES: This study aims to ascertain the prevalence of cavitations in pulmonary metastases among pediatric and young adult patients with sarcoma undergoing tyrosine kinase inhibitor (TKI) therapy, and assess whether cavitation can predict clinical response and survival outcomes.METHODS: In a single-center retrospective analysis, we examined chest computed tomography (CT) scans of 17 patients (median age 16years; age range: 4-25years) with histopathologically confirmed bone (n=10) or soft tissue (n=7) sarcoma who underwent TKI treatment for lung metastases. The interval between TKI initiation and the onset of lung nodule cavitation and tumor regrowth were assessed. The combination of all imaging studies and clinical data served as the reference standard for clinical responses. Progression-free survival (PFS) was compared between patients with cavitating and solid nodules using Kaplan-Meier survival analysis and log-rank test.RESULTS: Five out of 17 patients (29%) exhibited cavitation of pulmonary nodules during TKI therapy. The median time from TKI initiation to the first observed cavitation was 79days (range: 46-261days). At the time of cavitation, all patients demonstrated stable disease. When the cavities began to fill with solid tumor, 60% (3/5) of patients exhibited progression in other pulmonary nodules. The median PFS for patients with cavitated pulmonary nodules after TKI treatment (6.7months) was significantly longer compared to patients without cavitated nodules (3.8months; log-rank p-value=.03).CONCLUSIONS: Cavitation of metastatic pulmonary nodules in sarcoma patients undergoing TKI treatment is indicative of non-progressive disease, and significantly correlates with PFS.

View details for DOI 10.1002/pbc.30629

View details for PubMedID 37580891

Abstract

Pain is a common consequence of childhood cancer. While most research has examined biomedical predictors of post-cancer pain, biopsychosocial conceptualisations such as the Cancer Threat Interpretation (CTI) model hold promise for guiding comprehensive pain management strategies. Guided by the CTI model, this cross-sectional study evaluated correlates of post-cancer pain in childhood cancer survivors including threat-related risk factors (bodily threat monitoring, fear of cancer recurrence, help-seeking) and mindsets about the body. In the preceding three months, 21.8% of survivors reported chronic pain (>3 months) and 14.3% experienced pain most days. Greater bodily threat monitoring, more fear of cancer recurrence, and more help-seeking was associated with more pain. There was heterogeneity in the mindsets that survivors of childhood cancer hold about their bodies. Holding the mindset that the 'body is an adversary' was associated with more pain, greater bodily threat monitoring and more fear of cancer recurrence. Holding the mindset that the 'body is responsive' was associated with less bodily threat monitoring, while the mindset that the 'body is capable' was associated with greater help-seeking. A path model demonstrated a significant combined indirect effect of the 'body is an adversary' mindset on pain through bodily threat monitoring and fear of cancer recurrence. Overall, this study supported that a sub-group of childhood cancer survivors experience persistent and interfering pain and provided cross-sectional support for threat-related correlates for pain aligning with the CTI model. Body mindsets were associated with pain and threat-related correlates and may represent a novel target to support survivors with pain.

View details for DOI 10.1016/j.jpain.2023.07.030

View details for PubMedID 37549774

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B (P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B (P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.

View details for DOI 10.1200/JCO.23.00045

View details for PubMedID 37523624

Abstract

Kidney injury is a known late and potentially devastating complication of abdominal radiation therapy (RT) in pediatric patients. A comprehensive Pediatric Normal Tissue Effects in the Clinic review by the Genitourinary (GU) Task Force aimed to describe RT dose-volume relationships for GU dysfunction, including kidney, bladder, and hypertension, for pediatric malignancies. The effect of chemotherapy was also considered.We conducted a comprehensive PubMed search of peer-reviewed manuscripts published from 1990 to 2017 for investigations on RT-associated GU toxicities in children treated for cancer. We retrieved 3271 articles with 100 fulfilling criteria for full review, 24 with RT dose data and 13 adequate for modeling. Endpoints were heterogenous and grouped according to National Kidney Foundation: grade 1, grade 2, and grade 3. We modeled whole kidney exposure from total body irradiation (TBI) for hematopoietic stem cell transplant and whole abdominal irradiation (WAI) for patients with Wilms tumor. Partial kidney tolerance was modeled from a single publication from 2021 after the comprehensive review revealed no usable partial kidney data. Inadequate data existed for analysis of bladder RT-associated toxicities.The 13 reports with long-term GU outcomes suitable for modeling included 4 on WAI for Wilms tumor, 8 on TBI, and 1 for partial renal RT exposure. These reports evaluated a total of 1191 pediatric patients, including: WAI 86, TBI 666, and 439 partial kidney. The age range at the time of RT was 1 month to 18 years with medians of 2 to 11 years in the various reports. In our whole kidney analysis we were unable to include chemotherapy because of the heterogeneity of regimens and paucity of data. Age-specific toxicity data were also unavailable. Wilms studies occurred from 1968 to 2011 with mean follow-ups 8 to 15 years. TBI studies occurred from 1969 to 2004 with mean follow-ups of 4 months to 16 years. We modeled risk of dysfunction by RT dose and grade of toxicity. Normal tissue complication rates 5%, expressed as equivalent doses, 2 Gy/fx for whole kidney exposures occurred at 8.5, 10.2, and 14.5 Gy for National Kidney Foundation grades 1, 2, and 3, respectively. Conventional Wilms WAI of 10.5 Gy in 6 fx had risks of grade 2 toxicity 4% and grade 3 toxicity 1%. For fractionated 12 Gy TBI, those risks were 8% and <3%, respectively. Data did not support whole kidney modeling with chemotherapy. Partial kidney modeling from 439 survivors who received RT (median age, 7.3 years) demonstrated 5 or 10 Gy to 100% kidney gave a <5% risk of grades 3 to 5 toxicity with 1500 mg/m2 carboplatin or no chemo. With 480 mg/m2 cisplatin, a 3% risk of grade 3 toxicity occurred without RT and a 5% risk when 26% kidney received 10 Gy. With 63 g/m2 of ifosfamide, a 5% risk of grade 3 toxicity occurred with no RT, and a 10% toxicity risk occurred when 42% kidney received 10 Gy.In patients with Wilms tumor, the risk of toxicity from 10.5 Gy of WAI is low. For 12 Gy fractionated TBI with various mixtures of chemotherapy, the risk of severe toxicity is low, but low-grade toxicity is not uncommon. Partial kidney data are limited and toxicity is associated heavily with the use of nephrotoxic chemotherapeutic agents. Our efforts demonstrate the need for improved data gathering, systematic follow-up, and reporting in future clinical studies. Current radiation dose used for Wilms tumor and TBI appear to be safe; however, efforts in effective kidney-sparing TBI and WAI regimens may reduce the risks of renal injury without compromising cure.

View details for DOI 10.1016/j.ijrobp.2023.02.040

View details for PubMedID 37452796

Abstract

Pediatric soft tissue tumors are one of the areas of pediatric pathology that frequently generate consult requests. Evolving classification systems, ancillary testing methods, new treatment options, research enrollment opportunities, and tissue archival processes create additional complexity in handling these unique specimens. Pathologists are at the heart of this critical decision-making, balancing responsibilities to consider expediency, accessibility, and cost-effectiveness of ancillary testing during pathologic examination and reporting.To provide a practical approach to handling pediatric soft tissue tumor specimens, including volume considerations, immunohistochemical staining panel recommendations, genetic and molecular testing approaches, and other processes that impact the quality and efficiency of tumor tissue triage.The World Health Organization Classification of Soft Tissue and Bone Tumors, 5th edition, other recent literature investigating tissue handling, and the collective clinical experience of the group are used in this manuscript.Pediatric soft tissue tumors can be difficult to diagnose, and evaluation can be improved by adopting a thoughtful, algorithmic approach to maximize available tissue and minimize time to diagnosis.

View details for DOI 10.5858/arpa.2022-0364-RA

View details for PubMedID 37196343

Abstract

Purpose: Synovial sarcoma (SS) is a rare, high-grade soft tissue tumor that requires multidisciplinary and multimodal care with surgery, radiotherapy, and chemotherapy. We examined the impact of sociodemographic and clinical factors on treatment patterns and survival in localized SS patients. Methods: Adolescents and young adults (AYAs, 15-39 years) and older adults ("adults," 40 years) diagnosed with localized SS from 2000 to 2018 were identified in the California Cancer Registry. Multivariable logistic regression identified clinical and sociodemographic factors associated with receipt of chemotherapy and/or radiotherapy. Cox proportional hazards regression identified factors associated with overall survival (OS). Results are reported as odds ratios (ORs) and hazard ratios (HRs), respectively, with 95% confidence intervals (CIs). Results: More AYAs (n=346) than adults (n=272) received chemotherapy (47.7% vs. 36.4%) and radiotherapy (62.1% vs. 58.1%). Age at diagnosis, tumor size, treatment at National Cancer Institute-Children's Oncology Group (NCI-COG)-designated facilities, insurance status, and neighborhood socioeconomic status (SES) influenced treatment patterns. Among AYAs, treatment at NCI-COG-designated facilities was associated with receiving chemotherapy (OR 2.74, CI 1.48-5.07) and low SES was associated with worse OS (HR 2.28, 1.09-4.77). In adults, high SES was associated with receiving chemoradiotherapy (OR 3.20, CI 1.40-7.31), whereas public insurance was associated with decreased odds of chemoradiotherapy (OR 0.44, CI 0.20-0.95). With regard to treatment, absence of radiotherapy (HR 1.94, CI 1.18-3.20) was associated with worse OS in adults. Conclusion: In localized SS, both clinical and sociodemographic factors influenced treatment patterns. Further research should investigate how SES-related factors produce treatment disparities and identify interventions to improve treatment equity and outcomes.

View details for DOI 10.1089/jayao.2022.0143

View details for PubMedID 37104039

Abstract

Purpose To evaluate if ferumoxytol can improve the detection of bone marrow metastases at diffusion-weighted (DW) MRI in pediatric and young adult patients with cancer. Materials and Methods In this secondary analysis of a prospective institutional review board-approved study (ClinicalTrials.gov identifier NCT01542879), 26 children and young adults (age range: 2-25 years; 18 males) underwent unenhanced or ferumoxytol-enhanced whole-body DW MRI between 2015 and 2020. Two reviewers determined the presence of bone marrow metastases using a Likert scale. One additional reviewer measured signal-to-noise ratios (SNRs) and tumor-to-bone marrow contrast. Fluorine 18 (18F) fluorodeoxyglucose (FDG) PET and follow-up chest CT, abdominal and pelvic CT, and standard (non-ferumoxytol enhanced) MRI served as the reference standard. Results of different experimental groups were compared using generalized estimation equations, Wilcoxon rank sum test, and Wilcoxon signed rank test. Results The SNR of normal bone marrow was significantly lower at ferumoxytol-enhanced MRI compared with unenhanced MRI at baseline (21.380 19.878 vs 102.621 94.346, respectively; P = .03) and after chemotherapy (20.026 7.664 vs 54.110 48.022, respectively; P = .006). This led to an increased tumor-to-marrow contrast on ferumoxytol-enhanced MRI scans compared with unenhanced MRI scans at baseline (1397.474 938.576 vs 665.364 440.576, respectively; P = .07) and after chemotherapy (1099.205 864.604 vs 500.758 439.975, respectively; P = .007). Accordingly, the sensitivity and diagnostic accuracy for detecting bone marrow metastases were 96% (94 of 98) and 99% (293 of 297), respectively, with the use of ferumoxytol-enhanced MRI compared with 83% (106 of 127) and 95% (369 of 390) with the use of unenhanced MRI. Conclusion Use of ferumoxytol helped improve the detection of bone marrow metastases in children and young adults with cancer. Keywords: Pediatrics, Molecular Imaging-Cancer, Molecular Imaging-Nanoparticles, MR-Diffusion Weighted Imaging, MR Imaging, Skeletal-Appendicular, Skeletal-Axial, Bone Marrow, Comparative Studies, Cancer Imaging, Ferumoxytol, USPIO RSNA, 2023 ClinicalTrials.gov registration no. NCT01542879 See also the commentary by Holter-Chakrabarty and Glover in this issue.

View details for DOI 10.1148/rycan.220080

View details for PubMedID 36999999

Abstract

OBJECTIVES/PURPOSE: Childhood cancer survival brings continued mental and physical health challenges both for the child and for the family. In this study, we investigated how parents viewed their roles in their child's health and symptom monitoring during the survivorship period.METHODS: Twenty-one parents of childhood cancer survivors (n=18 mothers; parent mage=49.78years, child mage=18.50years; range=12-25years), whose children were at least one year off-treatment (m=3.67years; SD=2.25; various diagnoses), completed semi-structured interviews. Interviews were recorded, transcribed, and analyzed using reflexive thematic analysis.RESULTS: Analyses generated three themes which reflect roles that parents may adopt in the context of monitoring symptoms in their childhood cancer survivor. "Vigilant Mama and Papa" (theme 1) described parents who expressed a strong sense of responsibility for protecting their child's health during survivorship resulting in careful monitoring of their child's symptoms and health. "Pragmatic Mamas and Papas" (theme 2) described parents who adopted an approach to symptom and health monitoring that emphasized moving past cancer and focusing on the future. Finally, "Encouraging Mamas and Papas" (theme 3) described parents who focused on educating and preparing their child to develop an autonomous approach to health and symptom self-monitoring as they transitioned to survivorship and adulthood.CONCLUSION: Parents take on varying roles in monitoring their child's symptoms and health after finishing childhood cancer treatment.IMPLICATIONS FOR CANCER SURVIVORS: Understanding the ways in which parents continue to be involved in their child's cancer journey helps researchers develop interventions to support dyadic coping in survivorship.

View details for DOI 10.1007/s11764-023-01353-w

View details for PubMedID 36821041

Abstract

Childhood cancer survivors report self-monitoring for and worrying about symptoms of disease recurrence and secondary cancers, although symptom-related worry is associated with poorer health-related quality of life. This survey captured pediatric oncologists' beliefs and communication practices regarding symptom self-monitoring for childhood cancer survivors.Using a closed-loop snowball sampling technique, pediatric oncologists completed an online survey regarding the importance of symptom self-monitoring for off-therapy patients, the degree to which symptom self-monitoring was perceived to cause stress and worry, and communication practices.196 pediatric oncologists (White [78%]; female [64%]; Mage = 47 years) from every continent except Antarctica participated. Oncologists believed it is important for off-therapy patients to self-monitor for symptoms of cancer recurrence (90%) and treatment late effects (94%), although some noted that recurrence (30%) and late effects (55%) are typically detected by routine surveillance before symptoms appear. Oncologists varied in their beliefs that off-therapy patients do (31%) or do not (31%) worry unnecessarily about symptoms of recurrence. Two thirds (62%) of oncologists reported often/always discussing with off-therapy patients which symptoms could indicate cancer recurrence, whereas fewer than half (43%) often/always discussed which symptoms were unlikely to indicate recurrence. Oncologists identified a need for education regarding how to communicate around symptom self-monitoring and the potential utility of a screening tool to identify those who worry excessively.Despite nearly universal belief that their off-therapy patients should self-monitor for symptoms of disease recurrence and late effects, a substantial proportion of pediatric oncologists do not counsel patients on symptom self-monitoring. Since nearly one-third believe that off-therapy patients worry unnecessarily about symptoms of recurrence, improving patient education regarding which symptoms are and are not medically concerning could decrease stress and improve health-related quality of life for pediatric cancer survivors.

View details for DOI 10.1200/OP.22.00630

View details for PubMedID 36800566

Abstract

The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT)+/- chemotherapy for soft tissue sarcoma.Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT,+/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy.Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib+RT+ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID+RT alone. In nonchemotherapy study arms, pazopanib+RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites.The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

View details for DOI 10.1002/jso.27205

View details for PubMedID 36779385

Abstract

BACKGROUND: Margin status following surgery in children, adolescents, and young adults with soft tissue sarcomas is controversial and has been defined differently by various specialties, with definitions changing over time and by cooperative group. The International Soft Tissue Sarcoma Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft Tissue sarcoma Study Group (EpSSG), and the European Cooperative Weichteilsarkom Studiengruppe (CWS) devoted to improving patient outcomes by pooling and mining cooperative group clinical trial data.METHODS: The INSTRuCT non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) working group aimed to develop international harmonized recommendations regarding surgical margin assessment and definitions in children and adolescents with soft tissue tumors.RESULTS AND CONCLUSION: This review addresses accepted principles and areas of controversy, including the perspectives of surgeons, pathologists, radiation oncologists, and pediatric oncologists, to develop a framework for building common guidelines for future research.

View details for DOI 10.1002/cam4.5671

View details for PubMedID 36744538

View details for DOI 10.1002/pbc.30111

View details for PubMedID 36495537

Abstract

OBJECTIVE: To compare the diagnostic accuracy of diffusion-weighted (DW)-MRI with b-values of 50s/mm2 and 800s/mm2 for the detection of bone marrow metastases in children and young adults with solid malignancies.METHODS: In an institutional review board-approved prospective study, we performed 51 whole-body DW-MRI scans in 19 children and young adults (14 males, 5 females; age range: 1-25years) with metastasized cancers before (n=19 scans) and after (n=32 scans) chemotherapy. Two readers determined the presence of focal bone marrow lesions in 10 anatomical areas. A third reader measured ADC and SNR of focal lesions and normal marrow. Simultaneously acquired 18F-FDG-PET scans served as the standard of reference. Data of b=50s/mm2 and 800s/mm2 images were compared with the Wilcoxon signed-rank test. Inter-reader agreement was evaluated with weighted kappa statistics.RESULTS: The SNR of bone marrow metastases was significantly higher compared to normal bone marrow on b=50s/mm2 (meanSD: 978.4361239.436 vs. 108.881109.813, p<0.001) and b=800s/mm2 DW-MRI (499.638612.721 vs. 86.28089.120; p<0.001). On 30 out of 32 post-treatment DW-MRI scans, reconverted marrow demonstrated low signal with low ADC values (0.385*10-30.168*10-3mm2/s). The same number of metastases (556/588; 94.6%; p>0.99) was detected on b=50s/mm2 and 800s/mm2 images. However, both normal marrow and metastases exhibited low signals on ADC maps, limiting the ability to delineate metastases. The inter-reader agreement was substantial, with a weighted kappa of 0.783 and 0.778, respectively.CONCLUSION: Bone marrow metastases in children and young adults can be equally well detected on b=50s/mm2 and 800s/mm2 images, but ADC values can be misleading.

View details for DOI 10.1007/s00256-022-04240-0

View details for PubMedID 36441237

Abstract

PURPOSE: The aim of this paper is to better define the clinical features and outcomes of young patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) with regional and distant lymph node (LN) metastases treated in a standardised fashion, we analysed LN involvement in COG study ARST0332, which evaluated a risk-based treatment strategy for young patients with all stages of NRSTS.PATIENTS AND METHODS: Patients <30 years old with newly diagnosed NRSTS and LN metastases enrolled on ARST0332 were studied. Regional LN sampling was required for those with epithelioid sarcoma, clear cell sarcomaor clinically/radiographically enlarged LNs. Tumour features and extent of pre-enrolment resection determined treatment, including chemotherapy, radiotherapy, and delayed surgery. Recommendations for LN metastases included LN dissection at the time of primary tumour resection and dose-adapted radiotherapy based on extent of LN resection.RESULTS: Twenty of 529 eligible and evaluable ARST0332 patients with NRSTS had LN metastases; epithelioid sarcoma had the highest incidence (18%, 5 of 28). Pre-treatment imaging identified LN enlargement in 19 of 20 patients; 1 had no pre-treatment LN imaging. At 6.9 years median follow-up for surviving patients, 5-year overall survival was 85.7% (95% CI: 33.4%, 97.9%) for seven patients with isolated LN metastases and 15.4% (95% CI: 2.5%, 38.8%) for 13 patients with additional extranodal metastases. LN recurrence occurred in only one patient without LNs sampled at initial diagnosis.CONCLUSION: LN metastases occur in about 4% of paediatric/young adult NRSTS, are limited to a few histologic subtypes, and are rare in patients who did not have clinical or imaging evidence of lymphadenopathy, suggesting that biopsies of non-enlarged LNs are not necessary to identify occult involvement. Patients with isolated LN metastases have high 5-year overall survival (85%) and should be treated with curative intent.CLINICALTRIALS: GOV REGISTRY NO: NCT00346164.

View details for DOI 10.1016/j.ejca.2022.11.014

View details for PubMedID 36566574

View details for Web of Science ID 000859203900291

View details for Web of Science ID 000892639302168

View details for Web of Science ID 000847787800089

Abstract

Integrated 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/magnetic resonance (MR) imaging can provide "one stop" local tumor and whole-body staging in one session, thereby streamlining imaging evaluations and avoiding duplicate anesthesia in young children. 18F-FDG PET/MR scans have the benefit of lower radiation, superior soft tissue contrast, and increased patient convenience compared to 18F-FDG PET/computerized tomography scans. This article reviews the 18F-FDG PET/MR imaging technique, reporting requirements, and imaging characteristics of the most common pediatric bone tumors, including osteosarcoma, Ewing sarcoma, primary bone lymphoma, bone and bone marrow metastases, and Langerhans cell histiocytosis.

View details for DOI 10.1007/s00256-022-04113-6

View details for PubMedID 35804163

View details for Web of Science ID 000892509504475

View details for Web of Science ID 000863680300346

View details for Web of Science ID 000863680304596

Abstract

The current article focuses on non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), the heterogeneous group of mesenchymal tumours different from rhabdomyosarcoma that may affect children and adolescents, with clinical behaviour varying from relatively benign to highly malignant. This review represents the effort of the international scientific paediatric community within the context of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT), a project founded by the leadership of three large cooperative groups - Children's Oncology Group, Cooperative Weichteilsarkom Studiengruppeand European paediatric Soft tissue sarcoma Study Group- with the main goal to pool expertise and resources on a broader international level in order to improve knowledge of soft tissue sarcomas of children, adolescents and young adults. This article describes the current standard treatment approach in NRSTS, with a focus on the controversies and challenges in the management of these tumours. Developing research projects and clinical protocols for NRSTS has always been challenging, supporting the need to develop international integrated prospective dedicated programs, including paediatric NRSTS experts together with the adult sarcoma community. INSTRuCT provides a unique mechanism to increase international collaboration by agreeing on a common language, developing consensus standards to guide diagnosis and treatment, comparing clinical trial results across cooperative groups, and through a shared data dictionary providing answers to questions that can only be addressed by a larger data set.

View details for DOI 10.1016/j.ejca.2022.03.028

View details for PubMedID 35490564

Abstract

OBJECTIVE: Scan-related anxiety ("scanxiety") refers to the fear, stress, and anxiety in anticipation of tests and scans in follow-up cancer care. This study assessed the feasibility of Ecological Momentary Assessment (EMA) for real-world, real-time capture of scanxiety using patients' personal smartphone.METHODS: Adolescent and Young Adult (AYA) survivors of childhood cancer were prompted to complete EMA surveys on a smartphone app three times per day for 11 days (33 surveys total) around their routine surveillance scans. Participants provided structured feedback on the EMA protocol.RESULTS: Thirty out of 46 contacted survivors (65%) enrolled, exceeding the preregistered feasibility cutoff of 55%. The survey completion rate (83%) greatly exceeded the preregistered feasibility cutoff of 65%. Participants generally found the smartphone app easy and enjoyable to use and reported low levels of distress from answering surveys. Participants reported significantly more daily fear of cancer recurrence (FCR) and negative affect in the days before compared to the days after surveillance scans, aligning with the expected trajectory of scanxiety. Participants who reported greater FCR and scanxiety using comprehensive measures at baseline also reported significantly more daily FCR around their surveillance scans, indicating validity of EMA items. Bodily threat monitoring was prospectively and concurrently associated with daily FCR, thus warranting further investigation as a risk factor for scanxiety.CONCLUSIONS: Findings indicate the feasibility, acceptability, and validity of EMA as a research tool to capture the dynamics and potential risk factors for scanxiety. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/pon.5935

View details for PubMedID 35411626

View details for DOI 10.1016/S2352-4642(22)00036-0

View details for PubMedID 35176224

Abstract

OBJECTIVES: To compare the diagnostic accuracy of 2-[18F]fluoro-2-deoxy-D-glucose-enhanced positron emission tomography (2-[18F]FDG-PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) for the detection of bone marrow metastases in children and young adults with solid malignancies.METHODS: In this cross-sectional single-center institutional review board-approved study, we investigated twenty-three children and young adults (mean age, 16.8years5.1 [standard deviation]; age range, 7-25years; 16 males, 7 females) with 925 bone marrow metastases who underwent 66 simultaneous 2-[18F]FDG-PET and DW-MRI scans including 23 baseline scans and 43 follow-up scans after chemotherapy between May 2015 and July 2020. Four reviewers evaluated all foci of bone marrow metastasis on 2-[18F]FDG-PET and DW-MRI to assess concordance and measured the tumor-to-bone marrow contrast. Results were assessed with a one-sample Wilcoxon test and generalized estimation equation. Bone marrow biopsies and follow-up imaging served as the standard of reference.RESULTS: The reviewers detected 884 (884/925, 95.5%) bone marrow metastases on 2-[18F]FDG-PET and 893 (893/925, 96.5%) bone marrow metastases on DW-MRI. We found different "blind spots" for 2-[18F]FDG-PET and MRI: 2-[18F]FDG-PET missed subcentimeter lesions while DW-MRI missed lesions in small bones. Sensitivity and specificity were 91.0% and 100% for 18F-FDG-PET, 89.1% and 100.0% for DW-MRI, and 100.0% and 100.0% for combined modalities, respectively. The diagnostic accuracy of combined 2-[18F]FDG-PET/MRI (100.0%) was significantly higher compared to either 2-[18F]FDG-PET (96.9%, p<0.001) or DW-MRI (96.3%, p<0.001).CONCLUSIONS: Both 2-[18F]FDG-PET and DW-MRI can miss bone marrow metastases. The combination of both imaging techniques detected significantly more lesions than either technique alone.KEY POINTS: DW-MRI and 2-[18F]FDG-PET have different strengths and limitations for the detection of bone marrow metastases in children and young adults with solid tumors. Both modalities can miss bone marrow metastases, although the "blind spot" of each modality is different. A combined PET/MR imaging approach will achieve maximum sensitivity and specificity for the detection of bone marrow metastases in children with solid tumors.

View details for DOI 10.1007/s00330-021-08529-x

View details for PubMedID 35099603

Abstract

PURPOSE: The use of tyrosine kinase inhibitors for the treatment for soft tissue sarcomas is increasing given promising signals of activity in a variety of tumor types. The recently completed study in non-rhabdomyosarcoma soft tissue sarcomas, ARST1321, demonstrated that the addition of pazopanib to neoadjuvant ifosfamide, doxorubicin, and radiation improved the pathological near complete response rate compared with chemoradiotherapy alone. Pharmacokinetic (PK) evaluation of doxorubicin with pazopanib has not been previously reported. As an exploratory aim, doxorubicin PK data were collected during the dose-finding phase of the study in patients receiving chemotherapy and pazopanib to assess the effect of pazopanib on doxorubicin PK parameters.METHODS: Blood samples were collected during cycle 2 (week 4) of chemotherapy at the following time points from doxorubicin administration: predose, 5, 30, and 60min, and 2, 4, 8, 243, and 483h after dosing. The population pharmacokinetic and individual post hoc estimates of doxorubicin and doxorubicinol were determined by nonlinear mixed-effects modeling.RESULTS: There were 52 doxorubicin and doxorubicinol samples from 7 individuals in this study (median age: 17years; range 14-23). The doxorubicin clearance was 26.9 (16.1, 36.4, and 33.9) L/h/m2 (post hoc median and range) and 25.8 (23.3%) L/h/m2 [population estimate and IIV (CV%)]. The doxorubicinol apparent clearance was 67.5 (18.2, 1701) L/h/m2 (post hoc median and range) and 58.7 (63.7%) L/h/m2 [population estimate and IIV (CV%)].CONCLUSION: The PK data of seven patients treated on ARST1321 is consistent with previously reported population and post hoc doxorubicin clearance and doxorubicinol apparent clearance estimates, showing that the addition of pazopanib does not significantly alter doxorubicin pharmacokinetics. These data support the safety of administration of pazopanib with doxorubicin-containing chemotherapy.

View details for DOI 10.1007/s00280-022-04397-4

View details for PubMedID 35083502

Abstract

PURPOSE: Little is known regarding long-term neurocognitive outcomes in osteosarcoma and Ewing sarcoma (EWS) survivors despite potential risk factors. We evaluated associations among treatment exposures, chronic health conditions, and patient-reported neurocognitive outcomes in adult survivors of childhood osteosarcoma and EWS.METHODS: Five-year survivors of osteosarcoma (N=604; median age 37.0years) and EWS (N=356; median age 35.0years) diagnosed at<21years from 1970 to 1999, and 697 siblings completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire and reported chronic health conditions, education, and employment. Prevalence of reported neurocognitive difficulties were compared between diagnostic groups and siblings. Modified Poisson regression identified factors associated with neurocognitive difficulties.RESULTS: Osteosarcoma and EWS survivors, vs. siblings, reported higher prevalences of difficulties with task efficiency (15.4% [P=0.03] and 14.0% [P=0.04] vs. 9.6%, respectively) and emotional regulation (18.0% [P<0.0001] and 15.2% [P=0.03] vs. 11.3%, respectively), adjusted for age, sex, and ethnicity/race. Osteosarcoma survivors reported greater memory difficulties vs. siblings (23.5% vs. 16.4% [P=0.01]). Comorbid impairment (i.e.,2 neurocognitive domains) was more prevalent in osteosarcoma (20.0% [P<0.001]) and EWS survivors (16.3% [P=0.02]) vs. siblings (10.9%). Neurological conditions were associated with worse task efficiency (RR=2.17; 95% CI=1.21-3.88) and emotional regulation (RR=1.88; 95% CI=1.01-3.52), and respiratory conditions were associated with worse organization (RR=2.60; 95% CI=1.05-6.39) for EWS. Hearing impairment was associated with emotional regulation difficulties for osteosarcoma (RR=1.98; 95% CI=1.22-3.20). Patient report of cognitive difficulties was associated with employment but not educational attainment.CONCLUSIONS: Survivors of childhood osteosarcoma and EWS are at increased risk for reporting neurocognitive difficulties, which are associated with employment status and appear related to chronic health conditions that develop over time.IMPLICATIONS FOR CANCER SURVIVORS: Early screening, prevention, and treatment of chronic health conditions may improve/prevent long-term neurocognitive outcomes.

View details for DOI 10.1007/s11764-021-01154-z

View details for PubMedID 35059962

Abstract

Background: Soft tissue sarcomas (STS) are a heterogeneous group of tumors whose management benefits from a multidisciplinary therapeutic approach. Published data suggest that cancer treatment at a specialized cancer center (SCC) can improve survival in other cancers. Therefore, we examined the impact of the location of treatment on survival in children and adolescents and young adults (AYAs) with STS. Methods: We performed a population-based analysis of children and AYAs hospitalized within 1 year of diagnosis with first primary STS (2000-2014) using the California Cancer Registry linked with hospitalization data. Patients were categorized based on receiving all inpatient treatments at a SCC versus part/none. Multivariable Cox proportional hazards regression identified factors associated with overall and STS-specific survival by age group. Results are presented as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Of the 1,674 patients with STS, 142 were children (0-14) and 1,532 were AYAs (15-39) and 89.4% and 40.4% received all inpatient treatments at a SCC, respectively. Overall, the 5-year survival was improved for patients who received all inpatient care at a SCC (59.8% vs. those who received part/none, 50.7%). Multivariable regression analysis found that having all treatments at a SCC was associated with better overall survival (HR, 0.79, CI: 0.65-0.95) in AYAs, but not in children. Conclusions: Our findings demonstrate that treatment for STS at a SCC is associated with better survival in AYAs. Eliminating barriers to treatment of AYAs with STS at SCCs could improve survival in this population.

View details for DOI 10.1089/jayao.2021.0110

View details for PubMedID 34910881

Abstract

AIMS: Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated "NTRK-rearranged" spindle cell neoplasms. These two groups of tumors demonstrate overlapping morphologies and harbor alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1, and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of pediatric tumors with clinicopathologic features not typical for inflammatory myofibroblastic tumor, but rather with similarities to cCMN/IFS harboring ALK fusions.METHODS AND RESULTS: Clinicopathologic features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumors occurred in patients from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumors arose in soft tissues and 2 in the kidney. Morphologic features included spindle to ovoid cells arranged in long fascicles or haphazardly within a myxoid to collagenized stroma; a subset of cases had either dilated, ectatic vessels or focal perivascular hyalinosis. By immunohistochemistry, all cases tested showed cytoplasmic expression of ALK and one case demonstrated co-expression of CD34 and S100.CONCLUSIONS: This series of ALK rearranged IFS-like tumors expands the spectrum of targetable kinases altered in these tumors and reinforces the potential overlap between IFS/cCMN-like tumors and the provisional entity of "NTRK-rearranged" spindle cell neoplasms.

View details for DOI 10.1111/his.14603

View details for PubMedID 34843129

Abstract

Purpose: To investigate if a deep learning convolutional neural network (CNN) could enable low-dose fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/MRI for correct treatment response assessment of children and young adults with lymphoma.Materials and Methods: In this secondary analysis of prospectively collected data (ClinicalTrials.gov identifier: NCT01542879), 20 patients with lymphoma (mean age, 16.4 years 6.4 [standard deviation]) underwent 18F-FDG PET/MRI between July 2015 and August 2019 at baseline and after induction chemotherapy. Full-dose 18F-FDG PET data (3 MBq/kg) were simulated to lower 18F-FDG doses based on the percentage of coincidence events (representing simulated 75%, 50%, 25%, 12.5%, and 6.25% 18F-FDG dose [hereafter referred to as 75%Sim, 50%Sim, 25%Sim, 12.5%Sim, and 6.25%Sim, respectively]). A U.S. Food and Drug Administration-approved CNN was used to augment input simulated low-dose scans to full-dose scans. For each follow-up scan after induction chemotherapy, the standardized uptake value (SUV) response score was calculated as the maximum SUV (SUVmax) of the tumor normalized to the mean liver SUV; tumor response was classified as adequate or inadequate. Sensitivity and specificity in the detection of correct response status were computed using full-dose PET as the reference standard.Results: With decreasing simulated radiotracer doses, tumor SUVmax increased. A dose below 75%Sim of the full dose led to erroneous upstaging of adequate responders to inadequate responders (43% [six of 14 patients] for 75%Sim; 93% [13 of 14 patients] for 50%Sim; and 100% [14 of 14 patients] below 50%Sim; P < .05 for all). CNN-enhanced low-dose PET/MRI scans at 75%Sim and 50%Sim enabled correct response assessments for all patients. Use of the CNN augmentation for assessing adequate and inadequate responses resulted in identical sensitivities (100%) and specificities (100%) between the assessment of 100% full-dose PET, augmented 75%Sim, and augmented 50%Sim images.Conclusion: CNN enhancement of PET/MRI scans may enable 50% 18F-FDG dose reduction with correct treatment response assessment of children and young adults with lymphoma.Keywords: Pediatrics, PET/MRI, Computer Applications Detection/Diagnosis, Lymphoma, Tumor Response, Whole-Body Imaging, Technology AssessmentClinical trial registration no: NCT01542879 Supplemental material is available for this article. RSNA, 2021.

View details for DOI 10.1148/ryai.2021200232

View details for PubMedID 34870211

View details for DOI 10.1002/pbc.29399

View details for PubMedID 34613653

Abstract

Cutaneous adverse events (cAEs) from targeted antineoplastic agents and immune checkpoint inhibitors are common in children with cancer and may lead to dose reduction or cessation of critical oncologic treatment. Timely diagnosis and proper management of cAEs in pediatric oncology patients is essential to optimize ongoing cancer-directed therapy and improve quality of life. This systematic review of published studies summarizes dermatologic toxicities to targeted anticancer treatments and immune checkpoint inhibitors.

View details for DOI 10.1002/pbc.29346

View details for PubMedID 34569142

Abstract

Sclerosing epithelioid fibrosarcoma (SEF) is a rare and aggressive soft tissue sarcoma thought to originate in fibroblasts of the tissues comprising tendons, ligaments and muscles. Minimally responsive to conventional cytotoxic chemotherapies, greater than 50% of SEF patients experience local recurrence and/or metastatic disease. SEF is most commonly discovered in middle-aged and elderly adults, but also rarely in children. A common gene fusion occurring between the EWSR1 and CREB3L1 genes has been observed in 80-90% of SEF cases. We describe here the youngest SEF patient reported to date (a 3-year-old Caucasian male) who presented with numerous bony and lung metastases. Additionally, we perform a comprehensive literature review of all SEF-related articles published since the disease was first characterized. Finally, we describe the generation of an SEF primary cell line, the first such culture to be reported. The patient described here experienced persistent disease progression despite aggressive treatment including multiple resections, radiotherapy and numerous chemotherapies and targeted therapeutics. Untreated and locally recurrent tumor and metastatic tissue were sequenced by whole genome, whole exome, and deep transcriptome next generation sequencing with comparison to a patient-matched normal blood sample. Consistent across all sequencing analyses was the disease-defining EWSR1-CREB3L1 fusion as a single feature consensus. We provide an analysis of our genomic findings and discuss potential therapeutic strategies for SEF.

View details for DOI 10.1101/mcs.a006093

View details for PubMedID 34362827

Abstract

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy number changes. We applied CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy number alterations. We analyzed 64 prospectively collected plasma samples from 17 pediatric sarcoma patients. Translocations were detected in the pre-treatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy number changes in the pre-treatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and copy number alterations in the plasma of pediatric sarcoma patients. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

View details for DOI 10.1158/1535-7163.MCT-20-0987

View details for PubMedID 34353895

View details for DOI 10.1016/S2352-4642(21)00178-4

View details for PubMedID 34214483

View details for Web of Science ID 000661623200140

Abstract

PURPOSE: XXX trial for pediatric and young adults with NRSTS used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR).PATIENTS AND METHODS: Patients <30 years with high-grade NRSTS received RT (55.8 Gy) for R1 5cm tumor (Arm B), RT (55.8 Gy)/CT for R0/R1 >5 cm tumor (Arm C), or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and post-operative boost for 10.8 Gy R0 <5mm margins/R1,19.8 Gy R2/U (Arm D).RESULTS: 193 eligible patients had 24 LR: Arm B 1/15 (6.7%), Arm C 7/65 (10.8%), Arm D 16/113 (14.2%) at median time to LR 1.1 years (range 0.11-5.27). Of 95 eligible for delayed surgery after neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. Overall LC after RT were: R0 106/109 (97%), R1 51/60 (85%), R2/unresectable 2/6 (33%). LR predictors include extent of delayed resection (p<0.001), imaging response before delayed surgery (p<0.001), histologic subtype (p<0.001), and no RT (p=0.046). The 5-year event-free survival (EFS) was significantly lower (p=0.0003) for patients unable to undergo R0/R1 resection.CONCLUSION: Risk-based treatment for young patients with high-grade NRSTS treated on xxx produced very high LC, particularly after R0 resection (97%) despite lower-than-standard RT doses. Neoadjuvant CT/RT enabled delayed R0/R1 resection in most patients and is preferred over adjuvant therapy due to the lower RT dose delivered.

View details for DOI 10.1016/j.ijrobp.2021.01.051

View details for PubMedID 33548339

Abstract

Gadolinium chelates have been used as standard contrast agents for clinical MRI for several decades. However, several investigators recently reported that rare Earth metals such as gadolinium are deposited in the brain for months or years. This is particularly concerning for children, whose developing brain is more vulnerable to exogenous toxins compared to adults. Therefore, a search is under way for alternative MR imaging biomarkers. The United States Food and Drug Administration (FDA)-approved iron supplement ferumoxytol can solve this unmet clinical need: ferumoxytol consists of iron oxide nanoparticles that can be detected with MRI and provide significant T1- and T2-signal enhancement of vessels and soft tissues. Several investigators including our research group have started to use ferumoxytol off-label as a new contrast agent for MRI. This article reviews the existing literature on the biodistribution of ferumoxytol in children and compares the diagnostic accuracy of ferumoxytol- and gadolinium-chelate-enhanced MRI. Iron oxide nanoparticles represent a promising new class of contrast agents for pediatric MRI that can be metabolized and are not deposited in the brain.

View details for DOI 10.1007/s00247-021-05098-5

View details for PubMedID 34046709

Abstract

Synovial sarcoma (SS) is the second most common malignant soft tissue tumor in children. ARST0332 evaluated a risk-based treatment strategy for young patients with soft tissue sarcoma designed to limit therapy for low-risk (LR) disease and to test neoadjuvant chemoradiotherapy for unresected higher-risk disease.Newly diagnosed patients with SS age < 30 years were assigned to four treatment arms based on disease features: A (surgery only), B (55.8 Gy radiotherapy [RT]), C (ifosfamide and doxorubicin [ID] chemotherapy plus 55.8 Gy RT), and D (neoadjuvant ID and 45 Gy RT, then surgery and RT boost based on margins followed by adjuvant ID). Patients treated in Arms A and B were considered LR, arms C and D without metastases as intermediate-risk (IR), and those with metastases as high-risk (HR).Of the 146 patients with SS enrolled, 138 were eligible and evaluable: LR (46), IR (71), and HR (21). Tumors were 80% extremity, 70% > 5 cm, 70% high-grade, 62% invasive, 95% deep, and 15% metastatic. Treatment was on arm A (29.7%), B (3.6%), C (16.7%), and D (50%). There were no toxic deaths and four unexpected grade 4 adverse events. By risk group, at a median follow-up of 6.8 years, estimated 5-year event-free survival was LR 82%, IR 70%, and HR 8%, and overall survival was LR 98%, IR 89%, and HR 13%. After accounting for the features that defined risk category, none of the other patient or disease characteristics (age, sex, tumor site, tumor invasiveness, and depth) improved the risk stratification model.The risk-based treatment strategy used in ARST0332 produced favorable outcomes in patients with nonmetastatic SS relative to historical controls despite using RT less frequently and at lower doses. The outcome for metastatic SS remains unsatisfactory and new therapies are urgently needed.

View details for DOI 10.1200/JCO.21.01628

View details for PubMedID 34623899

Abstract

Osteosarcoma is the most common primary bone malignancy in both children and adults. Despite introduction of intensive multimodal treatment with chemotherapy and surgery, outcomes are still poor, especially for patients with metastatic disease and adults. Hence, there is an ongoing need for better prognostic markers and outcome data to inform management decisions in both the adult and pediatric setting. Here, we retrospectively analyzed 112 patients with bone osteosarcoma treated at two large adult and pediatric tertiary academic centers between 1989 and 2019. Patients were divided into an adult (18 years) and pediatric (<18 years) cohort for comparison. Our aim was to evaluate predictors of outcomes in pediatric and adult patients, with a specific focus on the role of methotrexate when added to a combination of doxorubicin-cisplatin; the prognostic value of tumor necrosis after neoadjuvant chemotherapy; and outlining any differences in outcomes between adults and pediatric patients that could inform clinical management. Adult patients treated with methotrexate-doxorubicin-cisplatin and those treated with doxorubicin-cisplatin had similar 5-year PFS (26%, 95%CI: 45.5%-10% vs. 50%, 95%CI: 69.6%-26.2%, p = 0.1) and 5-year OS (63%, 95%CI: 82%-34%, vs. 78%, 95%CI: 90.6%-52.6%, p = 0.5). In the adult cohort, there was no difference between patients with 90% necrosis and <90% necrosis in either 5-year PFS (42%, 95%CI: 71.1%-11.3% vs. 38%, 95%CI: 57.7%-18.2%, p = 0.4) or 5-year OS (85%, 95%CI: 97.8%-33.4% vs. 56%, 95%CI: 76.8%-27.6%, p = 0.4). In the pediatric cohort, compared to patients with <90% necrosis, those with 90% necrosis had significantly better 5-year PFS (30%, 95%CI: 49.3%-14.1% vs. 55%, 95%CI: 73.9%-38.5%, p = 0.003) and 5-year OS (64%, 95%CI: 80.8%-41.1% vs. 78%, 95%CI: 92%-60.9%, p = 0.04). Adult and pediatric patients had similar 5-year OS (69%, 95%CI: 83.2%-49.8% vs. 73%, 95%CI: 83.2%-59.3%, p = 0.8) and 5-year PFS (37%, 95%CI: 52.4%-22.9% vs. 43%, 95%CI: 56.2%-30.4% p = 0.3) even though the proportion of patients with 90% necrosis after neoadjuvant chemotherapy was higher for children compared to adults (60.3% vs. 30%, OR: 3.54, 95%CI: 1.38-8.46, p = 0.006). In conclusion, in adult patients, the addition of methotrexate to doxorubicin and cisplatin did not correlate with a significant survival benefit, questioning the therapeutic value of methotrexate overall. Our study confirms the prognostic utility of percent tumor necrosis after neoadjuvant chemotherapy in pediatric patients but not in adult patients. Lastly, this is one of the few reported studies where patients with osteosarcoma younger and older than 18 years had similar PFS and OS.

View details for DOI 10.3390/curroncol28060443

View details for PubMedID 34940082

Abstract

The diagnosis of joint infiltration by a malignant bone tumor affects surgical management. The specificity of standard magnetic resonance imaging (MRI) for diagnosing joint infiltration is limited. During our MRI evaluations with ferumoxytol nanoparticles of pediatric and young adult patients with bone sarcomas, we observed a surprising marked T1 enhancement of joint and pleural effusions in some patients but not in others.To evaluate if nanoparticle extravasation differed between joints and pleura with and without tumor infiltration.We retrospectively identified 15 pediatric and young adult patients (mean age: 164years) with bone sarcomas who underwent 18 MRI scans at 1h (n=7) or 24h (n=11) after intravenous ferumoxytol infusion. Twelve patients also received a gadolinium-enhanced MRI. We determined tumor invasion into the joint or pleural space based on histology (n=11) and imaging findings (n=4). We compared the signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) of the joint or pleural fluid for tumors with and without invasion using a Mann-Whitney U test.MRI scans 24h after intravenous ferumoxytol infusion demonstrated a positive T1 enhancement of the effusion in all joints and pleural spaces with tumor infiltration and no joint or pleural space without infiltration. Corresponding SNR (P=0.004) and CNR (P=0.004) values were significantly higher for joints and pleural spaces with tumor infiltration than without. By contrast, unenhanced MRI, gadolinium-enhanced MRI and 1-h post-contrast ferumoxytol MRI did not show any enhancement of the joint or pleural effusion, with or without tumor infiltration.This pilot study suggests that 24-h post-contrast ferumoxytol MRI scans can noninvasively differentiate between joints with and without tumor infiltration.

View details for DOI 10.1007/s00247-021-05156-y

View details for PubMedID 34410452

Abstract

OBJECTIVE: Somatic symptoms capture attention, demand interpretation, and promote health behaviors. Symptom appraisal is particularly impactful within uncertain health contexts such as cancer survivorship. Yet, little is known about how individuals make sense of somatic symptoms within uncertain health contexts, nor how this process guides health behaviors.DESIGN: 25 adolescent and young adult survivors of childhood cancer completed semi-structured interviews regarding how they appraise and respond to changing somatic sensations within the uncertain context of survivorship.MAIN OUTCOME MEASURES: Interviews were transcribed verbatim and subjected to a hybrid deductive-inductive thematic analysis, guided by the Cancer Threat Interpretation model.RESULTS: We constructed three themes. Symptoms as signals of bodily threat (theme 1) captured that participants described commonly interpreting and worrying about everyday sensations as indicating cancer recurrence or new illness. Playing detective with bodily signals (theme 2) captured participants' felt need to employ cognitive and behavioral strategies to determine whether somatic sensations indicated a credible health threat. These two themes are qualified by the final theme, Living with symptom-related uncertainty (theme 3), which captured participants' recognition that post-cancer symptoms are wily and influenced by psychological factors such as anxiety.CONCLUSIONS: These data highlight that making sense of everday somatic sensations can be particularly challenging following an experience of cancer. There is a need for novel symptom management approaches that target how somatic sensations are appraised and responded to as signals of bodily threat.

View details for DOI 10.1080/08870446.2020.1836180

View details for PubMedID 33073604

Abstract

BACKGROUND: The impact of specific treatment modalities on long-term renal function and blood pressure among adult survivors of Wilms tumor (WT) has not been well documented.METHODS: Among 40 WT survivors and 35 noncancer controls, we estimated the glomerular filtration rate (eGFR) using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equations with and without cystatin C, obtained 24-hour ambulatory blood pressure readings, and, among survivors only, measured 99m Tc diethylenetriamine pentaacetic acid (DTPA) plasma clearance. Survivors were treated with unilateral nephrectomy and nonnephrotoxic chemotherapy. Twenty received whole abdomen radiation therapy (WART) [median -16.5 Gray (Gy)], and 20 received no radiation therapy. Pairwise comparisons between survivors treated with and without WART, and each group to controls were performed using two-sample t tests.RESULTS: Twenty-six (65%) WT survivors were female, and 33 (83%) were non-Hispanic white. GFR estimated with creatinine or creatinine + cystatin C was decreased among irradiated survivors compared with controls. No irradiated or unirradiated participant had an eGFR (creatinine + cystatin C)<60mL/min/1.73m2 . The prevalence of hypertension was significantly increased among unirradiated (25%) and irradiated survivors (35%) compared with controls (0%). Of the 24-hour ambulatory blood pressure monitoring parameters evaluated, only mean sleep period diastolic blood pressure load of those who received WART was significantly different from that of controls.CONCLUSIONS: Chronic kidney disease was infrequent in long-term survivors of unilateral nonsyndromic WT, whether treated with WART or no radiation. The prevalence of hypertension was increased in both groups compared with controls, emphasizing the need for ongoing monitoring of renal and cardiovascular health.

View details for DOI 10.1002/pbc.28271

View details for PubMedID 32706494

Abstract

Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li Fraumeni Syndrome (LFS). Here we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited Chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison to TP53 normal lines showed that while classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3 and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R mutant tetramer, and the G334R mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison to classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance Li Fraumeni Syndrome.

View details for DOI 10.1158/0008-5472.CAN-20-1390

View details for PubMedID 32675277

View details for Web of Science ID 000551367400129

View details for Web of Science ID 000551367400088

View details for Web of Science ID 000530401600002

View details for Web of Science ID 000529525900038

Abstract

Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-seq data from 498 neuroblastoma patients and revealed a differentially overexpressed gene signature in MYCN non-amplified neuroblastomas with telomerase reverse transcriptase (TERT) gene overexpression and coordinated activation of oncogenic signaling pathways, including E2Fs, Wnt, Myc, and the DNA repair pathway. Promoter rearrangement of the TERT gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis in neuroblastoma, but TERT-associated oncogenic signaling remains unclear. ChIP-seq analysis of the human CLB-GA neuroblastoma cells harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. Brd4 and cyclin-dependent kinases (CDKs) had critical regulatory roles in the expression and chromatin activation of TERT and multiple TERT-associated genes. Epigenetically targeting Brd4 or CDKs with their respective inhibitors suppressed the expression of TERT and multiple TERT-associated genes in neuroblastoma with TERT overexpression or MYCN amplification. ChIP-seq and ChIP-qPCR provided evidence that the CDK inhibitor directly inhibited Brd4 recruitment to activate chromatin globally. Therefore, inhibiting Brd4 and CDK concurrently with AZD5153 and dinaciclib would be most effective in tumor growth suppression, which we demonstrated in neuroblastoma cell lines, primary human cells, and xenografts. In summary, we describe a unique mechanism in neuroblastoma with TERT overexpression and an epigenetically targeted novel therapeutic strategy.

View details for DOI 10.1158/0008-5472.CAN-19-2560

View details for PubMedID 31900258

Abstract

Purpose: Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175mg orally, once daily, for up to thirteen 28-day cycles.Results: Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm.Conclusions: Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.

View details for DOI 10.1155/2020/7935475

View details for PubMedID 32398945

Abstract

Strategies to optimize management in rhabdomyosarcoma (RMS) include risk stratification to assign therapy aiming to minimize treatment morbidity yet improve outcomes. This analysis evaluated the relationship between complete metabolic response (CMR) as assessed by 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET) imaging and event-free survival (EFS) in intermediate-risk (IR) and high-risk (HR) RMS patients.FDG-PET imaging characteristics, including assessment of CMR and maximum standard uptake values (SUVmax) of the primary tumor, were evaluated by central review. Institutional reports of SUVmax were used when SUVmax values could not be determined by central review. One hundred and thirty IR and 105 HR patients had FDG-PET scans submitted for central review or had SUVmax data available from institutional report at any time point. A Cox proportional hazards regression model was used to evaluate the relationship between these parameters and EFS.SUVmax at study entry did not correlate with EFS for IR (p=0.32) or HR (p=0.86) patients. Compared to patients who did not achieve a CMR, EFS was not superior for IR patients who achieved a CMR at weeks 4 (p=0.66) or 15 (p=0.46), nor for HR patients who achieved CMR at week 6 (p=0.75) or 19 (p=0.28). Change in SUVmax at week 4 (p=0.21) or 15 (p=0.91) for IR patients or at week 6 (p=0.75) or 19 (p=0.61) for HR patients did not correlate with EFS.Based on these data, FDG-PET does not appear to predict EFS in IR or HR-RMS. It remains to be determined whether FDG-PET has a role in predicting survival outcomes in other RMS subpopulations.

View details for DOI 10.1002/cam4.3667

View details for PubMedID 33340280

Abstract

Background Whole-body diffusion-weighted (DW) MRI can help detect cancer with high sensitivity. However, the assessment of therapy response often requires information about tumor metabolism, which is measured with fluorine 18 fluorodeoxyglucose (FDG) PET. Purpose To compare tumor therapy response with whole-body DW MRI and FDG PET/MRI in children and young adults. Materials and Methods In this prospective, nonrandomized multicenter study, 56 children and young adults (31 male and 25 female participants; mean age, 15 years 4 [standard deviation]; age range, 6-22 years) with lymphoma or sarcoma underwent 112 simultaneous whole-body DW MRI and FDG PET/MRI between June 2015 and December 2018 before and after induction chemotherapy (ClinicalTrials.gov identifier: NCT01542879). The authors measured minimum tumor apparent diffusion coefficients (ADCs) and maximum standardized uptake value (SUV) of up to six target lesions and assessed therapy response after induction chemotherapy according to the Lugano classification or PET Response Criteria in Solid Tumors. The authors evaluated agreements between whole-body DW MRI- and FDG PET/MRI-based response classifications with Krippendorff statistics. Differences in minimum ADC and maximum SUV between responders and nonresponders and comparison of timing for discordant and concordant response assessments after induction chemotherapy were evaluated with the Wilcoxon test. Results Good agreement existed between treatment response assessments after induction chemotherapy with whole-body DW MRI and FDG PET/MRI ( = 0.88). Clinical response prediction according to maximum SUV (area under the receiver operating characteristic curve = 100%; 95% confidence interval [CI]: 99%, 100%) and minimum ADC (area under the receiver operating characteristic curve = 98%; 95% CI: 94%, 100%) were similar (P = .37). Sensitivity and specificity were 96% (54 of 56 participants; 95% CI: 86%, 99%) and 100% (56 of 56 participants; 95% CI: 54%, 100%), respectively, for DW MRI and 100% (56 of 56 participants; 95% CI: 93%, 100%) and 100% (56 of 56 participants; 95% CI: 54%, 100%) for FDG PET/MRI. In eight of 56 patients who underwent imaging after induction chemotherapy in the early posttreatment phase, chemotherapy-induced changes in tumor metabolism preceded changes in proton diffusion (P = .002). Conclusion Whole-body diffusion-weighted MRI showed significant agreement with fluorine 18 fluorodeoxyglucose PET/MRI for treatment response assessment in children and young adults. RSNA, 2020 Online supplemental material is available for this article.

View details for DOI 10.1148/radiol.2020192508

View details for PubMedID 32368961

Abstract

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View details for DOI 10.1002/pon.5544

View details for PubMedID 32909342

Abstract

The composition of lymph nodes in pediatric patients is different from that in adults. Most notably, normal lymph nodes in children contain less macrophages. Therefore, previously described biodistributions of iron oxide nanoparticles in benign and malignant lymph nodes of adult patients may not apply to children. The purpose of our study was to evaluate if the iron supplement ferumoxytol improves the differentiation of benign and malignant lymph nodes in pediatric cancer patients on 18F-FDG PET/MRI. Methods: We conducted a prospective clinical trial from May 2015 to December 2018 to investigate the value of ferumoxytol nanoparticles for staging of children with cancer with 18F-FDG PET/MRI. Ferumoxytol is an FDA-approved iron supplement for the treatment of anemia and has been used "off-label" as an MRI contrast agent in this study. Forty-two children (7-18 years, 29 male, 13 female) received a 18F-FDG PET/MRI at 2 (n=20) or 24 hours (h) (n=22) after intravenous injection of ferumoxytol (dose 5 mg Fe/kg). The morphology of benign and malignant lymph nodes on ferumoxytol-enhanced T2-FSE sequences at 2 and 24 h were compared using a linear regression analysis. In addition, ADCmean-values, SUV-ratio (SUVmax lesion/SUVmean liver) and R2*-relaxation rate of benign and malignant lymph nodes were compared with a Mann-Whitney-U test. The accuracy of different criteria was assessed with a receiver operating characteristics (ROC) curve. Follow-up imaging for at least 6 months served as the standard of reference. Results: We examined a total of 613 lymph nodes, of which 464 (75.7%) were benign and 149 (24.3%) were malignant. On ferumoxytol-enhanced T2-FSE images, benign lymph nodes showed a hypointense hilum and hyperintense parenchyma, while malignant lymph nodes showed no discernible hilum. This pattern was not significantly different at 2 h and 24 h postcontrast (p=0.82). Benign and malignant lymph nodes showed significantly different ferumoxytol enhancement patterns, ADCmean values of 1578 and 852 x10-6 mm2/s, mean SUV-ratios of 0.5 and 2.8, and mean R2*-relaxation rate of 127.8 and 84.4 Hertz (Hz), respectively (all p<0.001). The accuracy of ADCmean, SUV-ratio and pattern (area under the curve (AUC): 0.99; 0.98; 0.97, respectively) was not significantly different (p=0.07). Compared to these three parameters, the accuracy of R2* was significantly lower (AUC: 0.93; p=0.001). Conclusion: Lymph nodes in children show different ferumoxytol-enhancement patterns on MRI than previously reported for adult patients. We found high accuracy (>90%) of ADCmean, SUV-ratio, pattern, and R2* measurements for the characterization of benign and malignant lymph nodes in children. Ferumoxytol nanoparticle accumulation at the hilum can be used to diagnose a benign lymph node. In the future, the delivery of clinically applicable nanoparticles to the hilum of benign lymph nodes could be harnessed to deliver theranostic drugs for immune cell priming.

View details for DOI 10.7150/thno.40606

View details for Web of Science ID 000518768400016

View details for PubMedID 32206111

View details for PubMedCentralID PMC7069081

Abstract

CIC-rearranged sarcomas (CRSs) have recently been characterized as a distinct sarcoma subgroup with a less favorable prognosis compared to other small round cell sarcomas. CRSs share morphologic features with Ewing's sarcoma and prior to 2013 were grouped under undifferentiated sarcomas with round cell phenotype by the WHO classification. In this report, whole-genome sequencing and RNA sequencing were performed for an adolescent male patient with CRS who was diagnosed with undifferentiated pleomorphic sarcoma (UPS) by three contemporary institutions. Somatic mutation analysis identified mutations in IQGAP1, CCNC, and ATXN1L in pre- and post-treatment tissue samples, as well as a CIC-DUX4 fusion that was confirmed by qPCR and DUX4 immunohistochemistry. Of particular interest was the overexpression of the translation factor eEF1A1, which has oncogenic properties and has recently been identified as a target of the investigational agent plitidepsin. This case may provide a valuable waypoint in the understanding and classification of CRSs and may provide a rationale for targeting eEF1A1 in similar soft tissue sarcoma cases.

View details for DOI 10.1101/mcs.a004812

View details for PubMedID 32014859

Abstract

Patients with metastatic Ewing sarcoma experience poor outcomes despite intensive systemic and local therapy. Early chemotherapy response of pulmonary metastases has been associated with prognosis in other pediatric malignancies. We reviewed the outcomes of patients with Ewing sarcoma and pulmonary metastases treated at our institution based on therapy received and early pulmonary response.We retrospectively reviewed patients with newly diagnosed Ewing sarcoma and pulmonary metastases at St. Jude Children's Research Hospital between 1979 and 2015. Data obtained included demographic and treatment characteristics including chemotherapy, local control measures, whole lung irradiation (WLI) administration, autologous stem cell transplantation, and outcomes. Patients were evaluated for radiographic post-induction pulmonary complete response (CR). We estimated event-free survival (EFS) and overall survival (OS) and used Cox proportional hazards regression to examine the effects of clinical and treatment factors on outcomes.Fifty-four patients (median age, 12.9 years) were evaluated. Post-induction pulmonary CR was observed in 33 (61%) patients. WLI was delivered to 16 patients (4/33 with pulmonary CR and 12/21 with non-CR). At median 3.6 years follow-up, five-year EFS and OS were 30.8% 6.4% and 49.6% 7.1%, respectively. Post-induction pulmonary CR was associated with prolonged EFS (P<0.001) but not improved OS (P=0.065). Post-induction pulmonary CR was associated with a lower incidence of lung failure (P=0.031).Post-induction pulmonary CR is associated with improved EFS in patients with Ewing sarcoma who present with pulmonary metastases.

View details for DOI 10.1002/pbc.28150

View details for PubMedID 31944574

Abstract

To assess disease outcomes and late toxicities in pediatric patients with rhabdomyosarcoma treated with conformal photon radiation therapy (RT).Sixty-eight patients (median age, 6.9 years) were treated with conformal photon RT to the primary site on a prospective clinical trial. Target volumes included a 1-cm expansion encompassing microscopic disease. Prescribed doses were 36 Gy to this volume and 50.4 Gy to gross residual disease. Chemotherapy consisted of vincristine/dactinomycin (n=6); vincristine/dactinomycin/cyclophosphamide (VAC) (n=37); or VAC-based combinations (n=25). Patients were evaluated with primary-site MRI, whole-body [18F]FDG-PET, and chest CT for 5 years after treatment.Five-year disease-free survival was 88% for low-risk (LR) (n=8), 76% for intermediate-risk (IR) (n=37), and 36% for high-risk (HR) (n=23) patients (P0.01 for LR/IR vs. HR). The cumulative incidence (CIN) of local failure (LF) at 5 years for the entire cohort was 10.4%. Tumor size at diagnosis was a significant predictor of LF (P<0.01). Patients with head and neck primary tumors (n=31) had a 35% CIN of cataracts, the risk correlating with lens dose (P=0.0025). Jaw dysfunction was more severe when the pterygoid and masseter muscles received a mean dose of >20 Gy (P=0.013). Orbital hypoplasia developed more frequently after a mean bony orbit dose of >30 Gy (P=0.041). Late toxicity in patients with genitourinary tumors included microscopic hematuria (9/14), bladder-wall thickening (10/14), and vaginal stenosis (2/5).Long-term LF rates were low, and higher rates correlated with larger tumors. Treatment-related toxicities resulting in measurable functional deficits were not infrequent, despite the conformal RT approach.

View details for DOI 10.1016/j.ijrobp.2020.01.011

View details for PubMedID 31987969

Abstract

Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone.In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged 18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged 16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (25 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (375 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients 18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867.Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 08 years (IQR 03-16) in the pazopanib group and 1 year (03-16) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 361% (838% CI 165-558). On the basis of an interim analysis significance level of 0081 (overall one-sided significance level of 020, power of 080, and O'Brien-Fleming-type cumulative error spending function), the 838% CI for response difference was between 165% and 558% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related.In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up.National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

View details for DOI 10.1016/S1470-2045(20)30325-9

View details for PubMedID 32702309

Abstract

OBJECTIVES: We compared the value of ferumoxytol (FMX)- and gadolinium (Gd)-enhanced MRI for assessment of sarcomas in paediatric/adolescent patients and hypothesised that tumour size and morphological features can be equally well assessed with both protocols.METHODS: We conducted a retrospective study of paediatric/adolescent patients with newly diagnosed bone or soft tissue sarcomas and both pre-treatment FMX- and Gd-MRI scans, which were maximal 4 weeks apart. Both protocols included T1- and T2-weighted sequences. One reader assessed tumour volumes, signal-to-noise ratios (SNR) of the primary tumour and adjacent tissues and contrast-to-noise ratios (CNR) ofFMX- and Gd-MRI scans. Additionally, four readers scored FMX- and Gd-MRI scansaccording to15 diagnostic parameters, using a Likert scale. The results were pooled across readers and compared between FMX- and Gd-MRI scans. Statistical methods included multivariate analyses with different models.RESULTS: Twenty-two patients met inclusion criteria (16 males, 6 females; mean age 15.3 5.0). Tumour volume was not significantly different on T1-LAVA (p = 0.721), T1-SE (p = 0.290) and T2-FSE (p = 0.609)sequences. Compared to Gd-MRI, FMX-MRI demonstrated significantly lower tumour SNR on T1-LAVA (p < 0.001), equal tumour SNR on T1-SE (p = 0.104) and T2-FSE (p = 0.305), significantly higher tumour-to-marrow CNR (p < 0.001) on T2-FSE as well as significantly highertumour-to-liver (p = 0.021) and tumour-to-vessel (p = 0.003) CNR on T1-LAVAimages. Peritumoural and marrow oedema enhancedsignificantly more on Gd-MRIcompared to FMX-MRI (p < 0.001/p = 0.002, respectively). Tumour thrombi and neurovascular bundle involvement were assessed with a significantly higher confidence on FMX-MRI (both p < 0.001).CONCLUSIONS: FMX-MRI provides equal assessment of the extent of bone and soft tissue sarcomas compared to Gd-MRI with improvedtumour delineation and improved evaluation of neurovascular involvement and tumour thrombi. Therefore,FMX-MRI is a possiblealternative to Gd-MRIfor tumour staging in paediatric/adolescent sarcoma patients.KEY POINTS: Ferumoxytol can be used as an alterative to gadolinium chelates for MRI staging ofpaediatric sarcomas. Ferumoxytol-enhanced MRI provides equal assessment of tumour size and other diagnostic parameters compared to gadolinium chelate-enhanced MRI. Ferumoxytol-enhanced MRI provides improved delineation of sarcomas from bone marrow, liver and vessels compared to gadolinium chelate-enhanced MRI.

View details for DOI 10.1007/s00330-019-06569-y

View details for PubMedID 31844962

View details for Web of Science ID 000488458000121

View details for DOI 10.1101/mcs.a004929

View details for Web of Science ID 000512328600001

View details for PubMedID 31836591

View details for PubMedCentralID PMC6913145

Abstract

BACKGROUND: Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We developed a risk stratification system from known prognostic factors and assessed it in the context of risk-adapted therapy for young patients with NRSTS.METHODS: In this prospective study, eligible patients enrolled in 159 hospitals in three countries were younger than 30 years, had a Lansky (patients 16 years) or Karnofsky (patients >16 years) performance status score of at least 50, and a new diagnosis of a WHO (2002 criteria) intermediate (rarely metastasising) or malignant soft-tissue tumour (apart from tumour types eligible for other Children's Oncology Group studies and tumours for which the therapy in this trial was deemed inappropriate), malignant peripheral nerve sheath tumour, non-metastatic and grossly resected dermatofibrosarcoma protuberans, undifferentiated embryonal sarcoma of the liver, or unclassified malignant soft-tissue sarcoma. Each patient was assigned to one of three risk groups and one of four treatment groups. Risk groups were: low (non-metastatic R0 or R1 low-grade, or 5 cm R1 high-grade tumour); intermediate (non-metastatic R0 or R1 >5 cm high-grade, or unresected tumour of any size or grade); or high (metastatic tumour). The treatment groups were surgery alone, radiotherapy (558 Gy), chemoradiotherapy (chemotherapy and 558 Gy radiotherapy), and neoadjuvant chemoradiotherapy (chemotherapy and 45 Gy radiotherapy, then surgery and radiotherapy boost based on margins with continued chemotherapy). Chemotherapy included six cycles of ifosfamide 3 g/m2 per dose intravenously on days 1-3 and five cycles of doxorubicin 375 mg/m2 per dose intravenously on days 1-2 every 3 weeks with sequence adjusted on the basis of timing of surgery or radiotherapy. The primary outcomes were event-free survival, overall survival, and the pattern of treatment failure. Analysis was done per protocol. This study has been completed and is registered with ClinicalTrials.gov, NCT00346164.FINDINGS: Between Feb 5, 2007, and Feb 10, 2012, 550 eligible patients were enrolled, of whom 21 were treated in the incorrect group and excluded from this analysis. 529 evaluable patients were included in the analysis: low-risk (n=222), intermediate-risk (n=227), high-risk (n=80); surgery alone (n=205), radiotherapy (n=17), chemoradiotherapy (n=111), and neoadjuvant chemoradiotherapy (n=196). At a median follow-up of 65 years (IQR 49-79), 5-year event-free survival and overall survival were: 889% (95% CI 840-938) and 962% (932-992) in the low-risk group; 650% (582-718) and 792% (734-850) in the intermediate-risk group; and 212% (114-311) and 355% (236-474) in the high-risk group, respectively. Risk group predicted event-free survival and overall survival (p<00001). No deaths from toxic events during treatment were reported. Nine patients had unexpected grade 4 adverse events (chemoradiotherapy group, n=2; neoadjuvant chemoradiotherapy group, n=7), including three wound complications that required surgery (all in the neoadjuvant chemoradiotherapy group).INTERPRETATION: Pre-treatment clinical features can be used to effectively define treatment failure risk and to stratify young patients with NRSTS for risk-adapted therapy. Most low-risk patients can be cured without adjuvant therapy, thereby avoiding known long-term treatment complications. Survival remains suboptimal for intermediate-risk and high-risk patients and novel therapies are needed.FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation, American Lebanese Syrian Associated Charities.

View details for DOI 10.1016/S1470-2045(19)30672-2

View details for PubMedID 31786124

View details for DOI 10.1200/JCO.2019.37.31_suppl.147

View details for Web of Science ID 000518224200145

Abstract

Importance: Pediatric cancers are epigenetic diseases; therefore, considering tumor gene expression information is necessary for a complete understanding of the tumorigenic processes.Objective: To evaluate the feasibility and utility of incorporating comparative gene expression information into the precision medicine framework for difficult-to-treat pediatric and young adult patients with cancer.Design, Setting, and Participants: This cohort study was conducted as a consortium between the University of California, Santa Cruz (UCSC) Treehouse Childhood Cancer Initiative and clinical genomic trials. RNA sequencing (RNA-Seq) data were obtained from the following 4 clinical sites and analyzed at UCSC: British Columbia Children's Hospital (n=31), Lucile Packard Children's Hospital at Stanford University (n=80), CHOC Children's Hospital and Hyundai Cancer Institute (n=46), and the Pacific Pediatric Neuro-Oncology Consortium (n=24). The study dates were January 1, 2016, to March 22, 2017.Exposures: Participants underwent tumor RNA-Seq profiling as part of 4 separate clinical trials at partner hospitals. The UCSC either downloaded RNA-Seq data from a partner institution for analysis in the cloud or provided a Docker pipeline that performed the same analysis at a partner institution. The UCSC then compared each participant's tumor RNA-Seq profile with more than 11000 uniformly analyzed tumor profiles from pediatric and young adult patients with cancer, downloaded from public data repositories. These comparisons were used to identify genes and pathways that are significantly overexpressed in each patient's tumor. Results of the UCSC analysis were presented to clinical partners.Main Outcomes and Measures: Feasibility of a third-party institution (UCSC Treehouse Childhood Cancer Initiative) to obtain tumor RNA-Seq data from patients, conduct comparative analysis, and present analysis results to clinicians; and proportion of patients for whom comparative tumor gene expression analysis provided useful clinical and biological information.Results: Among 144 samples from children and young adults (median age at diagnosis, 9 years; range, 0-26 years; 72 of 118 [61.0%] male [26 patients sex unknown]) with a relapsed, refractory, or rare cancer treated on precision medicine protocols, RNA-Seq-derived gene expression was potentially useful for 99 of 144 samples (68.8%) compared with DNA mutation information that was potentially useful for only 34 of 74 samples (45.9%).Conclusions and Relevance: This study's findings suggest that tumor RNA-Seq comparisons may be feasible and highlight the potential clinical utility of incorporating such comparisons into the clinical genomic interpretation framework for difficult-to-treat pediatric and young adult patients with cancer. The study also highlights for the first time to date the potential clinical utility of harmonized publicly available genomic data sets.

View details for DOI 10.1001/jamanetworkopen.2019.13968

View details for PubMedID 31651965

View details for DOI 10.1016/j.ijrobp.2019.06.206

View details for Web of Science ID 000485671503063

Abstract

There are very few reported cases of stereotactic radiosurgery delivered in children under 3 years of age. We report an 18 month old boy with metastatic recurrence of undifferentiated round cell sarcoma to the brain which was treated with chemotherapy, resection, and robotic frameless stereotactic radiosurgery (SRS). Frameless SRS was delivered without technical difficulties, acute adverse events, or clinical sequelae 1.5 months post-radiation. Longer term follow-up will be needed to evaluate local tumor control and effects on neurocognitive development, endocrine function, and growth. This report adds to the literature of the few reported cases of successfully attempted SRS in very young children.

View details for DOI 10.1080/00207454.2019.1655015

View details for PubMedID 31401906

View details for DOI 10.1158/1538-7445.AM2019-3665

View details for Web of Science ID 000488279403070

View details for DOI 10.1007/s11307-018-1272-1

View details for Web of Science ID 000468363800023

View details for DOI 10.1007/s00247-019-04389-2

View details for Web of Science ID 000469812600011

View details for Web of Science ID 000487345804165

View details for DOI 10.1200/JCO.2019.37.15_suppl.10010

View details for Web of Science ID 000487345803599

View details for Web of Science ID 000487345804099

View details for DOI 10.1200/JCO.2019.37.15_suppl.TPS10066

View details for Web of Science ID 000487345803218

View details for DOI 10.1016/j.ejca.2019.02.001

View details for Web of Science ID 000466069400016

Abstract

BACKGROUND: Data on the clinical features, optimal treatmentand outcomes of paediatric patients with epithelioid sarcoma (ES) are limited and mostly retrospective.METHODS: A subset analysis of ES patients<30 years of age enrolled on two international prospective clinical trials conducted between 7/2005 and 11/2015 was performed. Risk-adapted therapy was based on tumour diameter, histologic grade, extent of surgeryand presence/absence of metastasesand included surgeryradiotherapy for all patients with the addition of ifosfamide/doxorubicin chemotherapy for intermediate-/high-risk patients. Response to therapy, event-free and overall survivaland pattern and predictors of treatment failure were evaluated.RESULTS: Sixty-three ES patients (median age 13.1 years, 52% male) were eligible. Clinical features included the following: 68% extremity, median tumour diameter 3.5cm, 56% high histologic grade, 14% nodal metastases, 14% distant metastases. Thirty-four low-risk patients underwent surgery (n=30) or surgery/radiotherapy (n=4); 16 intermediate-risk and 13 high-risk patients received chemotherapysurgeryradiotherapy. Partial response was observed in 11/22 (50%) patients receiving neoadjuvant therapy. Events were local recurrence (n=10) and distant recurrence (n=15); estimated 5-year survival was 86.4%, 63.5%and 0%, respectively, for low-, intermediate-and high-risk patients. Locoregional nodal involvement, invasive tumour, high gradeand lesser extent of resection predicted event-free survival in patients without metastases.CONCLUSIONS: Most low-risk ES patients who have undergone an adequate resection fare well without adjuvant therapy. Large tumour size, high histologic grade, tumour invasiveness, inadequate tumour resectionand metastatic disease predict poorer outcomes in higher risk ES patients, for whom more effective therapies are needed.CLINICAL TRIAL REGISTRATION: COG ARST0332: ClinicalTrials.gov Identifier NCT00346164, EpSSG NRSTS 2005: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31.

View details for PubMedID 30954717

Abstract

OBJECTIVE: To correlate imaging features of epithelioid sarcoma in children and young adults enrolled in Children's Oncology Group study ARST0332 with clinical and pathological findings.MATERIALS AND METHODS: Fifteen patients (6 males; median age 16.1years, range 6.5-24.8years) with epithelioid sarcoma enrolled in ARST0332 had preoperative imaging (MRI, n=10; CT, n=5) that was reviewed by two radiologists who recorded numerous features including presence and percentage of tumor necrosis, presence of surrounding edema, and lymph node involvement. Discrepancies between reviewers were adjudicated by concurrent re-review. We correlated imaging findings with histological assessment of percentage tumor necrosis, proximal- vs. classic-type histology, lymph node involvement and recurrence.RESULTS: Eleven patients (11/15, 73%) had proximal-type histology tumors. Ten of 14 tumors (71%) had imaging evidence of necrosis. Among the nine tumors with imaging and histological estimates of percentage necrosis, agreement was within 30% (in six tumors there was 10% difference between pathology and imaging). All 10 tumors imaged with MRI had surrounding edema. Four patients had biopsy-proven nodal involvement; all had necrotic nodes on imaging. There were four false-positives for nodal involvment by imaging. Twelve patients (12/15, 80%) had recurrences (local only, n=1; local and distant, n=1; distant only, n=10).CONCLUSION: Proximal-type histology was prevalent in this young cohort with preoperative imaging. Necrosis is common in primary tumors and involved nodes. There is good agreement between histological and imaging estimates of primary tumor necrosis. Surrounding tumor edema is common in this tumor, which is known to spread along fascial planes.

View details for PubMedID 30929036

View details for DOI 10.1002/cncr.31770

View details for Web of Science ID 000455536300016

Abstract

Gliomatosis peritonei is a rare pathologic finding that is associated with ovarian teratomas and malignant mixed germ cell tumors. The occurrence of gliomatosis as a mature glial implant can impart an improved prognosis to patients with immature ovarian teratoma, making prompt and accurate diagnosis important. We describe a case of recurrent immature teratoma in a 10-yr-old female patient, in which comparative analysis of the RNA sequencing gene expression data from the patient's tumor was used effectively to aid in the diagnosis of gliomatosis peritonei.

View details for DOI 10.1101/mcs.a004317

View details for PubMedID 31645344

Abstract

Previous studies of the prognostic importance of FOXO1 fusion status in patients with rhabdomyosarcoma (RMS) have had conflicting results. We re-examined risk stratification by adding FOXO1 status to traditional clinical prognostic factors in children with localized or metastatic RMS.Data from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531; two studies each for low-, intermediate- and high-risk patients) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1727 evaluable patients. Survival tree regression for event-free survival (EFS) was conducted to recursively select prognostic factors for branching and split. Factors included were age, FOXO1, clinical group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Definition and outcome of the proposed risk groups were compared to existing systems and cross-validated results.The 5-year EFS and overall survival (OS) for evaluable patients were 69% and 79%, respectively. Extent of disease (localized versus metastatic) was the first split (EFS 73% vs 30%; OS 84% vs. 42%). FOXO1 status (positive vs negative) was significant in the second split both for localized (EFS 52% vs 78%; OS 65% vs 88%) and metastatic disease (EFS 6% vs 46%; OS 19% vs 58%).After metastatic status, FOXO1 status is the most important prognostic factor in patients with RMS and improves risk stratification of patients with localized RMS. Our findings support incorporation of FOXO1 status in risk stratified clinical trials.

View details for DOI 10.1002/cam4.2504

View details for PubMedID 31456361

Abstract

Few studies have addressed the efficacy of palliative radiotherapy (RT) for pediatric osteosarcoma (OS), a disease generally considered to be radioresistant. We describe symptom relief, local control, and toxicity associated with palliative RT among children with OS.Patients diagnosed with OS at age 18 and under and treated with RT for palliation of symptomatic metastases or local recurrence at the primary site from 1997 to 2017 were included. We retrospectively reviewed details of RT, symptom improvement, local control, survival, and toxicity.Thirty-two courses of palliative RT were given to 20 patients with symptomatic metastatic and/or locally recurrent primary disease. The median equivalent dose in 2Gy fractions (EQD2) was 40.0Gy (range, 20.0-60.4). The median number of fractions per course was 15 (range, 5-39). Symptom improvement occurred in 24 (75%) courses of RT at a median time of 15.5days (range, 3-43). In nine courses (37.5%), symptoms recurred after a median duration of symptom relief of 140days (range, 1-882). Higher EQD2 correlated with longer duration of response (r=0.39, P=0.0003). Imaging revealed local failure in 3 of 14courses followed with surveillance imaging studies (21.4%). The median time to progression was 12.9 months (range, 4.4-21.8). The median follow-up time following the first course of palliative RT was 17.5 months (range, 1.74-102.24), and median time to overall survival was 19.4 months. Toxicity was mild, with grade 2 toxicity occurring in one course (3.1%).RT is an effective method of symptom palliation for patients with recurrent or metastatic OS, with higher delivered dose correlating with longer symptom relief and with little associated toxicity.

View details for DOI 10.1002/pbc.27967

View details for PubMedID 31407520

Abstract

The primary aim of this clinical trial was to prioritize bevacizumab or temsirolimus for additional investigation in rhabdomyosarcoma (RMS) when administered in combination with cytotoxic chemotherapy to patients with RMS in first relapse with unfavorable prognosis.Patients were randomly assigned to receive bevacizumab on day 1 or temsirolimus on days 1, 8, and 15 of each 21-day treatment cycle, together with vinorelbine on days 1 and 8, and cyclophosphamide on day 1 for a maximum of 12 cycles. Local tumor control with surgery and/or radiation therapy was permitted after 6 weeks of treatment. The primary end point was event-free survival (EFS). Radiographic response was assessed at 6 weeks. The study had a phase II selection that was design to detect a 15% difference between the two regimens ( = .2; 1- = 0.8; two sided test).Eighty-seven of 100 planned patients were enrolled when the trial was closed after the second interim analysis after 46 events occurred in 68 patients with sufficient follow-up. The O'Brien Fleming boundary at this analysis corresponded to a two-sided P value of .058 with an observed two-sided P value of .003 favoring temsirolimus. The 6-month EFS for the bevacizumab arm was 54.6% (95% CI, 39.8% to 69.3%) and 69.1% (95% CI, 55.1% to 83%) for the temsirolimus arm. Objective response rates were 28% (95% CI, 13.7% to 41.3%) and 47% (95% CI, 31.5% to 63.2%) for the bevacizumab and temsirolimus arms, respectively (P = .12) and, 28% of patients on bevacizumab and 11% on temsirolimus had progressive disease at 6 weeks.Patients who received temsirolimus had a superior EFS compared with bevacizumab. Temsirolimus has been selected for additional investigation in newly diagnosed patients with intermediate-risk RMS.

View details for DOI 10.1200/JCO.19.00576

View details for PubMedID 31513481

Abstract

PURPOSE: For pediatric patients with large, high-grade, extremity nonrhabdomyosarcoma soft-tissue sarcomas, preoperative radiation therapy (RT) provides the opportunity for smaller radiation fields and tumor shrinkage resulting in less extensive surgery. The potential disadvantage is an increased risk of wound complications after surgery compared with rates after postoperative chemoradiation. We assessed the impact of preoperative RT technique on target coverage in relationship to dose to skin and adjacent joints to determine whether acute wound complications and late musculoskeletal injury might be influenced by treatment technique.METHODS AND MATERIALS: Of 550 eligible patients <30years of age, 200 were enrolled in arm D of ARST0332 and received neoadjuvant ifosfamide/doxorubicin, then chemoradiotherapy (45Gy and ifosfamide) and surgery followed by postoperative RT if gross or microscopic positive surgical margins. One-hundred thirteen patients had extremity nonrhabdomyosarcoma soft-tissue sarcomas, of which 56 patients had preoperative RT plans for digital review. The doses to the target volume, skin (surface to 5mm depth), adjacent joint, and extremity diameter were analyzed with respect to RT technique.RESULTS: Thirty-eight patients (65%) received 3-dimensional conformal RT (3D-CRT) and 18 (32%) received intensity modulated RT (IMRT). There was no difference in clinical target volume (CTV) size between groups (P=.920); however, IMRT plans had improved CTV coverage to 100% of the prescription dose compared with 3D-CRT plans (median CTV coverage, 92.7% vs 98.6%; P=.011). In patients without target overlap with the skin, IMRT use was associated with reduced percent volume of skin receiving 45Gy or more (V45Gy) compared with 3D-CRT (median, 1.6% vs 6.3%, respectively; P=.005). IMRT was also associated with reduced V45Gy to the adjacent joint compared with 3D-CRT (median, 1.1% vs 13.2%; P=.018).CONCLUSIONS: Preoperative IMRT may improve CTV coverage and reduce the volume of skin and adjacent joint treated to high doses. Future studies should assess whetherthese dosimetric findings produce differences in clinical and toxicity outcomes.

View details for PubMedID 30213752

View details for PubMedID 30614475

View details for DOI 10.1016/j.ijrobp.2018.09.005

View details for Web of Science ID 000452811900010

Abstract

Genomic data offer valuable insights that can be used to help find treatments and cures for disease. Precision medicine, defined by the NIH as "an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person," is gaining acceptance among physicians, who are beginning to integrate patient-centric data analysis into clinical decision-making. Although precision medicine makes use of various types of data, this piece focuses on molecular characterization data specifically, as the discoveries yielded from these data can advance thinking around clinical care for cancer patients. Our pediatrics genomics team at the University of California Santa Cruz Genomics Institute is uniquely situated to discuss the use of shared genomic data for clinical benefit because our collaborations with hospital partners in the United States and internationally rely on big-data comparative genomic analysis. Using shared data, Treehouse Childhood Cancer Initiative develops methods for comparative analysis of tumor RNA sequencing profiles from single patients for the purposes of identifying overexpressed oncogenes that could be targeted by therapies in the clinic. To enable and improve this analysis, we continuously increase the size of our data compendium by adding public pediatric tumor RNA sequencing data sets. We developed an approach for assessing the quality of shared RNA sequencing data to ensure the integrity of the data. In this approach we calculate the number of mapped exonic nonduplicate (MEND) reads, applying a 10 million MEND read minimum threshold for inclusion in our comparative analysis. In collaboration with Stanford University and Lucile Packard Children's Hospital Stanford, our team at Treehouse Childhood Cancer Initiative explores the value to researchers everywhere of shared genomic data for clinical utility and the challenges of data sharing that threaten to impede otherwise rapid advances in precision medicine. This Perspective offers recommendations for maximizing the use of genomic data to make discoveries that will benefit patients.

View details for DOI 10.1101/mcs.a004689

View details for PubMedID 31645349

View details for DOI 10.1016/S1470-2045(18)30910-0

View details for Web of Science ID 000454901700003

View details for DOI 10.1158/2159-8290.CD-17-1152

View details for Web of Science ID 000455598900022

Abstract

BACKGROUND: The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone.METHODS: Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m2 ) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites.RESULTS: One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged 10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide.CONCLUSIONS: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.

View details for PubMedID 30351457

Abstract

Wellbeing after successful cancer treatment depends on more than merely reducing the risk of disease recurrence. Cancer survival can be characterised by uncertainty, fear, and the interpretation of bodily sensations as potentially symptomatic of cancer recurrence. This fear can lead to over-vigilance about bodily sensations and precautionary visits to the doctor, both of which can increase the chance of early detection but can also increase anxiety and decrease quality of life. In this Personal View, we consider the medical, psychological, and ethical issues related to the practice of self-directed symptom monitoring after completion of cancer treatment, focusing on the role of doctor-patient communication. We ask how clinicians can account for the plurality of values that patients might have when it comes to deciding on how to manage and respond to experiences of post-cancer symptoms. We advocate a shared decision-making approach that incorporates the assessment of an individual's cancer recurrence risks as well as psychosocial considerations regarding fear of cancer recurrence and mental health. We aim to raise awareness of the potential quality-of-life implications of symptom-monitoring practices, emphasising the need for a balance between physical and psychological health in people living beyond cancer.

View details for PubMedID 30303128

Abstract

Osteosarcoma (OS) is a highly aggressive cancer for which treatment has remained essentially unchanged for over 30 years. OS is characterized by widespread and recurrent somatic copy-number alterations (SCNAs) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across OS cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy number amplification (identified by Whole Genome Sequencing) and changes in gene expression as identified by RNAseq. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific somatic copy number alterations leads to significant decrease in tumor burden, providing a roadmap for genome-informed treatment of OS.

View details for PubMedID 30266815

View details for DOI 10.1200/JCO.2018.77.9694

View details for Web of Science ID 000451484000005

Abstract

PURPOSE: To evaluate whether the extent of restricted diffusion and 2-deoxy-2-[18F] fluoro-D-glucose ([18F]FDG) uptake of pediatric rhabdomyosarcomas (RMS) on positron emission tomography (PET)/magnetic resonance (MR) images provides prognostic information.PROCEDURE: In a retrospective, IRB-approved study, we evaluated [18F]FDG PET/CT and diffusion-weighted (DW) MR imaging studies of 21 children and adolescents (age 1-20years) with RMS of the head and neck. [18F]FDG PET and DW MR scans at the time of the initial tumor diagnosis were fused using MIM software. Quantitative measures of the tumor mass with restricted diffusion, [18F]FDG hypermetabolism, or both were dichotomized at the median and tested for significance using Gray's test. Data were analyzed using a survival analysis and competing risk model with death as the competing risk.RESULTS: [18F]FDG PET/MR images demonstrated a mismatch between tumor areas with increased [18F]FDG uptake and restricted diffusion. The DWI, PET, and DWI+PET tumor volumes were dichotomized at their median values, 23.7, 16.4, and 9.5cm3, respectively, and were used to estimate survival. DWI, PET, and DWI+PET overlap tumor volumes above the cutoff values were associated with tumor recurrence, regardless of post therapy COG stage (p=0.007, p=0.04, and p=0.07, respectively).CONCLUSION: The extent of restricted diffusion within RMS and overlap of hypermetabolism plus restricted diffusion predict unfavorable clinical outcomes.

View details for PubMedID 30187233

View details for DOI 10.1158/1078-0432.CCR-18-0673

View details for Web of Science ID 000444040400008

Abstract

Purpose: A comprehensive analysis of the genomics of undifferentiated sarcomas (UDS) is lacking. We analyzed copy-number alterations and fusion status in patients with UDS prospectively treated on Children's Oncology Group protocol ARST0332.Experimental Design: Copy-number alterations were assessed by OncoScan FFPE Express on 32 UDS. Whole-exome and transcriptome libraries from eight tumors with sufficient archived material were sequenced on HiSeq (2 100 bp). Targeted RNA-sequencing using Archer chemistry was performed on two additional cases.Results: Five-year overall survival for patients with UDS was 83% (95% CI, 69%-97%) with risk-adapted therapy (surgery, chemotherapy, and radiotherapy). Both focal and arm-level copy-number alterations were common including gain of 1q (8/32, 25%) and loss of 1p (7/32, 22%), both of which occurred more often in clinically defined high-risk tumors. Tumors with both loss of 1p and gain of 1q carried an especially poor prognosis with a 5-year event-free survival of 20%. GISTIC analysis identified recurrent amplification of FGF1 on 5q31.3 (q = 0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q = 0.07). Known oncogenic fusions were identified in eight of 10 cases analyzed by next-generation sequencing.Conclusions: Pediatric UDS generally has a good outcome with risk-adapted therapy. A high-risk subset of patients whose tumors have copy-number loss of 1p and gain of 1q was identified with only 20% survival. Oncogenic fusions are common in UDS, and next-generation sequencing should be considered for children with UDS to refine the diagnosis and identify potentially targetable drivers. Clin Cancer Res; 24(16); 3888-97. 2018 AACR.

View details for PubMedID 29691299

Abstract

Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials. Patients and Methods Patients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m2) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m2) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided alpha-level) to detect an improved long-term EFS from 65% (with VAC) to 76% (with VAC/VI). Results A total of 448 eligible patients were enrolled in the study. At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year overall survival was 73% for VAC and 72% for VAC/VI ( P = .80). Within the ARMS and ERMS subgroups, no difference in outcome by treatment arm was found. Severe hematologic toxicity was less common with VAC/VI therapy. Conclusion The addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk RMS. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk RMS.

View details for PubMedID 30091945

View details for DOI 10.1200/JCO.2018.36.15_suppl.10546

View details for Web of Science ID 000442916003535

View details for DOI 10.1200/JCO.2018.36.15_suppl.e23551

View details for Web of Science ID 000442916007248

View details for DOI 10.1200/JCO.2018.36.15_suppl.10545

View details for Web of Science ID 000442916003534

View details for DOI 10.1200/JCO.2018.36.15_suppl.10566

View details for Web of Science ID 000442916003555

Abstract

Tumor associated macrophages (TAM) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with non-invasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults.In a first-in-patient, IRB-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (2 lymphoma, 3 bone sarcoma) underwent pre- and post-contrast MRI. Subsequently, 20 patients (10 lymphoma, 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24-48 hours after intravenous injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology.Significant ferumoxytol tumor enhancement was noted on post-contrast scans compared to pre-contrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05).Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies.

View details for PubMedID 29764855

Abstract

Indications for and delivery of adjuvant therapies for pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) have been derived largely from adult studies; therefore, significant concern remains regarding radiation exposure to normal tissue. The authors report long-term treatment outcomes and toxicities for pediatric and young adult patients with high-grade NRSTS who were treated on a prospective trial using limited-margin radiotherapy.Sixty-two patients (ages 3-22 years) with predominantly high-grade NRSTS requiring radiation were treated on a phase 2 institutional study of conformal external-beam radiotherapy and/or brachytherapy using a 1.5-cm to 2-cm anatomically constrained margin. The estimated cumulative incidence of local failure, Gray's method estimated cumulative incidence of local failure, Kaplan-Meier method estimated survival, competing-risk regression model determined predictors of disease outcome, and toxicity was reported according to CTCAE v2.0.At a median follow-up of 5.1 years (range, 0.2-10.9 years), 9 patients had experienced local failure. The 5-year overall cumulative incidence of local failure was 14.8% (95% confidence interval [CI], 7.2%-25%), and all but 1 local failure occurred outside the highest-dose irradiation volume. The 5-year Kaplan-Meier estimates for event-free and overall survival were 49.3% (95% CI, 36.3%-61.1%) and 67.9% (95% CI, 54.2%-78.3%), respectively. Multivariable analysis indicated that younger age was the only independent predictor of local recurrence (P=.004). The 5-year cumulative incidence of grade 3 or 4 late toxicity was 15% (95% CI, 7.2%-25.3%).The delivery of limited-margin radiotherapy using conformal external-beam radiotherapy or brachytherapy provides a high rate of local tumor control without an increase in marginal failures and with acceptable treatment-related morbidity. Cancer 2017;123:4419-29. 2017 American Cancer Society.

View details for PubMedID 28759114

View details for PubMedCentralID PMC5673566

View details for Web of Science ID 000408978203179

View details for DOI 10.1016/j.ijrobp.2017.06.080

View details for Web of Science ID 000411559106145

View details for Web of Science ID 000411324001076

Abstract

Multimodal risk-adapted treatment is used in paediatric protocols for synovial sarcoma (SS). Retrospective analyses suggest that low-risk SS patients can be safely treated with surgery alone, but no prospective studies have confirmed the safety of this approach. This analysis pooled data from the two prospective clinical trials to assess outcomes in SS patients treated with a surgery-only approach and to identify predictors of treatment failure.Patients with localised SS enrolled on the European paediatric Soft tissue sarcoma Study Group (EpSSG) NRSTS2005 and on the Children Oncology Group (COG) ARST0332 trials, treated with surgery alone were eligible for this analysis. Patients must have undergone initial complete resection with histologically free margins, with a grade 2 tumour of any size or a grade 3 tumour 5cm.Sixty patients under 21 years of age were eligible for the analysis; 36 enrolled in the COG (from 2007 to 2012) and 24 in the EpSSG study (from 2005 to 2012). The 3-year event-free survivalwas 90% (median follow-up 5.2 years, range 1.9-9.1). All eight events were local tumour recurrence, whereas no metastatic recurrences were seen. All patients with recurrence were effectively salvaged, resulting in 100% overall survival.This joint prospective analysis showed that patients with adequately resected 5cm SS, regardless of grade, can be safely treated with a surgery-only approach. Avoiding the use of adjuvant chemotherapy and radiotherapy in this low-risk patient population may decrease both short- and long-term morbidity and mortality.

View details for DOI 10.1016/j.ejca.2017.03.003

View details for PubMedID 28391003

View details for DOI 10.1200/JCO.2017.35.15_suppl.TPS10577

View details for Web of Science ID 000411932206127

Abstract

We present the case of a 15-year-old female with a right perineal mass that was found to be pleomorphic myxoid liposarcoma, a recently recognized, rare subtype of liposarcoma. The patient had a strong family history of malignancy and genetic screening revealed a pathogenic TP53 mutation consistent with Li-Fraumeni syndrome.

View details for DOI 10.1007/s00383-017-4063-x

View details for PubMedID 28160093

Abstract

Integrated PET/MRI is a hybrid imaging technique enabling clinicians to acquire diagnostic images for tumor assessment and treatment monitoring with both high soft tissue contrast and added metabolic information. Integrated PET/MRI has shown to be valuable in the clinical setting and has many promising future applications. The protocol presented here will provide step-by-step instructions for the acquisition of whole-body 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) PET/MRI data in children with cancer. It also provides instructions on how to combine a whole-body staging scan with a local tumor scan for evaluation of the primary tumor. The focus of this protocol is to be both comprehensive and time-efficient, which are two ubiquitous needs for clinical applications. This protocol was originally developed for children above 6 years, or old enough to comply with breath-hold instructions, but can also be applied to patients under general anesthesia. Similarly, this protocol can be modified to fit institutional preferences in terms of choice of MRI pulse sequences for both the whole-body scan and local tumor assessment.

View details for PubMedID 29286486

View details for Web of Science ID 000384818800434

View details for DOI 10.1016/j.ijrobp.2016.06.290

View details for Web of Science ID 000387655804603

Abstract

To determine the rate of local failure using focal conformal, limited margin radiation therapy (RT) and dose escalation for tumors 8cm (greatest dimension at diagnosis) in children and young adults with Ewing sarcoma (EWS).Eligible patients with EWS were treated on a phase 2 institutional trial of focal conformal, limited margin RT using conformal or intensity modulated techniques. The treatment volume incorporated a 1-cm constrained margin around the gross tumor. Unresected tumors, <8cm at diagnosis, received a standard dose of 55.8Gy and tumors 8cm, an escalated dose to 64.8Gy. Patients with microscopic residual disease after resection received adjuvant RT to 50.4Gy. Adjuvant brachytherapy was permitted in selected patients.Forty-five patients were enrolled: 26 with localized and 19 with metastatic disease. Median (range) age, tumor size, and follow-up were 13.0years (2.9-24.7years), 9.0cm (2.4-17.0cm), and 54.5months (1.9-122.2months), respectively. All patients received systemic chemotherapy. The median (range) RT dose for all patients was 56.1Gy (45-65.5 Gy). Seventeen patients received adjuvant, 16 standard-dose, and 12 escalated-dose RT. Failuresincluded 1 local, 10 distant, and 1 local/distant. The estimated 10-year cumulative incidence of local failure was 4.4%3.1%, with no statistical difference seen between RTtreatment groups and no local failures in the escalated-dose RT treatment group.Treatment with focal conformal, limited margin RT, including dose escalation for larger tumors, provides favorable local tumor control in EWS.

View details for DOI 10.1016/j.ijrobp.2016.04.001

View details for PubMedID 27319287

Abstract

Treatment of soft tissue tumors in young patients relies on the diagnostic information conveyed in the pathology report. We examined pathology reports from Children's Oncology Group ARST0332 for inclusion of data elements required in published guidelines.Pathology reports for 551 eligible patients were examined for required data elements defined by the College of American Pathologists, including tissue type, procedure, tumor site, tumor maximum diameter, macroscopic extent of tumor, histologic type, mitotic rate, extent of necrosis, tumor grade, margin status, use of ancillary studies, and pathologic stage.Only 65 (12%) of 551 reports included all required data elements. Of reports containing synoptic templates, 57% were complete.This study reveals significant opportunity to improve the quality of pathology reports in young patients with soft tissue tumors. Use of templates or checklists improves completeness of reports.

View details for DOI 10.1093/ajcp/aqw114

View details for PubMedID 27510717

Abstract

The relationship between treatment-related impairment of pulmonary function in adult survivors of childhood cancer and subsequent physical function has not been studied.In this prospective evaluation of 606 adult survivors of childhood cancer, we sought to determine the risk factors for, as well as the functional impact of, clinically ascertained pulmonary function impairment.We measured FEV1, FVC, total lung capacity (TLC), and single-breath diffusing capacity of the lung for carbon monoxide corrected for hemoglobin (DlCOcorr), expressing the results as percent predicted and lower limit of normal (LLN) values, and we also assessed functional exercise capacity (6-minute-walk distance). Lung radiation exposure was expressed as the estimated percentage of lung tissue that received at least 10 Gy (V10). Associations of clinical and treatment factors with pulmonary function measures were assessed using log-binomial regression to calculate relative risks and 95% confidence intervals.The participants' median age at evaluation was 34.2 years, and the median elapsed time from diagnosis was 21.9 years. Among the sample population, 50.7% had an FEV1 percent predicted less than 80%, 47.2% had an FVC percent predicted less than 80%, 31.2% had a TLC percent predicted less than 75%, and 44.6% had DlCOcorr percent predicted less than 75%. Also, 49.0% had FEV1 less than the LLN on the basis of the Global Lung Function Initiative (GLI) criteria, and 45.4% had FVC less than LLN. Obstructive lung defects (FEV1/FVC, <0.7) were found in 0.8%, but none had obstructive lung defects on the basis of the GLI criterion of FEV1/FVC less than the LLN. Restrictive lung defects (TLC, <75%) were found in 31.2% of participants. V10 and elapsed time since diagnosis were associated with abnormal FEV1 and FVC based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 criteria, and with abnormal FEV1 using the GLI criterion. Age at diagnosis was an additional risk factor for abnormal FVC based on the GLI criteria. Age at diagnosis and V10 were associated with abnormal TLC. Increased body mass index, V10, and elapsed time since diagnosis were risk factors for abnormal DlCOcorr. Abnormal pulmonary function tests were associated with decreased 6-minute walk distance.Impaired pulmonary function in adult survivors of childhood cancer is associated with decreased physical function. These patients may benefit from interventions designed to preserve and/or improve pulmonary function.

View details for DOI 10.1513/AnnalsATS.201601-022OC

View details for PubMedID 27391297

View details for DOI 10.1200/JCO.2016.34.15_suppl.10571

View details for Web of Science ID 000404712500364

View details for DOI 10.1200/JCO.2016.34.15_suppl.10549

View details for Web of Science ID 000404712500343

View details for DOI 10.14814/phy2.12755

View details for Web of Science ID 000380241200008

Abstract

Measuring glomerular filtration rate (GFR) by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as part of standard of care clinicalMRIexams (e.g., in pediatric solid tumor patients) has the potential to reduce diagnostic burden. However, enthusiasm for this relatively newGFRtest may be curbed by the limited amount of cross-calibration studies with referenceGFRtechniques and the vast variety ofMRtracer model algorithms causing confusion on the choice of model. To advanceMRI-basedGFRquantification via improvedGFRmodeling and comparison with associated(99m)Tc-DTPA-GFR, 29 long-term Wilms' tumor survivors (19.0-43.3years, [median 32.06.0years]) treated with nephrectomy, nonnephrotoxic chemotherapy radiotherapy underwentMRIwith Gd-DTPAadministration and a(99m)Tc-DTPA GFRtest. ForDCE-MRI-basedGFRestimation, a subject-specific two-compartment (SS-2C) model was developed that uses individual hematocrit values, automatically defines subject-specific uptake intervals, and fits tracer-uptake curves by incorporating these measures. The association between reference(99m)Tc-DTPA GFRandMR-GFRs obtained bySS-2C, three published 2C uptake, and inflow-outflow models was investigated via linear regression analysis. Uptake intervals varied from 64sec to 141sec [96sec21sec] and hematocrit values ranged from 30% to 49% [41%4%]; these parameters can therefore not be assumed as constants in 2C modeling. OurMR-GFRestimates using theSS-2C model showed accordingly the highest correlation with(99m)Tc-DTPA-GFRs (R(2)=0.76,P<0.001) compared with other models (R(2)-range: 0.36-0.66). In conclusion,SS-2C modeling ofDCE-MRIdata improved the association betweenGFRobtained by(99m)Tc-DTPAand Gd-DTPA DCE-MRIto such a degree that this approach could turn into a viable, diagnosticGFRassay without radiation exposure to the patient.

View details for PubMedID 27081161

Abstract

Mass spectrometry-based methods have been widely applied - often as the sole method - to detect mutations in human cancer specimens. We applied this approach to 52 childhood soft tissue sarcoma specimens in an attempt to identify potentially actionable mutations. This analysis revealed that 25% of the specimens harbored high-confidence calls for mutated alleles, including a mutation encoding FLT3(I836M) that was called in four cases. Given the surprisingly high frequency and unusual nature of some of the mutant alleles, we carried out ultra-deep next generation sequencing to confirm them. We confirmed only three mutations, which encoded NRAS(A18T), JAK3(V722I) and MET(R970C) in three specimens. Beyond highlighting those mutations, our findings demonstrate potential pitfalls of primarily utilizing a mass spectrometry-based approach to broadly screen for DNA sequence variants in archived, clinical-grade tumor specimens. Duplicate mass spectrometric analyses and confirmatory next generation sequencing can help diminish false positive calls, but this does not ameliorate potential false negatives due in part to evaluating a limited panel of sequence variants.

View details for DOI 10.1038/srep33429

View details for PubMedID 27642091

View details for PubMedCentralID PMC5027578

Abstract

The purpose of this article is to determine the MRI and CT features of low-grade fibromyxoid sarcoma in children.We retrospectively analyzed images of 11 pediatric patients with low-grade fibromyxoid sarcoma from a phase 3 clinical trial of nonrhabdomyosarcoma soft-tissue sarcoma (Children's Oncology Group Protocol ARST0332). MRI and CT were performed in 10 and four patients, respectively. Location, size, margin, and composition on imaging were correlated with pathologic findings.Tumors were located in the extremities in nine patients, and one tumor each was located in the tongue and lung. Tumors were deep in seven patients and superficial in four patients. All tumors were well defined, solitary, and nonmetastatic at presentation. Tumors were complex solid-cystic in eight patients and completely solid in three patients. On T1-weighted images, all tumors had at least some areas hypointense to muscles, and six had a split-fat sign. On STIR or T2-weighted images, eight tumors had areas hypointense to adjacent muscle, and eight tumors had fluid signal intensity. On contrast-enhanced MRI studies, eight tumors had thick enhancing internal septations, and three had peripheral nodular gyriform enhancement. When we correlated imaging to pathologic findings, areas with hypointense signal intensity on both T1- and T2-weighted images were likely related to fibrous component; areas with fluid signal intensity on T2-weighted images were likely related to myxoid component. On CT, all four tumors were hypodense to muscle, and one tumor showed punctate calcific foci.Low-grade fibromyxoid sarcoma is hypodense to muscle on CT. MRI may identify both fibrous and myxoid components of this rare pediatric soft-tissue sarcoma.

View details for DOI 10.2214/AJR.14.13972

View details for Web of Science ID 000358436000045

Abstract

The purpose of this article is to determine the MRI and CT features of low-grade fibromyxoid sarcoma in children.We retrospectively analyzed images of 11 pediatric patients with low-grade fibromyxoid sarcoma from a phase 3 clinical trial of nonrhabdomyosarcoma soft-tissue sarcoma (Children's Oncology Group Protocol ARST0332). MRI and CT were performed in 10 and four patients, respectively. Location, size, margin, and composition on imaging were correlated with pathologic findings.Tumors were located in the extremities in nine patients, and one tumor each was located in the tongue and lung. Tumors were deep in seven patients and superficial in four patients. All tumors were well defined, solitary, and nonmetastatic at presentation. Tumors were complex solid-cystic in eight patients and completely solid in three patients. On T1-weighted images, all tumors had at least some areas hypointense to muscles, and six had a split-fat sign. On STIR or T2-weighted images, eight tumors had areas hypointense to adjacent muscle, and eight tumors had fluid signal intensity. On contrast-enhanced MRI studies, eight tumors had thick enhancing internal septations, and three had peripheral nodular gyriform enhancement. When we correlated imaging to pathologic findings, areas with hypointense signal intensity on both T1- and T2-weighted images were likely related to fibrous component; areas with fluid signal intensity on T2-weighted images were likely related to myxoid component. On CT, all four tumors were hypodense to muscle, and one tumor showed punctate calcific foci.Low-grade fibromyxoid sarcoma is hypodense to muscle on CT. MRI may identify both fibrous and myxoid components of this rare pediatric soft-tissue sarcoma.

View details for DOI 10.2214/AJR.14.13972

View details for PubMedID 26204295

Abstract

The majority of intermediate-risk rhabdomyosarcoma (RMS) patients have gross residual disease (Group III) after their first operative procedure. It is currently not known if local control rates can be maintained when, following induction chemotherapy, the radiation therapy (RT) dose is decreased after a delayed primary excision (DPE). To answer this question we evaluated patients enrolled on COG D9803 (1999-2005) who had Group III tumors of the bladder dome, extremity or trunk (thorax, abdomen and pelvis) were candidates for DPE at Week 12 if the primary tumor appeared resectable. RT dose was then adjusted by the completeness of DPE: no evidence of disease 36 Gy, microscopic residual 41.4 Gy and gross residual disease (GRD) 50.4 Gy. A total of 161 Group III patients were evaluated (24 bladder dome, 63 extremity and 74 trunk). Seventy-three patients (45%) underwent DPE which achieved removal of all gross disease in 61 (84%) who were then eligible for reduced RT dose (43/73 received 36 Gy, 19/73 received 41.4 Gy). The local 5-year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) was similar to IRS-IV, which did not encourage DPE and did not allow for DPE adapted RT dose reduction. In conclusion, DPE was performed in 45% of Group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk) and 84% of those who had DPE were eligible for RT dose reduction. Local control outcomes were similar to historic results with RT alone.

View details for DOI 10.1002/ijc.29351

View details for Web of Science ID 000353297600020

View details for PubMedID 25418440

View details for PubMedCentralID PMC4474372

View details for Web of Science ID 000358036900016

View details for Web of Science ID 000358036900022

Abstract

The surgical treatment of malignant bone tumors involving the pelvis represents a great challenge in terms of local control. Internal hemipelvectomy is a major surgical procedure that involves the resection of the entire hemipelvis or of a portion of the hemipelvis with preservation of the ipsilateral extremity. The need for a bilateral internal hemipelvectomy is an extraordinary situation. We describe the case of an 11-year-old girl with a primary diagnosis of rhabdomyosarcoma of the bladder at the age of two years who subsequently developed a right pelvis osteosarcoma at the age of six years and a left pelvis osteosarcoma at the age of nine years. She ultimately underwent sequential bilateral internal hemipelvectomies and she postoperatively ambulates without an assist device.

View details for DOI 10.1016/j.otsr.2015.01.012

View details for Web of Science ID 000353977600022

View details for PubMedID 25817906

Abstract

Pre-clinical studies suggest that anti-angiogenic agents may be toxic to the developing growth plate. The purpose of this study was to evaluate the incidence of growth plate abnormalities in children with refractory cancer undergoing anti-angiogenic therapy.Targeted radiographic studies from 53 subjects enrolled on six separate Children's Oncology Group Phase 1 and Pilot Consortium clinical trials evaluating new anti-cancer agents interfering with angiogenesis were reviewed. Subjects received tyrosine kinase inhibitors with anti-angiogenic effects (n = 35), monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (n = 13), or angiopoietin (n = 5). Radiographs of their distal femur/proximal tibia were obtained at baseline. Follow-up radiographs were obtained after odd-numbered treatment cycles in patients with open growth plates who did not experience disease progression prior to cycle 3.Baseline and follow-up growth plate radiographs were acquired in 48/53 (90%) of patients. Five patients (9.4%), all of whom received a specific VEGF/VEGFR blocking agent (sunitinib [n = 1] or pazopanib [n = 4]), had growth plate abnormalities. Four patients had growth plate widening that was apparent on at least two successive radiographs, but was not confirmed by MRI. The fifth patient had progressive growth plate widening and evidence of physeal cartilage hypertrophy on MRI. Subsequent off treatment radiographs showed that the growth plate changes were reversible.Growth plate abnormalities occur in a small, but relevant number of patients undergoing anti-angiogenic therapy. These results support the need for growth plate monitoring in children with open growth plates who are receiving anti-angiogenic therapy, and for improved methods to assess toxicity of anti-angiogenic agents to the developing skeleton.

View details for DOI 10.1002/pbc.25229

View details for Web of Science ID 000345319300010

View details for PubMedCentralID PMC4237627

Abstract

Oxaliplatin, although related to cisplatin and carboplatin, has a more favorable toxicity profile and may offer advantages in combination regimens. We combined oxaliplatin, ifosfamide, and etoposide (IOE) and estimated the regimen's maximum tolerated dose (MTD) in children with refractory solid tumors. Dose-limiting toxicity (DLT) and MTD were assessed at 3 dose levels in a 21-day regimen: day 1, oxaliplatin 130 mg/m (consistent dose); days 1 to 3, ifosfamide 1200 mg/m/d (level 0) or 1500 mg/m/d (levels 1 and 2) and etoposide 75 mg/m/d (levels 0 and 1) or 100 mg/m/d (level 2). Course 1 filgrastim/pegfilgrastim was permitted after initial DLT determination, if neutropenia was dose limiting. Seventeen patients received 59 courses. Without filgrastim (n=9), DLT was neutropenia in 2 patients at dose level 1. No DLT was observed after adding filgrastim (n=8). There was no ototoxicity, nephrotoxicity >grade 1, or neurotoxicity >grade 2. One patient experienced a partial response and 9 had stable disease after 2 courses. In conclusion, the IOE regimen was well tolerated. Without filgrastim, neutropenia was dose limiting with MTD at ifosfamide 1200 mg/m/d and etoposide 75 mg/m/d. The MTD with filgrastim was not defined due to early study closure. Filgrastim allowed ifosfamide and etoposide dose escalation and should be included in future studies.

View details for Web of Science ID 000346633800003

View details for PubMedID 24942022

Abstract

Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution.Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated.Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%0.7% and 4.6%1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome.Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.

View details for Web of Science ID 000346633800002

View details for PubMedID 24633303

Abstract

The history, prognostic factors, and outcome of young patients with head and neck non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) have not been adequately characterized.Medical records of 58 patients with head and neck NRSTS treated at St. Jude Children's Research Hospital were reviewed.The majority of tumors were 5 cm and high grade. Lymph node and/or distant metastases were present in 17% at presentation. Patients received a combination of surgery, chemotherapy, and radiotherapy. The 10-year event-free and survival rates were 53.1%7.3% and 63.2%7.1%, respectively. Features associated with inferior survival included high histologic grade (p=.006), tumor diameter >5 cm (p < .001), invasiveness (p < .001), and incomplete resection at diagnosis (p=.005).Most head and neck NRSTS in young patients are small, high grade, and nonmetastatic. The outcome is poor compared to NRSTS at other anatomic sites. Innovative approaches to local control and improved systemic therapy are needed.

View details for DOI 10.1002/hed.23564

View details for Web of Science ID 000346252200015

View details for PubMedID 24327514

Abstract

There are few studies in the literature regarding the imaging features of alveolar soft-part sarcoma (ASPS). We performed a comprehensive assessment of the imaging characteristics of this rare tumor to determine whether there are features that suggest the diagnosis.Twenty-two subjects with ASPS underwent pretherapy imaging as part of enrollment in Children's Oncology Group protocol ARST0332 for the treatment of nonrhabdomyosarcoma soft-tissue sarcomas: 16 patients underwent MRI; three, CT; and three, both MRI and CT. Two radiologists retrospectively reviewed the imaging studies by consensus and recorded tumor location, size, contour, internal architecture, signal characteristics, presence of flow voids, and enhancement patterns.The 12 females and 10 males in the study group ranged in age from 8 to 23 years 7 months (mean, 15 years 8 months). The most common anatomic site was the lower extremity (12/22, 55%) followed by the upper extremity (4/22, 18%). The maximal tumor diameter ranged from 2.3 to 20.0 cm (median, 5.9 cm). All tumors imaged with MRI had flow voids (19/19, 100%), and 19 (19/22, 86%) had large peripheral vessels, lobulated margins, and nodular internal architecture. Unenhanced T1-weighted MRI was available for 18 tumors: 14 (14/18, 78%) appeared slightly hyperintense to muscle. Of the 16 tumors imaged with contrast material, 11 (11/16, 69%) showed intense enhancement and five (5/16, 31%), moderate enhancement. Six tumors (6/16, 38%) had a thick enhancing peripheral rim with a nonenhancing center consistent with necrosis.The imaging features of ASPS include flow voids, large peripheral vessels, internal nodularity, and lobulated margins. Contrast administration produces intense to moderate enhancement, sometimes with a thick enhancing peripheral rim around central necrosis. Extremity tumors with these imaging features in a child or young adult should suggest the diagnosis of ASPS.

View details for DOI 10.2214/AJR.14.12462

View details for Web of Science ID 000347527500050

View details for PubMedID 25415714

Abstract

Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer.We did semen analysis on 214 adult male survivors of childhood cancer (median age 77 years [range 001-203] at diagnosis, 290 years [184-561] at assessment, and a median of 210 years [105-416] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling.Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration 15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m(2) were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=-037, p<00001). Mean CED was 10830 mg/m(2) (SD 7274) in patients with azoospermia, 8480 mg/m(2) (4264) in patients with oligospermia, and 6626 mg/m(2) (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m(2) CED for azoospermia (OR 122, 95% CI 111-134), and for oligospermia (114, 104-125), but age at diagnosis and age at assessment were not.Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m(2). Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services.US National Cancer Institute, American Lebanese Syrian Associated Charities.

View details for DOI 10.1016/S1470-2045(14)70408-5

View details for Web of Science ID 000343096800047

View details for PubMedCentralID PMC4192599

Abstract

Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer.We did semen analysis on 214 adult male survivors of childhood cancer (median age 77 years [range 001-203] at diagnosis, 290 years [184-561] at assessment, and a median of 210 years [105-416] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling.Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration 15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m(2) were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=-037, p<00001). Mean CED was 10830 mg/m(2) (SD 7274) in patients with azoospermia, 8480 mg/m(2) (4264) in patients with oligospermia, and 6626 mg/m(2) (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m(2) CED for azoospermia (OR 122, 95% CI 111-134), and for oligospermia (114, 104-125), but age at diagnosis and age at assessment were not.Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m(2). Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services.US National Cancer Institute, American Lebanese Syrian Associated Charities.

View details for DOI 10.1016/S1470-2045(14)70408-5

View details for PubMedID 25239573

View details for PubMedCentralID PMC4192599

View details for Web of Science ID 000358613204547

View details for Web of Science ID 000358613204549

View details for Web of Science ID 000358613204543

Abstract

Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.

View details for DOI 10.1016/j.ccr.2013.11.002

View details for Web of Science ID 000328443200006

View details for PubMedID 24332040

View details for PubMedCentralID PMC3904731

Abstract

Pediatric desmoid tumors (PDTs) represent a group of rare, distinct lesions. While sparse, available literature suggests that PDT are particularly aggressive and difficult to control when compared with their adult counterpart.A retrospective review identified 39 patients who underwent treatment of PDT at St. Jude Children's Research Hospital over a 12-year period. Clinicopathologic and treatment characteristics were analyzed to identify predictors of outcome.A total of 39 patients were treated during the study period, with a total number of 67 resections. Median age was 12.2years; 49% of patients were male, and 51% were female. Median tumor size was 9.8cm. PDT most commonly arose in the extremities (40%), thorax (23%), head and neck (21%), and trunk (16%). Also, 18% of resections had negative margins (R0), 48% were microscopic positive (R1), and 30% were macroscopic positive (R2). The 1- and 5-year recurrence-free survival (RFS) was 97.1 and 73.1%, respectively. Factors associated with worse RFS were patient age>12years (HR=5.08, p=0.038) and tumor size>5cm (HR=1.22, p=0.0597). Margin status did not affect RFS. Selective use of radiation therapy appeared to improve RFS.Our study suggests that margin status alone at the time of extirpation is not a predictor of ultimate cure or likelihood of recurrence. Many patients received adjuvant therapy, with benefits suggested after analysis. For patients with PDT, surgical extirpation should not come at the expense of functional preservation, as overall survival is excellent.

View details for DOI 10.1245/s10434-013-3090-7

View details for Web of Science ID 000324060100007

View details for PubMedID 23838914

Abstract

To simplify the recommended staging evaluation by correlating tumor and clinical features with patterns of distant metastasis in newly diagnosed patients with embryonal rhabdomyosarcoma (ERMS) or alveolar rhabdomyosarcoma (ARMS).Patient data from the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group over two periods were analyzed: 1991 to 1997 and 1999 to 2004. We used recursive partitioning analyses to identify factors (including histology, age, regional nodal and distant metastatic status, tumor size, local invasiveness, and primary site) that divided patients into subsets with the most different rates of metastatic disease.Of the 1,687 patients analyzed, 5.7% had lung metastases, 4.8% had bone involvement, and 6% had bone marrow (BM) involvement. Rhabdomyosarcoma (RMS) without local invasion (T1) had a low rate of metastasis for all distant sites, especially ERMS (0% bone, 0% BM). ARMS with local invasion (T2) had a higher rate of metastasis for all distant sites (13% lung, 18% bone, 23% BM). ERMS, T2 also had a higher rate of metastatic lung involvement (9%). The likelihood of bone or BM involvement increased in the presence of lung metastases (41% with, 6% without). Regional nodal metastases (N1) predicted a high rate of metastasis in all distant sites (14% lung, 14% bone, 18% BM). A staging algorithm was developed.Staging studies in childhood RMS can be tailored to patients' presenting characteristics. Bone marrow aspirate and biopsy and bone scan are unnecessary in at least one third of patients with RMS.

View details for DOI 10.1200/JCO.2012.44.6476

View details for Web of Science ID 000330541000012

View details for PubMedID 23940218

View details for PubMedCentralID PMC3757291

Abstract

To ascertain prevalence of peripheral sensory and motor neuropathy, and to evaluate impairments in relation to function.St. Jude Lifetime Cohort Study, a clinical follow-up study designed to evaluate adverse late effects in adult survivors of childhood cancer.A children's research hospital.Eligibility required treatment for an extracranial solid malignancy between 1962 and 2002, age 18 years, 10 years postdiagnosis, and no history of cranial radiation. Survivors (N=531) were included in the evaluation with a median age of 32 years and a median time from diagnosis of 25 years.Not applicable.Primary exposure measures were cumulative doses of vinca-alkaloid and platinum-based chemotherapies. Survivors with scores 1 on the sensory subscale of the Modified Total Neuropathy Score were classified with prevalent sensory impairment. Those with sex-specific z scores of -1.3 for dorsiflexion strength were classified with prevalent motor impairment. Participants completed the 6-minute walk test (endurance), the Timed Up & Go test (mobility), and the Sensory Organization Test (balance).The prevalence of sensory and motor impairment was 20% and 17.5%, respectively. Vinca-alkaloid exposure was associated with an increased risk of motor impairment (adjusted odds ratio [OR]=1.66; 95% confidence interval [CI], 1.04-2.64) without evidence for a dose response. Platinum exposure was associated with increased risk of sensory impairment (adjusted OR=1.62; 95% CI, .97-2.72) without evidence of a dose response. Sensory impairment was associated with poor endurance (OR=1.99; 95% CI, .99-4.0) and mobility (OR=1.65; 95% CI, .96-2.83).Vincristine and cisplatin exposure may increase risk for long-term motor and sensory impairment, respectively. Survivors with sensory impairment are at increased risk for functional performance limitations.

View details for DOI 10.1016/j.apmr.2013.03.009

View details for Web of Science ID 000322801600004

View details for PubMedID 23537607

View details for PubMedCentralID PMC3929944

Abstract

Over the past decade, PET-CT has been used to assess rhabdomyosarcoma (RMS) in children. However, the role of PET-CT in staging RMS is unknown.Thirty subjects with RMS, median age 7.3 years, underwent PET-CT before therapy. PET-CTs and conventional imaging (CI) were independently reviewed by two radiologists and two nuclear medicine physicians to determine the presence of metastases. Accuracy, sensitivity, and specificity of PET-CT for detecting metastases were compared to CI using biopsy and clinical follow-up as reference standards. Maximum standardized uptake values (SUV(max)) of primary tumors, lymph nodes, and pulmonary nodules were measured.Primary tumors had an average SUV(max) of 7.2 (range, 2.5-19.2). Accuracy rates for 17 subjects with nodal disease were 95% for PET-CT and 49% for CI. PET-CT had 94% sensitivity and 100% specificity for nodal disease. Of seven pulmonary nodules detected by CI, three were not identified by PET-CT, two were indeterminate, and one was malignant with a SUV(max) (3.4) > twice that of benign nodules. Two subjects had bone disease; both were identified by PET-CT but only one by CI. Four subjects had bone marrow disease, two had positive PET-CTs but none had positive CI. Two subjects had soft tissue metastases detected by PET-CT but not CI.PET-CT performed better than CI in identifying nodal, bone, bone marrow, and soft tissue disease in children with RMS. CI remains essential for detection of pulmonary nodules. We recommend PET-CT for staging of children with RMS. CI with Tc(99m) bone scan can be eliminated.

View details for DOI 10.1002/pbc.24430

View details for Web of Science ID 000319361300020

View details for PubMedID 23255260

View details for PubMedCentralID PMC4266929

Abstract

Children with solid tumors, most of which are malignant, have an excellent prognosis when treated on contemporary regimens. These regimens, which incorporate chemotherapeutic agents and treatment modalities used for many decades, have evolved to improve relapse-free survival and reduce long-term toxicity. This review discusses the evolution of the treatment regimens employed for management of the most common solid tumors, emphasizing the similarities between contemporary and historical regimens. These similarities allow the use of historical patient cohorts to identify the late effects of successful therapy and to evaluate remedial interventions for these adverse effects.

View details for DOI 10.1002/pbc.24487

View details for Web of Science ID 000319361300013

View details for PubMedID 23418018

View details for PubMedCentralID PMC3810072

Abstract

Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children's Oncology Group.Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging.Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10-18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23-0.48) and 96%, respectively. All three deaths were due to progressive DT.Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates.

View details for DOI 10.1002/pbc.24457

View details for Web of Science ID 000319361300016

View details for PubMedID 23281268

View details for PubMedCentralID PMC4646066

Abstract

In the US, approximately 850-900 children are diagnosed each year with soft tissue sarcomas (STS). Key findings from recent Children's Oncology Group (COG) clinical trials include safe reduction in therapy for low risk rhabdomyosarcoma (RMS), validation of FOXO1 fusion as a prognostic factor, a modest improvement in outcome for high-risk RMS, and a biologically designed non-cytotoxic therapy for pediatric desmoid tumor. Planned Phase 2 trials include targeted agents for VEGF/PDGF, mTOR, and IGF-1R for children with RMS and VEGF for children with non-RMS STS (NRSTS). For RMS, COG Phase 3 trials potentially will explore VEGF/mTOR inhibition or chemotherapy interval compression. For NRSTS, a COG Phase 3 trial will explore VEGF inhibition.

View details for DOI 10.1002/pbc.24435

View details for Web of Science ID 000317934800029

View details for PubMedID 23255356

View details for PubMedCentralID PMC3777409

View details for Web of Science ID 000335419605357

Abstract

Many male survivors of childhood cancer are at risk for azoospermia. Although both the levels of follicle-stimulating hormone (FSH) and inhibin B are correlated with sperm concentration, their ability to predict azoospermia in survivors of childhood cancer remains uncertain.Semen analysis was performed and serum levels of FSH and inhibin B were measured in 275 adult male survivors of childhood cancer who had received gonadotoxic therapy. Receiver operating characteristic (ROC) analysis was performed to determine the optimal inhibin B and FSH values for identifying patients with azoospermia. The patient sample was divided into a learning set and a validation set. Sensitivity, specificity, and positive and negative predictive value were calculated.Inhibin B was dichotomized as 31 ng/L or more than 31 ng/L and FSH was dichotomized as 11.5 mIU/mL or more than 11.5 mIU/mL based on results of the ROC analysis. Using these values, the specificity of the serum level of inhibin B for identifying azoospermic survivors was 45.0%, and the positive predictive value was 52.1%. The specificity for FSH was 74.1%, and the positive predictive value was 65.1%.Neither serum inhibin B nor FSH is a suitable surrogate for determination of sperm concentration in a semen sample. Young men and their physicians should be aware of the limitations of these measures for assessment of fertility potential.

View details for DOI 10.1200/JCO.2012.43.7038

View details for Web of Science ID 000317003300020

View details for PubMedID 23423746

View details for PubMedCentralID PMC3607671

Abstract

More than 13,000 children annually in the United States and Canada under the age of 20 will be diagnosed with cancer at a mortality approaching 20% 1,2. Tumor samples obtained by autopsy provide an innovative way to study tumor progression, potentially aiding in the discovery of new treatments and increased survival rates. The purpose of this study was to identify barriers to autopsies and develop guidelines for requesting autopsies for research purposes.Families of children treated for childhood cancer were referred by patient advocacy groups and surveyed about attitudes and experiences with research autopsies. From 60 interviews, barriers to autopsy and tumor banking were identified. An additional 14 interviews were conducted with medical and scientific experts.Ninety-three percent of parents of deceased children did or would have consented to a research autopsy if presented with the option; however, only half of these families were given the opportunity to donate autopsy tissue for research. The most significant barriers were the physicians' reluctance to ask a grieving family and lack of awareness about research opportunities.The value of donating tumor samples to research via an autopsy should be promoted to all groups managing pediatric cancer patients. Not only does autopsy tumor banking offer a potentially important medical and scientific impact, but the opportunity to contribute this Legacy Gift of autopsy tumor tissue also creates a positive outlet for the grieving family. Taking these findings into account, our multidisciplinary team has developed a curriculum addressing key barriers.

View details for DOI 10.1002/pbc.24320

View details for PubMedID 23015377

Abstract

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors.Sorafenib dose was escalated from 90 to 110 mg/m(2) twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m(2) daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was of 21 days. Pharmacokinetics and pharmacodynamics studies were conducted during the first course.Nineteen patients (11 males; median age, 9.2 years) received a median of four courses (range, 1-23). DLTs during course 1 included grade 3 rash (two), increased lipase (one), anorexia (one), and thrombus (one). With an additional 71 courses of therapy, the most common toxicities grade 3 included neutropenia (nine), lymphopenia (nine), and rashes (four). Five of 17 evaluable patients had partial tumor responses, and five had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m(2). Median day 1 sorafenib apparent oral clearance was 44 and 39 mL/min/m(2) at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGF receptor 2 (VEGFR2) was inversely correlated with sorafenib steady-state concentrations (P = 0.019).The recommended phase II doses are sorafenib, 90 mg/m(2) twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m(2) once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation.

View details for DOI 10.1158/1078-0432.CCR-12-1897

View details for Web of Science ID 000313051100025

View details for PubMedID 23143218

View details for PubMedCentralID PMC3537913

Abstract

Dermatofibrosarcoma protuberans (DFSP) is defined as a low-grade sarcoma derived from an uncertain cell of origin in the reticular dermis. We report a fibrosarcomatous variant of DFSP (FS-DFSP) that arose primarily in the deep thoracic soft tissue. The patient was a 9-year-old girl who presented with dyspnea and low-grade fevers without a clinically detectable mass or a history of skin lesion. Imaging studies revealed a 10-cm mass entirely confined within the thoracic cavity. Three years after a marginal excision with adjuvant chemotherapy and radiotherapy, the tumor recurred in the paraspinal region. Histologically, the primary and recurrent tumors comprised a high-grade spindle cell sarcoma, with a small component of storiform, low-grade, CD34-positive spindle cells, classic for an ordinary DFSP. The diagnosis of FS-DFSP was confirmed molecularly by the demonstration of a COL1A1-PDGFB fusion by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction analyses. To our knowledge, this is the first documented case of a genetically confirmed deep-seated DFSP without an associated superficial soft tissue or dermal component. The implication of this case on expanding the clinical spectrum of DFSP will have to be elucidated in future studies by applying molecular pathologic tools in deep-seated sarcomas in the proper morphologic context.

View details for DOI 10.1097/PAS.0b013e31826b7919

View details for Web of Science ID 000311233500019

View details for PubMedID 23108023

Abstract

Our objective was to evaluate the association between low bone mineral density (BMD) and incidental renal stones among long-term survivors of childhood acute lymphoblastic leukemia (ALL).Adult participants who were 10+years from their childhood ALL diagnosis and members of the St. Jude Lifetime Cohort study were recruited between December 2007 and March 2011. During their risk-based medical evaluations, they underwent quantitative computed tomography (QCT) to evaluate BMD. Incidental renal stones were identified by radiologists' review of axial QCT source images. Demographic and dietary information were abstracted from health surveys and the Block Food Frequency questionnaire, respectively. The multivariable logistic regression model was used for analysis.At a median of 26.1years from diagnosis, BMD Z scores were -2 in 34 of 662 (5.2%) and renal stones detected in 73 of 662 (11%) participants. Adjusted for age, renal radiation, dietary vitamin D, gender, and body mass index, when compared to those with BMD Z scores 0, the risk of renal stones was increased among those with BMD Z scores -2 (odds ratio [OR], 2.92; 95% confidence interval [CI] 1.14-7.48). Risk of renal stones significantly increased for older age (45-54 vs.18-24years; OR, 3.70; 95% CI 1.11-12.35) whereas the risk was higher but nonsignificant for >141.5IU (sample median) daily intake of vitamin D (OR, 1.64; 95% CI 0.98-2.75).Older ALL survivors with BMD Z scores -2 are at risk for renal stones and should be counseled so that appropriate follow-up care can be provided for those among whom renal stones are detected.

View details for DOI 10.1007/s11764-012-0241-y

View details for Web of Science ID 000311534600005

View details for PubMedID 22956305

View details for PubMedCentralID PMC3529472

Abstract

In this single-site study, we evaluated the feasibility of a parent-clinician communication intervention designed to: identify parents' rationale for the phase I, do-not-resuscitate (DNR), or terminal care decision made on behalf of their child with incurable cancer; identify their definition of being a good parent to their ill child; and provide this information to the child's clinicians in time to be of use in the family's care.Sixty-two parents of 58 children and 126 clinicians participated. Within 72 hours after the treatment decision, parents responded to 6 open-ended interview questions and completed a 10-item questionnaire about the end-of-life communication with their child's clinicians. They completed the questionnaire again two to three weeks later and responded to three open-ended questions to assess the benefit:risk ratio of their study participation three months after the intervention. Clinicians received the interview data within hours of the parent interview and evaluated the usefulness of the information three weeks later.All preestablished intervention feasibility criteria were met; 77.3% of families consented; and in 100% of interventions, information was successfully provided individually to 3 to 11 clinicians per child before the child died. No harm was reported by parents as a result of participating; satisfaction and other benefits were reported. Clinicians reported moderate to strong satisfaction with the intervention.The communication intervention was feasible within hours of decision making, was acceptable and beneficial without harm to participating parents, and was acceptable and useful to clinicians in their care of families.

View details for DOI 10.1089/jpm.2012.0006

View details for Web of Science ID 000307095200014

View details for PubMedID 22734685

View details for PubMedCentralID PMC3396144

View details for PubMedID 22006470

Abstract

Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome between black and white pediatric patients.In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Children's Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007.Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Children's Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period.With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.

View details for DOI 10.1200/JCO.2011.40.8617

View details for Web of Science ID 000304596800023

View details for PubMedID 22547602

View details for PubMedCentralID PMC3383176

Abstract

Fanconi anemia (FA) is characterized by progressive marrow failure, congenital anomalies, and predisposition to malignancy. Biallelic FANCD1/BRCA2 mutations are the genetic basis of disease in a small proportion of children with FA with earlier onset and increased incidence of leukemia and solid tumors. Patients with FA have increased sensitivity to chemotherapy and radiation, and upon development of a solid tumor, require modification of these therapies. We report clinical and molecular features of three patients with FA associated with FANCD1/BRCA2 mutations, including two novel mutations, and discuss treatment of malignancy and associated side effects in this particularly vulnerable group.

View details for DOI 10.1002/pbc.23168

View details for Web of Science ID 000298953700027

View details for PubMedID 21548014

Abstract

Although whole lung irradiation is used to treat pulmonary metastases of pediatric solid malignancies, few studies have addressed its long-term pulmonary consequences.The authors conducted a retrospective study of longitudinal changes in 171 pulmonary function tests (PFTs) and their relation with clinical features in 48 survivors of pediatric malignant solid tumors treated with whole lung irradiation.Although active respiratory symptoms were seen in only 9 patients (18.8%), abnormalities in forced vital capacity (FVC; 58.3%), forced expiratory volume in 1 second (FEV(1) ; 64.6%), total lung capacity (TLC; 72.9%), and diffusion capacity of the lung for carbon monoxide corrected for hemoglobin (DLCO(corr) ; 70.8%) were common. At a median follow-up of 9.7 years after whole lung irradiation, FVC, FEV(1) , and TLC significantly declined longitudinally (P = .04, .03, and .02, respectively). Focal pulmonary boost irradiation was significantly associated with abnormal FEV(1) /FVC (P = .03), forced expiratory flow between 25% and 75% forced vital capacity (P = .005), residual volume (RV; P = .005), and RV/TLC (P = .002). Ten patients had baseline PFTs, and FVC, FEV(1) , TLC, and DLCO(corr) worsened immediately after radiation, followed by transient improvement but subsequent decline. Thirteen of 32 (40.6%) patients aged >18 years were smokers.Pulmonary dysfunction was prevalent after whole lung irradiation and worsened over time, although most patients were asymptomatic. Boost irradiation impaired pulmonary function, and a significant proportion of patients were smokers. Further studies are planned to assess the predictors and clinical consequences of progressive PFT abnormalities and to evaluate educational interventions.

View details for DOI 10.1002/cncr.26371

View details for Web of Science ID 000300667800033

View details for PubMedID 21800284

View details for PubMedCentralID PMC3233655

Abstract

Patients aged >10 years with rhabdomyosarcoma have an inferior outcome compared with patients ages 1 to 9 years, which may be explained by toxicities (adverse events [AEs]) that result in chemotherapy dose reductions.AEs observed during 1 of 3 randomized chemotherapy regimens (vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide [VAI]; or vincristine, ifosfamide, and etoposide [VIE]) in the Fourth Intergroup Rhabdomyosarcoma Study were recorded. The incidence of toxicities by age and treatment regimen was determined. The odds of developing AEs in a particular age group (ages 5-9 years, 10-14 years, and 15-20 years) were compared with the odds in the control group of patients ages 1 to 4 years.In total, 657 patients were eligible for analysis. The estimated 5-year event-free survival rates were 78%, 83%, 67%, and 58% for the groups ages 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 20 years, respectively. Patients ages 15 to 20 years experienced less neutropenia (odds ratio [OR], 0.43; P < .0001), thrombocytopenia (OR, 0.41; P < .0001), anemia (OR, 0.34; P < .0001), and infection (OR, 0.41; P < .0001) compared with younger patients, although they received similar amounts of chemotherapy. In contrast, peripheral nervous system toxicity was higher in adolescents aged >10 years (OR, 4.18; P < .0001). Females experienced more neutropenia (OR, 1.28; P = .05) and thrombocytopenia (OR, 1.26; P = .06) compared with males.Adolescents who received treatment for rhabdomyosarcoma experienced significantly less hematologic toxicity and more peripheral nervous system toxicity compared with younger children despite receiving similar amounts of chemotherapy. Although outcomes were inferior in adolescents, it was unclear whether the differences in toxicity observed in the current study had an impact on outcome. The authors concluded that future studies examining the age-related and sex-related differences in pharmacokinetics of chemotherapy are necessary.

View details for DOI 10.1002/cncr.26358

View details for Web of Science ID 000299834300032

View details for PubMedID 21761400

View details for PubMedCentralID PMC4008942

Abstract

To investigate the relationship between jaw function, patient and treatment variables, and radiation dosimetry of the mandibular muscles and joints in children and young adults receiving radiation for soft-tissue and bone sarcomas.Twenty-four pediatric and young adult patients with head-and-neck sarcomas were treated on an institutional review board-approved prospective study of focal radiation therapy for local tumor control. Serial jaw depression measurements were related to radiation dosimetry delivered to the medial and lateral pterygoid muscles, masseter muscles, and temporomandibular joints to generate mathematical models of jaw function.Baseline jaw depression was only influenced by the degree of surgical resection. In the first 12 weeks from initiation of radiation, surgical procedures greater than a biopsy, administration of cyclophosphamide containing chemotherapy regimes, and large gross tumor volumes adversely affected jaw depression. Increasing dose to the pterygoid and masseter muscles above 40 Gy predicted loss of jaw function over the full course of follow-up.Clinical and treatment factors are related to initial and subsequent jaw dysfunction. Understanding these complex interactions and the affect of specific radiation doses may help reduce the risk for jaw dysfunction in future children and young adults undergoing radiation therapy for the management of soft-tissue and bone sarcomas.

View details for DOI 10.1016/j.ijrobp.2010.09.031

View details for Web of Science ID 000298526100052

View details for PubMedID 21093167

View details for PubMedCentralID PMC3117097

Abstract

The youngest case of endometrial carcinoma in the English literature Endometrial cancer is diagnosed in approximately 13-19% of women with Cowden Syndrome. Screening guidelines should follow that of Lynch Syndrome.

View details for PubMedID 24371656

Abstract

A phase II study of temsirolimus was conducted in children and adolescents with high-grade glioma, neuroblastoma or rhabdomyosarcoma.Temsirolimus 75 mg/m(2) was administered once weekly until disease progression or intolerance. Using the Simon 2-stage design, further enrolment in each disease cohort required 2 objective responses within the first 12 weeks for the first 12 evaluable patients (those who received 3 temsirolimus doses).Fifty-two heavily pretreated patients with relapsed (12%) or refractory (88%) disease, median age 8 years (range 1-21 years), were enroled and treated. One patient with neuroblastoma achieved confirmed partial response within the first 12 weeks; thus, none of the 3 cohorts met the criterion for continued enrolment. Disease stabilisation at week 12 was observed in 7 of 17 patients (41%) with high-grade glioma (5 diffuse pontine gliomas, 1 glioblastoma multiforme and 1 anaplastic astrocytoma), 6 of 19 (32%) with neuroblastoma and 1 of 16 (6%) with rhabdomyosarcoma (partial response confirmed at week 18). In the three cohorts, median duration of stable disease or better was 128, 663 and 75 d, respectively. The most common treatment-related adverse events were thrombocytopaenia, hyperlipidaemia and aesthenia. Pharmacokinetic findings were similar to those observed in adults.Temsirolimus administered weekly at the dose of 75 mg/m(2) did not meet the primary objective efficacy threshold in children with high-grade glioma, neuroblastoma or rhabdomyosarcoma; however, meaningful prolonged stable disease merits further evaluation in combination therapy.

View details for DOI 10.1016/j.ejca.2011.09.021

View details for Web of Science ID 000300199800013

View details for PubMedID 22033322

View details for PubMedCentralID PMC3539305

Abstract

Soft tissue sarcomas (STS) are a heterogeneous group of mesenchymal malignancies that occur throughout the lifespan. The impact of age on disease features and outcome is unclear.We analyzed the clinical features and outcome of all STS cases registered between 1973 and 2006 in the SEER database.There were 48,012 cases that met the selection criteria. Individuals less than 20 years of age represented 5.6%, with rhabdomyosarcoma being the most common subtype. In adults, the most common types were Kaposi sarcoma, fibrohistiocytic tumors, and leiomyosarcoma. Rhabdomyosarcoma was the only entity with a median age <20 years. Male predominance (male/female of 1.5:1) was noticed for almost all types of STS, except for alveolar soft part sarcoma and leiomyosarcoma. Tumor stage was similar across different age groups. Younger patients (<50 years) had significantly better survival than older patients (88.8 0.2% vs. 40 0.3%, P < 0.001), but for most histologies the survival decline with advancing age was gradual and did not occur abruptly at the onset of adulthood. The decline in survival with advancing age was particularly significant for rhabdomyosarcoma.With few exceptions, the clinical features of STS are similar in children and adults. However, individuals over 50 years of age have an inferior survival.

View details for DOI 10.1002/pbc.23252

View details for Web of Science ID 000295257700010

View details for PubMedID 21793180

View details for PubMedCentralID PMC4261144

Abstract

There are limited data regarding the differences in clinical presentation and outcome of liposarcomas between adult and pediatric patients. The role of adjuvant radiotherapy in the treatment of childhood liposarcoma is unclear.A multi-institutional retrospective analysis of medical records was performed for patients 21 years of age presenting with a verified histologic diagnosis of liposarcoma.Thirty-three patients were evaluable for this study, 23 of whom were male. Median age was 17.2 years. Twenty-four cases were myxoid subtype and 7 were pleomorphic subtype. In myxoid cases, 17 (71%) presented with extremity tumors; none had metastases. Eleven of these patients with myxoid subtype were treated with surgery only, seven with surgery + radiation, three with surgery + radiation + chemotherapy. Median radiation therapy dose for patients with myxoid tumors was 60 Gy. At median follow-up of 4.2 years (range 0.1-32.2 years), two patients relapsed with one death from progressive disease. In seven pleomorphic cases, four patients had primary tumors at central axial sites. Six patients (86%) received multimodal therapy, but six patients experienced relapse of disease. Four patients died from progressive disease.Pediatric liposarcoma has a different spectrum of presentation compared to adult cases. Myxoid liposarcoma is the more common subtype, usually occurs in extremities, and has an excellent prognosis. Pleomorphic liposarcoma occurs in axial sites, and despite multimodal therapy, outcome is poor. Further study is needed to identify the optimal therapy for pediatric liposarcoma.

View details for DOI 10.1002/pbc.23095

View details for Web of Science ID 000296200800013

View details for PubMedID 21394894

View details for PubMedCentralID PMC3134599

Abstract

Not knowing about a child's death can result in poor quality of care coordination among staff and poor quality bereavement care for families. The purpose of this project was to create, implement, and evaluate an automated Patient Death Notification policy and procedure (PDNPP).Baseline and follow-up surveys of clinical staff.Implementation of a PDNPP that created an automated, systematic process for staff notification of patient deaths.Ninety-six percent of the staff rated the PDNPP as a significant improvement; 91% reported being "very" or "somewhat" satisfied with the PDNPP, whereas only 44% of the staff were satisfied with the process at baseline.Implementation of an automated PDNPP was feasible and improved staff satisfaction about how they were informed of patient deaths. Staff also reported being notified about patient deaths more quickly, performing their jobs more efficiently, being able to avoid doing something that might upset the deceased patient's family, and being able to better provide support to bereaved families.

View details for DOI 10.1016/j.jpainsymman.2011.07.002

View details for Web of Science ID 000297011800002

View details for PubMedID 22045367

View details for PubMedCentralID PMC3463934

Abstract

The aim of this study was to retrospectively analyze the clinical presentation, histology, treatment, and outcomes of children with vaginal tumors who were treated at a single institution.A retrospective review of medical records and pathologic materials of all children with vaginal tumors treated at St Jude Children's Research Hospital between 1970 and 2009 was conducted.Eighteen patients (median age, 3.7 years; range, 0.1-15 years) were identified. Three different histologies were found: rhabdomyosarcoma (RMS; n = 13), germ cell tumor (n = 3), and clear cell adenocarcinoma (n = 2). Bleeding or blood-tinged discharge was the most common clinical presentation (66%), followed by a protruding mass (39%). Vaginal and uterine salvage was 44.4% (8 of 18 patients). Thirteen patients (72.2%) remain disease-free, with a median follow-up of 23.2 years (range, 2-39 years). Four patients (22.2%) died of disease progression (1 RMS, 2 germ cell tumor, and 1 clear cell adenocarcinoma), and 1 patient with RMS died of colon cancer 12 years after the primary diagnosis had been made.Vaginal tumors are extremely rare in the pediatric population. Early recognition of symptoms like bleeding and a protruding vaginal mass may prevent morbidity and mortality. Our findings confirm the good prognosis of vaginal RMS.

View details for DOI 10.1016/j.jpedsurg.2011.05.003

View details for Web of Science ID 000296869100012

View details for PubMedID 22075335

View details for PubMedCentralID PMC3476720

Abstract

The purpose of this article is to summarize the literature that documents the long-term impact of cancer treatment modalities on pulmonary function among survivors of cancer and to identify potential areas for further research.Systematic reviews of clinical trials, observational studies, case series, and review articles were conducted. Articles were limited to the studies that discussed pulmonary toxicity or late effects among pediatric cancer survivors and to follow-up investigations that were conducted a minimum of 2 years after completion of cancer-related treatment or 1 year after hematopoietic stem cell transplant.Sixty publications (51 clinical studies/reports and nine reviews) published from January 1970 to June 2010 in PubMed met the inclusion criteria. Data showed an association between radiotherapy, alkylating agents, bleomycin, hematopoietic stem cell transplant, and thoracic surgery and pulmonary toxicity, as well as possible interactions among these modalities.Pulmonary toxicity is a common long-term complication of exposure to certain anticancer therapies in childhood and can vary from subclinical to life threatening. Pulmonary function and associated loss of optimal exercise capacity may have adverse effects on long-term quality of life in survivors. Lung function diminishes as a function of normal aging, and the effects of early lung injury from cancer therapy may compound these changes. The information presented in this review is designed to provide a stimulus to promote both observational and interventional research that expands our knowledge and aids in the design of interventions to prevent or ameliorate pulmonary late effects among survivors of childhood cancer.

View details for DOI 10.1378/chest.10-2133

View details for Web of Science ID 000295900300013

View details for PubMedID 21415131

View details for PubMedCentralID PMC3904488

Abstract

To determine dose-limiting toxicities, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of weekly intravenous temsirolimus, a mammalian target of rapamycin (mTOR) signaling pathway inhibitor, in pediatric patients with recurrent or refractory solid tumors.Cohorts of three to six patients 1 to 21 years of age with recurrent or refractory solid tumors were treated with a 1-hour intravenous infusion of temsirolimus weekly for 3 weeks per course at one of four dose levels: 10, 25, 75, or 150 mg/m(2). During the first two courses, pharmacokinetic and pharmacodynamic evaluations (phosphorylation of S6, AKT, and 4EBP1 in peripheral-blood mononuclear cells) were performed.Dose-limiting toxicity (grade 3 anorexia) occurred in one of 18 evaluable patients at the 150 mg/m(2) level, which was determined to be tolerable, and an MTD was not identified. In 13 patients evaluable for response after two courses of therapy, one had complete response (CR; neuroblastoma) and five had stable disease (SD). Four patients (three SDs + one CR) remained on treatment for more than 4 months. The sum of temsirolimus and sirolimus areas under the concentration-time curve was comparable to values in adults. AKT and 4EBP1 phosphorylation were inhibited at all dose levels, particularly after two courses.Weekly intravenous temsirolimus is well tolerated in children with recurrent solid tumors, demonstrates antitumor activity, has pharmacokinetics similar to those in adults, and inhibits the mTOR signaling pathway in peripheral-blood mononuclear cells. Further studies are needed to define the optimal dose for use in combination with other antineoplastic agents in pediatric patients.

View details for DOI 10.1200/JCO.2010.33.4649

View details for Web of Science ID 000292819700024

View details for PubMedID 21690471

View details for PubMedCentralID PMC3138720

Abstract

The objectives of this study were to compare tumor volume and patient weight versus traditional factors of tumor size (greatest dimension) and patient age and to determine which parameters best discriminated outcome among pediatric patients with intermediate-risk rhabdomyosarcoma (RMS).Complete information was available for 370 patients with nonmetastatic RMS who were enrolled in the Children's Oncology Group (COG) intermediate-risk study D9803 (1999-2005). The Kaplan-Meier method was used to estimate survival distributions. A recursive partitioning model was used to identify prognostic factors that were associated with event-free survival (EFS). Cox proportional hazards regression models were used to estimate the association between patient characteristics and the risk of failure or death.For all patients with intermediate-risk RMS, a recursive partitioning algorithm for EFS suggested that prognostic groups should be defined optimally by tumor volume (with a transition point at 20 cm(3) ), patient weight (with a transition point at 50 kg), and embryonal histology. Tumor volume and patient weight added significant outcome information to the standard prognostic factors, including greatest tumor dimension and patient age (P = .02). The ability to resect the tumor completely was not associated significantly with the size of the patient, and patient weight did not significantly modify the association between tumor volume and EFS after adjustment for standard risk factors (P = .2).The factors that had the strongest association with EFS were tumor volume, patient weight, and histology. On the basis of regression modeling, tumor volume and patient weight were superior predictors of outcome compared with greatest tumor dimension and patient age in children with intermediate-risk RMS. The current results indicated that the prognostic performance of tumor volume and patient weight should be assessed in an independent prospective study.

View details for DOI 10.1002/cncr.25719

View details for Web of Science ID 000290859900027

View details for PubMedID 24048802

View details for PubMedCentralID PMC3117103

View details for DOI 10.1200/jco.2011.29.15_suppl.9545

View details for Web of Science ID 000208880302568

Abstract

To facilitate prospective medical assessment of adults surviving pediatric malignancies and advance knowledge about long-term childhood cancer survivor health, St. Jude Children's Research Hospital (SJCRH) is establishing a lifetime cohort of survivors.Eligibility criteria for inclusion in the St. Jude Lifetime Cohort (SJLIFE) study include: (1) diagnosis of childhood malignancy treated at SJCRH; (2) survival 10 years from diagnosis; and (3) current age 18 years. Three levels of participation are offered: (1) comprehensive evaluation on SJCRH campus; (2) limited home evaluation; or (3) completion of health surveys only. A systematic recruitment structure based upon blocks of 50 patients initially focused on leukemia and lymphoma survivors and patients eligible for pilot studies.As of January 1, 2010, 1,625 (42%) of 3,900 eligible 10-year survivors have been contacted. Among the first 1,000 potentially eligible survivors selected for recruitment, 971 were subsequently confirmed to fulfill eligibility criteria. To date, 898/971 (92.5%) have been successfully contacted of whom 825 (91.8%) have agreed to participate. Among participants, 88.6% agreed to comprehensive medical evaluation, 0.4% limited local evaluation, and 11.0% survey only. Anticipated minimum overall participation rate for medical evaluation is 75.3% (731/971). Comparison of those contacted who agreed versus declined to participate revealed a greater proportion of males who declined participation (P = 0.001).Early results of the SJLIFE study support its feasibility to recruit aging childhood cancer survivors to research investigations evaluating late health outcomes by medical assessments.

View details for DOI 10.1002/pbc.22875

View details for Web of Science ID 000288132100021

View details for PubMedID 21370418

View details for PubMedCentralID PMC3088729

Abstract

Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with initially unresected tumours represent a particular subset of patients with a poor outcome. Various international research groups pooled their data in a joint study in order to investigate prognostic variables and treatment modalities.The study population consisted of 304 patients <21 years old treated between 1980 and 2005 using a multimodality therapeutic strategy.Synovial sarcoma and malignant peripheral nerve sheath tumour (MPNST) were the most frequent histotypes. Most patients received initial chemotherapy: major responses were recorded in 41% and minor in 16% of cases. Overall survival (OS) was 60.0% and 51.5% at 5 and 10 years, respectively, and it was significantly associated with patient's age, histological subtype, tumour site and size, quality of delayed surgical resection, radiotherapy administration and response to induction chemotherapy. MPNST associated to neurofibromatosis type 1 was the tumour type with the worst rate of response to chemotherapy and the worst outcome.In unresected NRSTS patients, radiotherapy and delayed surgery are of crucial importance. Patients who respond to chemotherapy have better chance of survival. However, given the relatively poor prognosis, research on intensive multimodal treatment approaches and novel strategies is warranted.

View details for DOI 10.1016/j.ejca.2010.11.013

View details for Web of Science ID 000288881700011

View details for PubMedID 21145727

View details for PubMedCentralID PMC3539303

Abstract

Rhabdomyosarcoma, a neoplasm composed of skeletal myoblast-like cells, represents the most common soft tissue sarcoma in children. The application of intensive chemotherapeutics and refined surgical and radiation therapy approaches have improved survival for children with localized disease over the past 3 decades; however, these approaches have not improved the dismal outcome for children with metastatic and recurrent rhabdomyosarcoma. Elegant studies have defined the molecular mechanisms driving skeletal muscle lineage commitment and differentiation, and the machinery that couples differentiation with irreversible cell proliferation arrest. Further, detailed molecular analyses indicate that rhabdomyosarcoma cells have lost the capacity to fully differentiate when challenged to do so in experimental models. We review the intersection of normal skeletal muscle developmental biology and the molecular genetic defects in rhabdomyosarcoma with the underlying premise that understanding how the differentiation process has gone awry will lead to new treatment strategies aimed at promoting myogenic differentiation and concomitant cell cycle arrest.

View details for DOI 10.1016/13978-0-12-380916-2.00007-3

View details for Web of Science ID 000287717300007

View details for PubMedID 21295688

Abstract

Cutaneous angiosarcomas are rare tumors, which predominantly arise in the sun-exposed skin of the head and neck of adult and elderly patients. Rarely, these tumors can be seen in children. We identified cutaneous angiosarcomas in 10 children and assessed clinical (patient age, tumor site, tumor size, and tumor focality) and histologic features including growth pattern (vasoformative vs. solid), mitotic rate (mitotic figures per 10 high power field), necrosis (present vs. absent), and cell shape (epithelioid vs. nonepithelioid). Tumors predominated in the lower extremities (6 of 10) of female patients (2 male and 8 female); age at diagnosis ranged from 1.5 months to 15 years. Four patients had preexisting conditions: congenital hemihypertrophy of the contralateral limb, the Aicardi syndrome, congenital lymphedema, and congenital hemangioma treated with radiation therapy. Tumors were located in the lower extremity (6), flank (1), elbow (1), and buccal mucosa (1), and ranged in size from 0.6 to 6.5 cm. Eight cases showed predominantly epithelioid morphology, 1 case showed mixed epithelioid and spindled morphology and 1 case was entirely spindled. Mitotic activity ranged from 1 to 55 mitotic figures per 10 high power field. Necrosis was seen in 5 cases. Clinical follow-up was obtained for 9 patients: 4 died of disease (range, 12 to 49 mo; mean, 25 mo) and 5 patients were alive without disease (18 mo to 28 y). Five patients had metastatic disease; sites of involvement included the lung, soft tissue, lymph node, pleura, liver, and bone. Cutaneous angiosarcomas in children are rare tumors, which are commonly associated with a preexisting condition, suggesting a greater role for genetics as opposed to environmental factors in the pathogenesis of these tumors.

View details for DOI 10.1097/PAS.0b013e3181ffd9d5

View details for Web of Science ID 000285409900008

View details for PubMedID 21164289

View details for Web of Science ID 000283115900562

Abstract

To provide a radiation pneumonitis risk estimate and investigate the correlation of clinical and dosimetric factors in pediatric patients receiving chest irradiation.A total of 122 patients diagnosed with sarcoma or Hodgkin lymphoma who received radiotherapy to the chest were evaluated for symptomatic radiation pneumonitis (Common Toxicity Criteria Grade 1 with respiratory symptom or higher grade). Pneumonitis data were collected from either prospective toxicity screenings as part of a clinical trial or through chart review. Dosimetric parameters including V(10)-V(25), mean lung dose, binned lung dose, and tissue complication probability models were used, as well as clinical features to correlate with the development of pneumonitis.The 1- and 2-year cumulative incidence of symptomatic radiation pneumonitis for all patients was 8.2% and 9.1%, respectively. Nine patients experienced symptomatic Grade 1 toxicity, and 2 experienced Grade 2. From univariate analysis, chemotherapy containing bleomycin (chi(2) test, p = 0.027) and V(24) (logistic regression, p = 0.019) were the clinical and dosimetric factors that resulted in statistically significant differences in the occurrence of pneumonitis. The probability of pneumonitis increased more dramatically with increasing V(24) in patients receiving bleomycin than in those who did not. Adult tissue complication models did not differentiate pediatric patients with radiation pneumonitis from those without.The incidence of symptomatic radiation pneumonitis in pediatric patients is low and its severity mild. Parameters frequently used in adult radiation oncology provide some guidance as to risk, but pediatric patients warrant their own specific models for risk assessment, incorporating dosimetry and clinical factors.

View details for DOI 10.1016/j.ijrobp.2009.07.1709

View details for Web of Science ID 000281304600021

View details for PubMedID 20056346

View details for PubMedCentralID PMC3539302

Abstract

Parents of children with incurable cancer make complex and difficult decisions about remaining treatment options. We compared the self-reported rationale, good parent definition, and desired clinical staff behaviors of parents who recently decided for phase I (P1) chemotherapy with parents who chose a do not resuscitate (DNR) or terminal care (TC) option.Sixty-two parents of 58 children were asked for the basis of their decision, their definition of a good parent, and what staff behaviors supported their good parent role. After semantic content analysis, results were compared in the P1 versus DNR/TC groups. These categories were mutually exclusive but did not necessarily represent an either/or decision.Thirty-one decisions were for P1 chemotherapy and 27 for DNR/TC. Median survival time after study enrollment was greater in the P1 group (0.4 v 0.1 years). Most P1 group parents reported having felt compelled to continue cancer-directed therapy (71% v 7%), whereas those who opted for DNR/TC cited quality of life (QOL; 74% v 3%) and patient wishes (67% v 13%). Decision factors common to both groups were medical facts, doing right, and others' opinions. Both groups believed that a good parent did right, provided support and presence, and sacrificed for the child. The groups desired similar support from clinicians and expressed gratitude.Despite similar definitions of a good parent and desired staff behaviors, parents in the P1 group reported having felt compelled to continue cancer-directed therapy, whereas QOL and patient wishes were emphasized in decisions for DNR/TC.

View details for DOI 10.1200/JCO.2009.26.6502

View details for Web of Science ID 000279637600015

View details for PubMedID 20498399

View details for PubMedCentralID PMC2903327

Abstract

Two systems for grading soft tissue sarcoma are widely used currently: the National Cancer Institute (NCI) and the Fdration Nationale des Centers de Lutte Contre le Cancer (FNCLCC) systems. Both were developed using cohorts of predominantly adult patients. The Pediatric Oncology Group (POG) system, based on the NCI system, was adapted for grading pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). The applicability and prognostic utility of the FNCLCC system in pediatric NRSTS has not been assessed or compared with the POG system.Tumors from 130 patients with malignant NRSTS enrolled on 3 completed multi-institutional clinical trials were assessed. Of 130 tumors, 102 (78%) were localized and 28 (22%) metastatic. Of the localized tumors, 55 of 102 (54%) were >5 cm. The estimated 5-year event-free survival (EFS) for the entire group was 47%.As expected, stage and tumor sizes were predictive of EFS (P < .001). Both systems were predictive of 5-year EFS (POG, P = .0095 and FNCLCC, P = .0075). Patients whose tumors received discrepant grades (POG-G3 vs FNCLCC-G2/G1) (n = 44) had an intermediate outcome between those with concordant (G3 [n = 44] or G1/G2 [n = 42]) grades on both systems (P = .0018). By multivariate analysis, the mitotic index was predictive of EFS, using a cutoff of 10 mitotic figures per 10 high-power fields (P < .001).In conclusion, both FNCLCC and POG systems provide an adequate prognostic measure of outcome for pediatric NRSTS; albeit, a sizeable subset of cases with apparently intermediate prognosis was graded differently by the 2 systems. The mitotic index appears to be a key parameter in grading pediatric NRSTS.

View details for DOI 10.1002/cncr.24929

View details for Web of Science ID 000277111900027

View details for PubMedID 20166208

View details for PubMedCentralID PMC2987713

Abstract

In a previous study, we conducted telephone interviews with parents 6 to 10 months after their child's death from cancer, using open-ended questions to identify the type and frequency of cancer-related symptoms that most concerned them during the last week of their child's life. Because the parents identified many clinically striking symptoms (n=109) that were not of most concern to them, we conducted a secondary analysis of these interviews (48 mothers and four fathers of 52 patients) to identify descriptive factors associated with the parents' level of concern. Six descriptive factors were associated with symptoms of most concern and 10 factors with symptoms not of most concern. Ten of these 16 factors occurred in both categories, indicating that clinicians should directly query parents to identify the symptoms that concern parents the most. Six factors differed between the two categories, and only one (the continuous distress caused by a symptom that is unrelieved) was unique to the category of symptoms of most concern. Five factors (symptom present for at least one week, symptom not seen as remarkable by the parent or causing no distress to the child, symptom well managed, symptom improved, and symptoms for which the parent felt adequately prepared) were unique to the category of symptoms not of most concern. By inquiring about symptoms of most concern and factors that influence parental concern, clinicians may be better able to direct care efforts to reduce patients' and parents' distress and support parents during the difficult end-of-life period.

View details for PubMedID 20413052

Abstract

This multicenter, randomized, open-label study evaluated the efficacy, safety, and pharmacokinetics of a single subcutaneous pegfilgrastim injection with daily subcutaneous filgrastim administration in pediatric patients receiving myelosuppressive chemotherapy for sarcoma. PATIENTS AND METHODS Forty-four patients with previously untreated, biopsy-proven sarcoma stratified into three age groups (0-5, 6-11, and 12-21 years) were randomly assigned in a 6:1 randomization ratio to receive a single pegfilgrastim dose of 100 microg/kg (n = 38) or daily filgrastim doses of 5 microg/kg (n = 6) after chemotherapy (cycles 1 and 3: vincristine-doxorubicin-cyclophosphamide; cycles 2 and 4: ifosfamide-etoposide). The duration of grade 4 neutropenia, time to neutrophil recovery, incidence of febrile neutropenia, and adverse events were recorded. Results Pegfilgrastim and filgrastim were similar for all efficacy and safety end points, and their pharmacokinetic profiles were consistent with those in adults. Younger children experienced more protracted neutropenia and had higher median pegfilgrastim exposure than older children. CONCLUSION A single dose of pegfilgrastim at 100 microg/kg administered once per chemotherapy cycle is comparable to daily injections of filgrastim at 5 microg/kg for pediatric sarcoma patients receiving myelosuppressive chemotherapy.

View details for DOI 10.1200/JCO.2009.24.8872

View details for Web of Science ID 000275312300011

View details for PubMedID 20142595

View details for PubMedCentralID PMC2834494

Abstract

To demonstrate the safety and efficacy of limited margin radiotherapy in the local control of pediatric and young adult patients with high-grade nonrhabdomyosarcoma soft tissue sarcoma (NRSTS).Pediatric patients with high-grade NRSTS requiring radiation were treated on an institutional review board approved prospective institutional study of conformal/intensity-modulated/interstitial brachytherapy using a 2-cm anatomically constrained margin.A total of 32 patients (median age, 15.3 years; range, 2-22 years) received adjuvant (27 patients) or definitive (5 patients) irradiation. With a median follow-up of 32 months, the 3-year cumulative incidence of local failure was 3.7% for patients undergoing irradiation after surgical resection. Four patients experienced local failure; the mean dose to the volume of recurrence was >or=97% of the prescribed dose.Delivery of limited margin radiotherapy using external beam or brachytherapy provides a high rate of local tumor control without marginal failure. Further follow-up is required to determine whether normal tissue effects are minimized using this approach.

View details for DOI 10.1016/j.ijrobp.2009.02.074

View details for Web of Science ID 000275072200031

View details for PubMedID 19625137

View details for PubMedCentralID PMC2823850

Abstract

Effective vaccination is now available to prevent human papillomavirus (HPV), the most common sexually transmitted infection and the cause of cervical cancer, which is the second most common cancer among women worldwide. HPV vaccine uptake is particularly important for females surviving cancer, some of whom are at high risk for HPV complications because of the direct and indirect effects of cancer treatment. Thus, version 3.0 of the Children's Oncology Group's Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer recommends HPV vaccination for all eligible females surviving childhood cancer. Because this vaccine was only approved by the US Food and Drug Administration in 2006, little is known regarding the complexity of vaccination uptake among those surviving cancer. The purpose of this article was to describe the HPV vaccine and its usefulness in the survivorship population, provide a rationale for describing cancer survivors as being at increased risk for HPV complications, identify factors associated with HPV vaccination, and discuss the utilization of these predictors in designing strategies to promote adherence to HPV vaccination recommendations within the survivorship context.

View details for DOI 10.1002/cncr.24669

View details for Web of Science ID 000272545400007

View details for PubMedID 19813272

View details for PubMedCentralID PMC2801897

Abstract

When a child's cancer progresses beyond current treatment capability, the parents are likely to participate in noncurative treatment decision making. One factor that helps parents to make these decisions and remain satisfied with them afterward is deciding as they believe a good parent would decide. Because being a good parent to a child with incurable cancer has not been formally defined, we conducted a descriptive study to develop such a definition.In face-to-face interviews, 62 parents who had made one of three decisions (enrollment on a phase I study, do not resuscitate status, or terminal care) for 58 patients responded to two open-ended questions about the definition of a good parent and about how clinicians could help them fulfill this role. For semantic content analysis of the interviews, a rater panel trained in this method independently coded all responses. Inter-rater reliability was excellent.Among the aspects of the definition qualitatively identified were making informed, unselfish decisions in the child's best interest, remaining at the child's side, showing the child that he is cherished, teaching the child to make good decisions, advocating for the child with the staff, and promoting the child's health. We also identified 15 clinician strategies that help parents be a part of making these decisions on behalf of a child with advanced cancer.The definition and the strategies may be used to guide clinicians in helping parents fulfill the good parent role and take comfort afterward in having acted as a good parent.

View details for DOI 10.1200/JCO.2008.20.0204

View details for Web of Science ID 000272652700022

View details for PubMedID 19805693

View details for PubMedCentralID PMC2793041

Abstract

Predictors of outcome have not been established for pediatric visceral and body wall nonrhabdomyosarcoma soft tissue sarcomas (NRSTS).The study used a retrospective review of clinical features and outcome of 61 patients with visceral and body wall NRSTS evaluated at our institution between March 1962 and December 1999.Median age at diagnosis was 9.9 years (range, birth to 17.4 years). Tumors were greater than 5 cm in 43 (70%), high grade in 33 (54%), invasive in 25 (41%), and metastatic at presentation in 14 (23%) patients. Visceral tumors (n = 27) were more likely than body wall tumors (n = 34) to be greater than 5 cm (93% vs 53%; P < .001) and invasive (70% vs 18%; P < .001) and were less likely to be resected at diagnosis (44% vs 85%; P = .001). Estimated 10-year event-free survival (EFS) and overall survival (OS) for the entire cohort were 45.5% +/- 6.9% and 56.8% +/- 6.7%, respectively. The 10-year EFS and OS were better for patients with body wall sites than for those with visceral sites (61.8% +/- 8.5% and 67.5% +/- 8.2% vs 24.2% +/- 9.4% and 43.0% +/- 10.3%; P = .004 and P = .004). The 10-year estimated cumulative incidence (CI) of local recurrence was higher for patients with visceral sites than for those with body wall sites (64.3% +/- 9.8% vs 26.5% +/- 7.7%; P = .004), whereas CI of distant recurrence was similar for the 2 sites (15.2% +/- 7.2% vs 23.5% +/- 7.4%; P = .39).Pediatric patients with visceral NRSTS are more likely to have invasive, large, and unresectable tumors compared to those with body wall tumors. More than two thirds of visceral NRSTS recur locally, and fewer than half of patients with visceral tumors survive.

View details for DOI 10.1016/j.jpedsurg.2009.02.066

View details for Web of Science ID 000271331700017

View details for PubMedID 19853756

View details for PubMedCentralID PMC2768617

Abstract

The incidence of pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) of the groin and axilla is unknown, and the optimal surgical approach to these patients is unclear.We conducted a retrospective study of patients treated at St Jude Children's Research Hospital from January 1962 to March 2007 for NRSTSs of the groin and axilla. Demographic variables, tumor pathology, clinical management, and outcome were reviewed.Of the 300 patients treated for NRSTSs, only 10 had tumors of the axilla or groin (6 of whom had synovial sarcoma). Surgical interventions included wide resection of the tumor (n = 7), marginal resection (n = 1), subtotal resection (n = 1), and biopsy only (n = 1). Six patients underwent lymph node sampling; all were negative for tumor. Short- and long-term surgical complications were rare. Four patients received adjuvant chemotherapy (n = 3) and/or radiotherapy (n = 2). At a median follow-up of 8.5 years, 7 of the 10 were surviving free of disease. Two of these patients died of tumor progression (1 with metastases at diagnosis and 1 with an unresectable tumor at diagnosis), and one patient who was free of NRSTS died of secondary breast carcinoma.Pediatric NRSTSs of the axilla and groin are rare, but outcomes are similar to those of other patients with NRSTS. Wide local excision of the tumor with preservation of good limb function should be the surgical goal and may be sufficient therapy in some cases.

View details for DOI 10.1016/j.jpedsurg.2009.02.052

View details for Web of Science ID 000271331700018

View details for PubMedID 19853757

View details for PubMedCentralID PMC3748624

Abstract

Parents of terminally ill children with cancer frequently ask clinicians when their child will die. Such information helps parents prepare for the child's death. To identify how parents perceived when their child's cancer-related death would occur, we conducted a secondary analysis of telephone interviews with 49 bereaved parents 6-10 months after their child's death to extract their descriptions of this occurrence. The parents knew in advance that their child was going to die, but they described when their child's death would occur in three different ways: anticipated (parents observed changes that alerted them that death was imminent; n=22, 52.4%), surprising (parents were surprised that their child died on that particular day; n=13, 31.0%), and overdue (parents had been waiting for the end of their child's apparent suffering; n=7, 16.7%). These categories did not differ by patients' diagnosis, sex, or location of death but differed slightly by symptom patterns. Parents who reported the occurrence of their child's death as surprising reported fewer symptom changes on the last day of their child's life, compared with the last week of life, than did the parents in the other two categories. These findings indicate that parents of children with terminal cancer can perceive when their child's death would occur very differently: Some are surprised, whereas others feel they have waited too long for their child's release from suffering. Clinicians can use these descriptions and the associated symptom patterns to help families prepare for their child's last week and last day.

View details for DOI 10.1016/j.jpainsymman.2009.01.005

View details for Web of Science ID 000271297000009

View details for PubMedID 19822277

View details for PubMedCentralID PMC2941143

Abstract

To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan.IV irinotecan (15 or 20 mg/m(2)) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m(2)) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis.The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m(2)/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m(2)/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37% and 38%, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma.IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.

View details for DOI 10.1200/JCO.2008.19.6642

View details for Web of Science ID 000270019900026

View details for PubMedID 19687340

View details for PubMedCentralID PMC2754908

View details for Web of Science ID 000276606606523

View details for Web of Science ID 000276606606522

Abstract

For this report, the authors estimated the maximum tolerated dose (MTD) and investigated the toxicities of oxaliplatin combined with irinotecan in children with refractory solid tumors.Oxaliplatin was administered on Days 1 and 8 in combination with irinotecan on Days 1 through 5 and Days 8 through 12 of a 21-day cycle. An oral cephalosporin was administered daily to ameliorate irinotecan-associated diarrhea. Pharmacokinetic studies of oxaliplatin and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotyping were performed.Thirteen patients were enrolled. Dose-limiting diarrhea (n = 3), serum lipase elevation (n = 3), serum amylase elevation (n = 2), colitis, abdominal pain, and headache (n = 1 each) occurred at the first dose level (oxaliplatin at a dose of 60 mg/m(2); irinotecan at a dose of 20 mg/m(2)). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m(2)/dose oxaliplatin; 15 mg/m(2)/dose irinotecan) experienced a dose-limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re-escalated (60 mg/m(2)) with irinotecan at a dose of 15 mg/m(2), 2 of 3 patients had a DLT (1 episode of diarrhea, 1 episode of hypokalemia). Myelosuppression was minimal. One patient had a complete response, and another patient had stable disease for 6 cycles of therapy. The median oxaliplatin area under the concentration versus time curve (AUC(0-->infinity)) was 5.9 microg . hour/mL (range, 1.8-7.6 microg . hour/mL). The frequency of the 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes was 5 of 10, 4 of 10, and 1 of 10, respectively.The oxaliplatin MTD was 40 mg/m(2) per dose on Days 1 and 8 in combination with irinotecan 15 mg/m(2) per dose on Days 1-5 and Days 8-12. There was some evidence of antitumor activity; however, severe toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was observed.

View details for DOI 10.1002/cncr.24175

View details for Web of Science ID 000264918700021

View details for PubMedID 19170226

View details for PubMedCentralID PMC2897817

Abstract

Childhood cancer survivors who have had pelvic or central nervous system surgery or have received alkylator-containing chemotherapy or pelvic radiotherapy as part of their cancer therapy may experience urinary bladder late effects. This article reviews the medical literature on long-term bladder complications in survivors of childhood cancer and outlines the Children's Oncology Group Long-Term Follow-up (COG LTFU) Guidelines related to bladder function. An overview of the treatment of bladder late effects and recommended counseling for survivors with these complications are presented.

View details for DOI 10.1002/pbc.21826

View details for Web of Science ID 000263532500004

View details for PubMedID 18985721

View details for PubMedCentralID PMC2917580

Abstract

This prospective study was designed to be the first to evaluate the toxicity of radiofrequency ablation (RFA) in patients with recurrent pediatric solid tumors.From 2003 through 2008, a phase 1/pilot study of RFA for recurrent pediatric solid tumors was conducted. A multidisciplinary cancer management team selected appropriate candidates for the study. Imaging-guided RFA was performed percutaneously. Repeat RFA was performed for recurrences when appropriate. Toxicity and imaging response was assessed at 1 month and 3 months prospectively. Accrual stopped in 2006, and data collection stopped in 2008.Sixteen patients (ages 4 years-33 years; median age, 15 years) and 56 tumor sites were treated in 37 RFA sessions including 38 pulmonary, 11 musculoskeletal, and 7 hepatic lesions (82 lesion-treatments). Postprocedural pain was moderate (median 5 on a scale from 1 to 10) and lasted a median of 9 days. Prolonged hospitalization (beyond 1 day) occurred 17 times (range, 2 days-25 days; median, 3 days). Hypoxia supported by supplemental oxygen occurred in 8 of 16 patients and resolved within 1 month after each RFA. No patient had tumor lysis syndrome but myoglobinuria/hemoglobinuria occurred in 6 of 16 patients, all without renal damage. Serious complications from pulmonary RFA included 2 diaphragmatic hernias. Of 82 lesions imaged, 24 (29%) remained ablated at the end of the study.The toxicity from RFA of recurrent pediatric solid tumors was real but limited, and RFA may offer a local tumor control alternative in carefully selected cases.

View details for DOI 10.1002/cncr.24158

View details for Web of Science ID 000264148300023

View details for PubMedID 19180637

View details for PubMedCentralID PMC2814781

Abstract

Angiosarcomas are rare tumors that predominantly affect adult and elderly patients and pursue an aggressive clinical course with high mortality. Although angiosarcomas are well described in a variety of clinical settings, they have been incompletely characterized. We identified 15 high-grade angiosarcomas arising from the viscera and soft tissue of patients 21 years old and younger from institutional and consultation files. Both clinical (patient age, tumor site, tumor size, tumor focality) and histologic features including growth pattern (vasoformative vs. solid), nuclear grade (high vs. low), mitotic rate (mitotic figures/10 high-power fields), necrosis (present vs. absent), and cell shape (epithelioid vs. nonepithelioid) were assessed. Tumors arose in both sexes (8 males; 7 females); age at diagnosis ranged from 3 months to 19 years (mean, 10 y, 5 mo; median, 11 y). Tumors were located in the mediastinum (7), visceral organs (2 in liver, 1 in spleen), breast (2), mesentery (1), pelvis (1), and deep soft tissue of upper extremity (1). Tumor size was documented for 8 patients (range 3.5 to 13 cm; mean 8.1 cm). Eight cases showed epithelioid morphology and 7 cases were primarily spindled. Of 8 cases assessed for podoplanin expression by immunohistochemistry, 7 were negative and 1 was positive. Clinical follow-up was obtained for all patients: 10 (67%) died of disease (range, 27 mo to 11 y; mean, 6 y 8 mo) and 4 patients were alive without disease (range, 27 to 132 mo; mean, 79 mo). Although extremely rare, angiosarcomas do affect children and young adults and this diagnosis should be considered in atypical vascular tumors occurring in the mediastinum and those with brisk mitotic activity and/or necrosis.

View details for Web of Science ID 000262920400013

View details for PubMedID 18987547

Abstract

The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. The study estimated the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors.Oxaliplatin was administered on Day 1 and etoposide on Days 1 to 3 of each 21-day course. Cohorts of 3 to 6 patients were enrolled at 3 dose levels: 1) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 75 mg/m(2), 2) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 100 mg/m(2), and 3) oxaliplatin at a dose of 145 mg/m(2) and etoposide at a dose of 100 mg/m(2). Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single-agent MTD.The 16 patients received a total of 63 courses. At dose level 1, dose-limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose-limiting toxicity (DLT) occurred at dose level 2 (n = 6). At dose level 3, 2 of 4 patients experienced dose-limiting neutropenia; none experienced grade 3 or 4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 complete response) and pineoblastoma (1 partial response); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization.The MTD of this regimen was found to be oxaliplatin at a dose of 130 mg/m(2) given on Day 1 and etoposide at a dose of 100 mg/m(2)/d given on Days 1 to 3. Neutropenia was found to be the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well-tolerated and demonstrated antitumor activity.

View details for DOI 10.1002/cncr.24054

View details for Web of Science ID 000263003400024

View details for PubMedID 19117350

View details for PubMedCentralID PMC2852396

Abstract

To assess sperm cryopreservation among males newly diagnosed with cancer aged 13 years and older, attending oncologists assigned infertility risk (yes/no) to patients and reported whether their patients engaged in sperm cryopreservation. Only 28.1% of informed at-risk patients banked sperm. Utilization of sperm banking was significantly associated with a diagnosis of central nervous system (CNS) malignancy or non-CNS solid tumor diagnosis, higher socioeconomic status, and not being a member of an Evangelical religious group. These results suggest that sperm banking is underutilized among adolescent males newly diagnosed with cancer, and that strategies to increase the engagement in this fertility preservation method are needed.

View details for DOI 10.1080/08880010902901294

View details for Web of Science ID 000266026400010

View details for PubMedID 19437327

View details for PubMedCentralID PMC2801903

Abstract

Improvements in childhood cancer therapy have led to increasing numbers of long-term survivors. These survivors are at risk for a variety of late effects due to the disease itself, treatment exposures (surgery, chemotherapy, and radiotherapy), underlying medical problems, and health behaviors. The COG LTFU Guidelines are risk-based, exposure-related recommendations for the identification and management of late effects due to therapies utilized in the treatment of childhood cancer, and are designed for asymptomatic survivors presenting for routine medical follow-up 2 or more years after completion of cancer therapy. The COG Guidelines Task Force on Urinary Tract Complications conducted an extensive review of the medical literature via MEDLINE. Specific treatment exposures which were reviewed include nephrectomy, chemotherapy regimens known to be nephrotoxic (cisplatin, carboplatin, ifosfamide, and methotrexate), and renal irradiation. Literature sources were ranked according to the strength of evidence and are cited in the review. This review summarizes the literature that supported the recommendations for cancer survivors at risk for nephrotoxicity previously outlined in the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers (COG LTFU Guidelines).

View details for DOI 10.1002/pbc.21695

View details for Web of Science ID 000260289300003

View details for PubMedID 18677764

View details for PubMedCentralID PMC2734519

Abstract

Children treated for sarcoma are at risk of treatment-associated deficits in bone mineral density (BMD). We investigated the severity of risk factors for BMD deficits in this patient population.Using signed-rank test and logistic regression analysis, we retrospectively analyzed the relation of treatment variables and other potential risk factors to BMD (using quantitative computed tomography (QCT)) of 99 patients treated for pediatric sarcoma who had completed therapy at least 1 year previously.The study group (38% rhabdomyosarcoma (RMS), 25% osteosarcoma (OS), 24% Ewing-family tumors, and 12% non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS)) represented 22% of the sarcoma survivors treated between 1982 and 2003 who remained in follow-up at St. Jude. These patients underwent QCT between July 1, 1997 and February 5, 2003. Their median age was 8.7 years (range, 0.2-21.3 years) at diagnosis and 17.4 years (range, 3.3-30.2 years) at the time of BMD measurement; 58% were male and 82% Caucasian. Median BMD Z-score was -0.75 (range, -3.33-3.02), and median BMD was 168.0 mg/cc (range, 89.2-264.8 mg/cc). Risk of BMD deficit increased significantly with younger age at diagnosis (P = 0.044) and higher cumulative cyclophosphamide dose (P = 0.007). Patients with lower extremity primary disease had a significantly lower risk of BMD deficits than others. We found no association between BMD and body habitus, primary disease, lifestyle factors, or endocrinopathy.A significant subset of sarcoma survivors are at risk of BMD deficits warranting prospective study of BMD to verify our results and refine risk factors contributing to BMD deficits.

View details for DOI 10.1002/pbc.21281

View details for Web of Science ID 000254642900017

View details for PubMedID 17570705

View details for DOI 10.1016/j.jpeds.2007.10.002

View details for Web of Science ID 000254543200014

View details for PubMedID 18346496

Abstract

Most parents of children with cancer have dual primary goals: a primary cancer-directed goal of cure and a primary comfort-related goal of lessening suffering. Early introduction of palliative care principles and practices into their child's treatment is respectful and supportive of these goals. The Individualized Care Planning and Coordination Model is designed to integrate palliative care principles and practices into the ongoing care of children with cancer. Application of the model helps clinicians to generate a comprehensive individualized care plan that is implemented through Individualized Care Coordination processes as detailed here. Clinicians' strong desire to provide compassionate, competent, and sensitive care to the seriously ill child and the child's family can be effectively translated into clinical practice through these processes.

View details for DOI 10.1016/j.pcl.2007.10.011

View details for Web of Science ID 000253794400012

View details for PubMedID 18242323

View details for PubMedCentralID PMC2577813

Abstract

Familial adenomatous polyposis (FAP) is an inherited condition causing numerous adenomatous colorectal polyps and a markedly elevated risk of colon cancer. FAP may be associated with various extracolonic manifestations such as desmoid fibromatosis and osteomas (termed Gardner's syndrome) and brain tumors, usually medulloblastoma or glioma [termed Brain Tumor Polyposis (BTP) syndrome type 2]. We describe a pediatric patient who initially presented with prolactinoma and later was found to have Gardner's syndrome. A germline mutation of the APC (adenomatous polyposis coli) gene was identified. Our case illustrates the association between prolactinoma and FAP, which may represent a rare subtype of Gardner's and BTP syndromes.

View details for DOI 10.1002/pbc.20985

View details for Web of Science ID 000252006000055

View details for PubMedID 16862550

Abstract

Radiation therapy is often used to achieve local control of pelvic Ewing sarcoma in children. The effects of radiation on the female reproductive tract have been well documented in adults with gynecological malignancies, but the long-term consequences of pelvic radiation in pre-pubertal or adolescent girls are not as well described. We report a case of hematometrocolpos developing in an adolescent previously treated with chemotherapy and radiation therapy for pelvic Ewing sarcoma. We describe the clinical presentation, radiographic features, gross pathology, treatment strategies, outcome, as well as putative predisposing factors and preventative interventions.

View details for DOI 10.1002/pbc.20833

View details for Web of Science ID 000251410400035

View details for PubMedID 16550535

Abstract

The nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) are a heterogeneous group of mesenchymal cell neoplasms that account for about 4% of childhood cancers. Because each histologic subtype of NRSTS is rare, they have been poorly studied and little is known about their biology, natural history, or optimal treatment. Data from adults with soft tissue sarcomas provide some helpful insight, but adult and childhood NRSTSs differ considerably in the distribution of their histologic subtypes, and certain entities are known to behave differently in young children. The greater risks posed to children by treatment, particularly by radiotherapy, also must be considered in treatment planning for children. This article summarizes what is known to date about childhood NRSTS, including the epidemiology, pathogenesis, and clinical approach to diagnosis and treatment of these tumors.

View details for DOI 10.1634/theoncologist.2007-0182

View details for Web of Science ID 000257428500006

View details for PubMedID 18586922

Abstract

Pediatric colorectal carcinoma (CRC) is rare, but the available data suggest that it is more likely than adult CRC to be advanced at presentation and to have a poor outcome. We sought to better characterize pediatric CRC.We reviewed the clinical and pathologic features, prognostic factors, and outcome of CRC in 77 children and adolescents (ages 7 to 19 years) referred to St Jude Children's Research Hospital between 1964 and 2003.At presentation, 76 patients had one or more signs or symptoms of CRC (abdominal pain, altered bowel habits, weight loss, anemia). Tumors were evenly distributed between the right and left colon; 62% were mucinous adenocarcinoma. At presentation, 86% of patients had advanced-stage disease; more than half had distant metastases. Overall outcome was poor. Advanced stage and mucinous histology were significant predictors of adverse outcome. Stage-specific survival at 10 years was 67% +/- 27% (stage 1), 38% +/- 15% (stage 2), 28% +/- 11% (stage III), and 7% +/- 4% (stage 4). Although no patient had a diagnosis of polyposis syndrome before diagnosis of CRC, 17 (22%) had colon polyps and eight (including two who previously underwent pelvic radiotherapy) had multiple polyps.Initial signs and symptoms of CRC are similar in pediatric and adult patients. The strikingly higher frequency of mucinous histology suggests that the biology of CRC differs in pediatric and adult patients and may contribute to poor outcomes. Children should be included in prospective clinical trials for CRC.

View details for DOI 10.1200/JCO.2007.12.6102

View details for Web of Science ID 000253886600021

View details for PubMedID 18089879

Abstract

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic properties of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in children with refractory or recurrent solid tumors.Everolimus was administered orally at a daily dose of 2.1, 3, 5, or 6.5 mg/m2 in cohorts of three to six patients per dosage level. Pharmacokinetic and pharmacodynamic studies were performed during the first course. The phosphorylation status of various components of the mTOR signal pathway was assessed in peripheral-blood mononuclear cells (PBMCs) isolated from treated patients.There were 26 patients enrolled; 18 were assessable. DLTs included diarrhea (n = 1), mucositis (n = 1), and elevation of ALT (n = 1) at 6.5 mg/m2. At the MTD of 5 mg/m2, the median everolimus clearance was 15.2 L/h/m2, with a plasma everolimus concentration-time area under the curve (AUC) from 0 to infinity of 239.6 ng/mL x h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs 200 ng/mL x h, equivalent to dosages of 3 to 5 mg/m2 of everolimus. No objective tumor responses were observed.Continuous, orally administered everolimus is well tolerated in children with recurrent or refractory solid tumors and demonstrates similar pharmacokinetic properties to those observed in adults. Everolimus significantly inhibits the mTOR signaling pathway in children at the MTD. The recommended phase II dose in children with solid tumors is 5 mg/m2.

View details for DOI 10.1200/JCO.2007.11.4017

View details for Web of Science ID 000251073900017

View details for PubMedID 17947729

Abstract

Children living with and dying of advanced-stage cancer suffer physically, emotionally, and spiritually. Relief of their suffering requires comprehensive, compassionate palliative and end-of-life (EoL) care.However, an EoL care program might appear inconsistent with the mission of a pediatric oncology research center committed to seeking cures. Here the authors describe the methods used to achieve full institutional commitment to their EoL care program and those used to build the program's philosophical, research, and educational foundations after they received approval. The authors convened 10 focus groups to solicit staff perceptions of the hospital's current palliative and EoL care. They also completed baseline medical record reviews of 145 patient records to identify key EoL characteristics. The authors then crafted a vision statement and a strategic plan, implemented new research protocols,and established publication and funding trajectories. They conclude that establishing a state-of-the-art palliative and EoL program in a cure-oriented pediatric setting is achievable via consensus building and recruitment of diverse institutional resources.

View details for DOI 10.1177/1043454207303882

View details for Web of Science ID 000249143400002

View details for PubMedID 17827490

Abstract

Advances in systemic and local therapies have improved outcomes for patients with the Ewing sarcoma family of tumors (ESFT). As new treatments are developed, a critical review of data from past treatment eras is needed to identify clinically relevant risk groups.The authors reviewed the records of 220 patients with ESFT who were treated on protocols at St. Jude Children's Research Hospital from 1979 to 2004. Two treatment eras were defined. Factors predictive of outcome were analyzed to identify distinct risk groups.The median age at diagnosis was 13.7 years (range, 1.1-25.2 years). Metastatic disease was associated with tumors measuring >8 cm (P = .002) and axial location (P = .014). The 5-year overall survival (OS) estimate (63.5% +/- 3.5%) did not appear to differ by protocol. Tumor stage and size were found to be the only independent predictors of outcome. Treatment era and type of local control therapy were found to influence the outcome of patients with localized disease. Four risk groups were defined: favorable risk (age <14 years with localized, nonpelvic tumors), intermediate risk (localized, age >/=14 years, or pelvic tumors), unfavorable-pulmonary (isolated lung metastases), and unfavorable-extrapulmonary (extrapulmonary metastases). The 5-year OS estimates for these groups were 88.1% +/- 4.4%, 64.9% +/- 5.2%, 53.8% +/- 9.4%, and 27.2% +/- 7.3%, respectively (P < .001). The incidence of therapy-related leukemia was significantly higher during the second treatment era, when more intensified regimens were used (6.1% +/- 2.7% vs 0% +/- 0%; P = .005).Risk stratification schemes such as this should be used to prospectively evaluate novel risk-based therapies. Studies of biologic pathways may help to refine this model.

View details for DOI 10.1002/cncr.22821

View details for Web of Science ID 000247985600019

View details for PubMedID 17569105

Abstract

To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors and to determine whether carbamazepine reduces oxaliplatin-induced neurotoxicity.Three regimens of oxaliplatin (given intravenously over 2 hours) were tested: regimen A (100 mg/m2, 130 mg/m2, or 160 mg/m2 every 3 weeks to determine the MTD of oxaliplatin); regimen B (to determine whether carbamazepine starting 24 hours before and ending 48 hours after oxaliplatin reduced the dose-limiting neurotoxicity and increased the MTD of regimen A); and regimen C (to evaluate the safety of a fixed dose two-thirds the MTD of regimen A given every 2 weeks [more frequent administration but comparable dose intensity]).Twenty-six patients were enrolled on regimens A (n = 11), B (n = 6), and C (n = 9). The DLT was grade 3 pharyngolaryngeal dysesthesia, sensory neuropathy, and ataxia at 160 mg/m2. The MTD was 130 mg/m2 every 3 weeks. At the MTD, the median clearance rate of ultrafiltrable platinum was 9.7 L/h/m2 (range, 6.5 to 15.5 L/h/m2). Addition of carbamazepine permitted dose escalation to 160 mg/m2 without DLT. DLT was not observed with a fixed dose of 85 mg/m2 given every 2 weeks. On all regimens, hematologic toxicity was mild. No significant nephrotoxicity, ototoxicity, or cumulative neurologic toxicity was observed.The DLT, MTD, PK, and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors are similar to those observed in adults. Carbamazepine may reduce the dose-limiting neurotoxicity of oxaliplatin.

View details for DOI 10.1200/JCO.2006.08.2388

View details for Web of Science ID 000247010400022

View details for PubMedID 17538173

Abstract

Morphologically, the distinction between undifferentiated embryonal sarcoma of the liver (UESL) and biliary tract rhabdomyosarcoma (RMS) can be uncertain because of some shared pathologic similarities. Patients with UESL have been consistently but erroneously enrolled in Children's Oncology Group (COG) treatment protocols because UESL was equated with RMS, despite the differing primary treatment modalities of these entities. Review of COG pathology files yielded 20 cases of UESL that were compared to 25 cases of biliary tract RMS. Clinicopathologic features including immunohistochemical staining were examined. In the UESL cases, the male:female ratio was 1:1 and the median age was 10.5 years. Histologically, hyaline globules and diffuse anaplasia were consistently present. The cases of RMS had a male:female ratio of 1.8:1 with a median age of 3.4 years and routinely lacked diffuse anaplasia and hyaline globules. Polyclonal desmin and muscle-specific actin were variably immunoreactive in UESL and RMS; however, myogenin and myogenic regulatory protein D1 (MyoD1) were uniformly negative in UESL and routinely positive in the majority of biliary tract RMS. Myogenin, in particular, was highly significant (P = 0.0003) in distinguishing RMS from UESL. With a median follow-up of 8 months, 11 of 18 patients with UESL were still alive. The estimated 5-year survival for biliary tract RMS was 66%. Establishing the correct diagnosis of these distinct clinical and pathologic entities is important, as surgery alone may be curative in UESL, whereas initial chemotherapy is often recommended for the treatment of biliary tract RMS.

View details for Web of Science ID 000247949700001

View details for PubMedID 17378682

Abstract

This study aimed to develop objective models of radiation effects on musculature in children with soft tissue sarcoma using treatment dosimetry and clinical and quantitative magnetic resonance imaging (MRI) parameters that may be used to guide treatment planning or predict side effects.In the initial 13 patients undergoing external beam radiation therapy (RT) on a Phase II study of conformal or intensity-modulated RT for the treatment of soft tissue sarcoma approved by an Institutional Review Board, we evaluated quantitative MRI changes in the musculature to assess radiation-related treatment effects. Patients with soft tissue sarcoma, including Ewing's sarcoma, had quantitative T1, T2 and dynamic enhanced MRI (DEMRI) performed before, during (Week 4) and after RT (Week 12). Regions of interest were selected in consistent locations within and outside the high-dose regions (on ipsilateral and contralateral sides when available). Mean RT dose, T1, T2 and DEMRI parameters were calculated and modeled using a mixed random coefficient dose model.The mean doses to the high- and low-dose regions were 56.4 Gy (41.8-75.3 Gy) and 13.0 Gy (0.1-37.5 Gy), respectively. Compared with tissues distant from the tumor bed, maximal enhancement was significantly increased in tissues adjacent to the tumor/tumor bed prior to RT (60.6 vs. 44.2, P=.045) and remained elevated after 12 weeks. T1 was significantly elevated in tissues adjacent to the tumor bed prior to RT (942.4 vs. 759.0, P=.0078). The slope of longitudinal change in T1 was greater for tissues that received low-dose irradiation than those that received high-dose irradiation (P=.0488). The effect of dose on the slope of T2 was different (P=.0333) when younger and older patients are compared.Acute affects of irradiation in muscle are quantifiable via MRI. These models provide evidence that quantifiable MRI parameters may be correlated with patient parameters of radiation dose and clinical factors including patient age. Long-term follow-up will be required to determine if acute changes correlate with clinically significant late effects.

View details for DOI 10.1016/j.mri.2006.08.004

View details for Web of Science ID 000242946800006

View details for PubMedID 17145403

Abstract

This paper describes a recent tumor board presentation conducted at our institution involving an adolescent with gestational choriocarcinoma. Despite its rarity in pediatrics, gestational choriocarcinoma offers unique diagnostic, treatment and off-therapy considerations in adolescent patients who have become pregnant. Key features and findings of the case as well as important management issues will be discussed.

View details for PubMedID 16220549

View details for DOI 10.1200/JCO.2006.07.1878

View details for Web of Science ID 000240052300048

Abstract

Unlike osteosarcoma, the Ewing sarcoma family of tumors (ESFT) has rarely been reported as secondary malignant neoplasms after treatment of childhood cancer. ESFT arising as a second cancer was reviewed and characterized at our childhood cancer center.A retrospective review was undertaken of 11,183 patients age <21 years who were treated for a primary cancer between March 1962 and December 2003 at St. Jude Children's Research Hospital. All cases of ESFT were confirmed to have a rearranged EWS gene.Six cases of ESFT (1.3% of 479 second cancers) were identified in patients previously treated for lymphoma (n = 3), leukemia (n = 1), retinoblastoma (n = 1), or Wilms tumor (n = 1). None of these patients had a family history suggestive of a familial cancer syndrome. The median time between diagnosis of primary cancer and diagnosis of ESFT was 5.9 years (range, 3.1-18.3 years). ESFT occurred in typical anatomic locations: rib (n = 2), chest wall soft tissues (n = 2), pelvis (n = 1), and extremity (n = 1). One tumor arose at the margin of a previous radiotherapy field and 1 arose distant from previous radiotherapy fields; all other patients had not received radiotherapy. Three patients are alive at the time of this report, including 2 whose ESFT was diagnosed more than 8 years ago.ESFT occurs rarely after treatment of a primary cancer during childhood, and most cases do not appear to be related to radiation therapy. Long-term survival can be achieved in some patients, and therefore secondary ESFT should be treated with curative intent.

View details for DOI 10.1002/cncr.21962

View details for Web of Science ID 000238469500026

View details for PubMedID 16721801

Abstract

Epithelioid sarcoma is a rare soft tissue sarcoma with a propensity for local aggressiveness, regional nodal spread, and pulmonary metastases. We report a case of epithelioid sarcoma in a neonate with bilateral optic nerve hypoplasia who developed liver, kidney, and bone metastases. The unusual presenting features and pattern of disease progression in this patient suggest that a different disease evaluation strategy should be considered for infants with epithelioid sarcoma.

View details for DOI 10.1016/j.jpedsurg.2006.03.014

View details for Web of Science ID 000239279200035

View details for PubMedID 16818048

View details for DOI 10.1200/JCO.2005.05.4957

View details for Web of Science ID 000237124300032

View details for PubMedID 16622276

Abstract

Intensified chemotherapy may improve the outcome of patients with high-risk pediatric sarcomas. Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide are highly effective against pediatric sarcomas. The authors investigated the feasibility of administering these agents concomitantly within a defined period.In the prospective high-risk sarcoma (HIRISA) Phase II trial HIRISA1, pediatric patients with high-risk sarcomas received 3 cycles of intensive vincristine, ifosfamide, etoposide, cyclophosphamide, and doxorubicin (VACIE) before radiotherapy and/or surgery began at Week 9 with concurrent vincristine, cyclophosphamide, and doxorubicin (Week 9) and vincristine and ifosfamide (Week 12). Three additional cycles of VACIE were then given. After delayed hematologic recovery in the first 11 patients, the protocol was modified (HIRISA2) to delay local control therapy until after 5 cycles of VACIE (to be completed within 18 weeks). Patients who responded to the protocols were eligible for myeloablative consolidation with autologous stem cell support.Eleven of 24 patients (median age, 14.9 years) had Ewing sarcoma family of tumors, 9 patients had rhabdomyosarcoma, and 4 patients had unresectable desmoplastic small round cell tumors. Seven of 13 patients on HIRISA2, but none of 11 patients on HIRISA1, completed therapy within the specified time. Reversible Grade 4 myelosuppression was the most common toxicity. Major nonhematologic toxic effects were mucositis, nutritional impairment, hypotension, and peripheral neuropathy. Three patients died of toxicity. The 5-year survival and 5-year event-free survival estimates both were 45.8% +/- 11.2%.The feasibility of administering intensive chemotherapy regimens like VACIE was dependent in part on the timing of local control therapy. This regimen was associated with significant toxicity.

View details for DOI 10.1002/cncr.21810

View details for Web of Science ID 000236787500028

View details for PubMedID 16541446

Abstract

The viewpoint of the terminally ill child at the time of an end-of-life decision has not been formally investigated. We identified the preferences of children and adolescents with advanced cancer about their end-of-life care and the factors that influenced their decisions.Pediatric patients 10 or more years of age were interviewed within 7 days of participating in one of the following three end-of-life decisions: enrollment onto a phase I trial (n = 7), adoption of a do not resuscitate order (n = 5), or initiation of terminal care (n = 8). The patient, a parent, and the primary pediatric oncologist were interviewed separately by using open-ended interview questions.Twenty patients, aged 10 to 20 years (mean, 17 years and 4 months), with a refractory solid tumor (n = 12), brain tumor (n = 4), or leukemia (n = 4) participated. Eighteen patients (90%) accurately recalled all of their treatment options and identified their own death as a consequence of their decision. The factors that were most frequently identified included the following: for patients, caring about others (n = 19 patients); for parents, the child's preferences (n = 18 parents); and for physicians, the patient's prognosis and comorbid conditions (n = 14 physicians).These children and adolescents with advanced cancer realized that they were involved in an end-of-life decision, understood the consequences of their decision, and were capable of participating in a complex decision process involving risks to themselves and others. The decision factors most frequently reported by patients were relationship based; this finding is contrary to existing developmental theories.

View details for DOI 10.1200/JCO.2005.10.538

View details for Web of Science ID 000234230400019

View details for PubMedID 16172453

Abstract

The aim of this study was to determine predictors of outcome in childhood truncal rhabdomyosarcoma.Retrospective chart review evaluating the impact of demographic features, disease characteristics, and the extent and timing of surgical intervention on outcome was performed.Thirty-three patients with a median age of 8 years were identified. Most had advanced Intergroup Rhabdomyosarcoma Study group III (n = 13) or group IV (n = 9) disease. Primary site included 20 (61%) chest wall, 6 (21%) paraspinal, 5 (15%) periscapular, and 1 (3%) abdominal wall. Most tumors were embryonal (n = 21), larger than 5 cm (n = 27), and locally invasive (n = 13); 7 had positive nodes. Tumor size, nodal status, and gross total tumor resection (upfront or delayed) were significant predictors of event-free and overall survival. Tumors 5 cm or smaller were amenable to upfront surgical resection (P = .007). In patients with tumors larger than 5 cm, resection at any time was associated with a 10-year overall survival 57% +/- 13% compared with 8% +/- 5% in those who had no surgery (P = .003). Tumor recurrence was local in 44% of cases, and survival after local recurrence was rare (1 of 8).Tumor size, nodal status, and gross total resection at any time are significant predictors of outcome in truncal rhabdomyosarcoma. Gross tumor excision should be the goal of surgical intervention in this disease.

View details for DOI 10.1016/j.jpedsurg.2005.07.042

View details for Web of Science ID 000233926000003

View details for PubMedID 16291153

Abstract

To document the spectrum and severity of late effects in female survivors of pelvic rhabdomyosarcoma.We reviewed the demographic, diagnostic, treatment, and outcome data of the 26 females treated for pelvic rhabdomyosarcoma at our institution between March 1962 and December 1996 who survived free of disease for 5 or more years. Adverse effects that occurred 5 or more years after diagnosis were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.The most common tumor sites were vagina (n = 7), pelvis/retroperitoneum (n = 6), and bladder (n = 4). All patients received chemotherapy (alkylating agent, n = 23; doxorubicin, n = 16); 22 received radiotherapy (median dose, 46 Gy). Median follow-up of the 23 survivors was 20.3 years. Late effects occurred in 24 patients, 23 of whom had grade 3/4 late effects (median grade 3/4 late effects per patient, three; range, zero to 14). Fourteen patients (54%) required surgery for late complications. The 22 patients who had received radiotherapy had a greater median number of late effects per patient than did the remaining four (9.5 v one; P = .002). The median number of late effects per patient was higher in the 12 patients treated during or after 1984 than in the 14 treated earlier (12.5 v 6.5; P = .041).The burden of late effects in girls treated for pelvic rhabdomyosarcoma is significant and does not seem to be diminishing with advances in treatment. Prospective studies are needed to better assess the impact of these late effects on quality of life and functional outcome, and to refine the treatment approach to pelvic rhabdomyosarcoma.

View details for DOI 10.1200/JCO.2005.12.096

View details for Web of Science ID 000232232000042

View details for PubMedID 16192598

Abstract

Our objective was to review our preliminary experience with PET/CT in evaluating childhood sarcomas including rhabdomyosarcoma (n = 28), the Ewing's sarcoma family of tumors (n = 14), nonrhabdomyosarcoma soft-tissue sarcoma (n = 9), osteosarcoma (n = 8), chondrosarcoma (n = 1), and embryonal sarcoma (n = 1).We found PET/CT useful in depicting an unknown primary rhabdomyosarcoma and detecting unsuspected and unusual metastatic sites of childhood sarcomas. It was useful in monitoring response to chemotherapy, radiation therapy, and radiofrequency ablation and aided the postoperative evaluation of tumor resection sites.

View details for Web of Science ID 000228035600044

View details for PubMedID 15788613

Abstract

More than half of pediatric rhabdomyosarcoma cases have intermediate-risk features and suboptimal outcome (3-year failure-free survival estimates, 55 to 76%). Dose intensification of known active agents may improve outcome.This pilot study evaluated the feasibility of dose intensification of cyclophosphamide in previously untreated patients ages < 21 years with intermediate-risk rhabdomyosarcoma. Induction therapy comprised four 3-week cycles of VAC: vincristine (V) 1.5 mg/m2 on days 0, 7, and 14; actinomycin D (A) 1.35 mg/m2 on day 0; and dose-intensified cyclophosphamide (C) on days 0, 1, and 2. The three cyclophosphamide dose levels tested were as follows: (a) 1.2 g/m2/dose; (b) 1.5 g/m2/dose; and (c) 1.8 g/m2/dose. Continuation therapy comprised nine additional cycles of VAC with 2.2 g/m2/cycle of C. Radiotherapy was administered at week 0 (parameningeal tumors with intracranial extension) or week 12 or 15 (all others).Between October 1996 and August 1999, 115 eligible patients were enrolled. Three of 15 patients treated at dose level 2 experienced life-threatening dose-limiting toxicity (typhlitis +/- other severe toxicity). Dose level 1 was the maximum-tolerated dose, and 91 evaluable patients were treated at this level. The 3-year failure-free and overall survival estimates for patients treated at the maximum-tolerated dose were 52% (95% confidence interval, 41-64%) and 67% (95% confidence interval, 56-77%), respectively, at a median follow-up of 3 years.A 64% increase in the standard cyclophosphamide dosage during induction (to 3.6 g/m2/cycle) was tolerated. However, outcomes were similar to those observed at lower dosages, suggesting that alkylator dose intensification does not benefit patients with intermediate-risk rhabdomyosarcoma.

View details for Web of Science ID 000224080200014

View details for PubMedID 15447992

Abstract

The aim of our study was to describe late failures in children who initially survived event-free five years from a diagnosis of rhabdomyosarcoma. Charts of children enrolled in the Intergroup Rhabdomyosarcoma Study Group (IRSG) trials III, IV pilot and IV (1984-1997) who survived five years event-free and subsequently experienced an adverse event (disease recurrence, second malignant neoplasm or death from other causes) were reviewed. Of the 2534 enrolled patients, 1160 were event-free at five years and 48 subsequently experienced a late event. The estimated 10-year event rate for the 1160 patients who were alive and event-free at five years was 9% (95% Confidence Interval (CI) 5%, 13%). Patients with both advanced disease (Group III/IV) and large primary tumours at diagnosis (> 5 cm) were at the highest risk for late events (19%; 95% CI 8%, 30%). Late events after successful treatment for rhabdomyosarcoma occur in 9%. Those with advanced disease and large primary tumours have the highest risk of late events.

View details for DOI 10.1016/j.ejca.2004.04.005

View details for Web of Science ID 000223456600018

View details for PubMedID 15288290

Abstract

Brain metastases of pediatric germ cell tumors are uncommon, and there is limited information regarding their incidence, clinical presentation, response to treatment, and influence on survival.The authors reviewed the experience with brain metastases from pediatric germ cell tumors at St. Jude Children's Research Hospital (Memphis, TN) over a 40-year period.Between March 1962 and February 2002, 16 of 206 patients with germ cell tumors (7.8%) had brain metastases at the time of initial presentation (n = 2), later in the course of the illness (n = 12), or at autopsy (n = 2). Twelve of 16 patients (75%) had symptoms referable to the brain (nausea/emesis, headaches, or seizures), and 14 (88%) had pulmonary metastases at the time brain metastases were identified. Patients with brain metastases were more likely to have an extragonadal primary tumor (P = 0.013), advanced-stage disease at initial presentation (P = 0.016), and choriocarcinoma within the primary tumor (P < 0.001). The incidence of brain metastases was significantly lower in the second 2 decades of the study period (5 of 135 patients [3.7%]) than in the first 2 decades (11 of 71 patients [15.5%]; P = 0.005). Two of the 16 patients in the current study are long-term survivors.Brain metastases are uncommon in childhood germ cell tumors, and their incidence appears to be decreasing. In the current study, most patients with such metastases were symptomatic and had pulmonary metastases at the time brain metastases were identified. Patients with the highest risk of developing brain metastases include those with extragonadal tumors, those with high disease stage at initial presentation, and those with choriocarcinoma as a component of the primary tumor. The probability of survival is poor, although a small proportion of patients may become long-term survivors.

View details for DOI 10.1002/cncr.20411

View details for Web of Science ID 000222770100021

View details for PubMedID 15274076

View details for DOI 10.1016/j.ctrv.2003.11.001

View details for Web of Science ID 000220831700004

View details for PubMedID 15059650

Abstract

Thyroid carcinomas can occur as a primary malignancy (PTM) or secondary after another malignancy (STM). Information about the presentations and outcomes of patients with STM are limited. The authors sought to compare the clinical characteristics, course, and outcomes of patients with primary or secondary thyroid malignancies.The authors reviewed the medical records of 8 children with PTM and 17 children with STM referred to St Jude Children's Research Hospital between February 1962 and February 2002 for evaluation and treatment of malignant thyroid carcinoma.The 8 children who had primary thyroid carcinoma had it diagnosed at a median age of 12.5 years (range, 7.3 to 16.3 years). Seven patients had papillary carcinoma, and 1 patient had follicular carcinoma. Three of the 8 (37.5%) had metastatic disease involving regional lymph nodes; 2 patients (25.0%) had lung metastases. Six patients required radioactive iodine (I 131) ablation for residual or metastatic disease after surgical resection. All 8 patients remain alive a median of 22.6 years after diagnosis (range, 0.7 to 30.5 years); 1 continues to receive radioactive iodine (I 131) ablation for persistent disease. Seventeen patients had thyroid carcinoma as a second malignant neoplasm after treatment for acute lymphoblastic leukemia (n = 6), Hodgkin's disease (n = 5), central nervous system tumor (n = 2), Wilms' tumor (n = 1), retinoblastoma (n = 1), non-Hodgkin's lymphoma (n = 1), or neuroblastoma (n = 1). Patients with secondary thyroid carcinoma presented at a median age of 21.5 years (range, 15.3 to 42.6 years), a median of 16.2 years (range, 0.9 to 29.2 years) after diagnosis of the primary cancer. Twelve of the 17 patients (70.6%) had received radiation to the thyroid gland during therapy for the primary cancer. Four patients (23.5%) had metastatic disease involving regional lymph nodes. Six patients (35.3%) required I(131) ablation for residual or metastatic disease after thyroidectomy. At the time of this report, all 17 patients are alive and in continue to be free of disease.Pediatric thyroid carcinoma is uncommon and responds well to current therapy. Given the limited period of follow-up of our cohort of secondary malignant thyroid tumors that arise after childhood cancer, these lesions appear to have similar presentations and outcomes when compared with primary carcinomas and can therefore be managed in the same manner.

View details for DOI 10.1016/S0022-3468(03)00563-3

View details for Web of Science ID 000186565200003

View details for PubMedID 14614703

Abstract

Pediatric paraganglioma is rare and extraadrenal paraganglioma has not been characterized in children.The authors reviewed the medical records and pathology samples of children with extraadrenal paraganglioma treated at our institution between December 1978 and September 2000. Clinical presentation, treatment, and outcome were evaluated.Eight patients (median age, 11.4 years) were identified, 4 were boys and none had a family history of paraganglioma or associated syndromes. Primary tumors arose in the retroperitoneum (n = 3), carotid body (n = 2), jugulotympanic ganglion (n = 1), cervical-paraspinal region (n = 1), and lung (n = 1). Extraadrenal paraganglioma had not been suspected at presentation in any patient. Of 5 patients who underwent gross total resection at the time of diagnosis, 4 remain disease free, 1 had microscopic residual tumor and died of disease. Three patients had initially unresectable disease, 2 are disease free after neoadjuvant therapy and delayed surgery, and 1 has persistent disease after tumor embolization and radiotherapy.Pediatric extraadrenal paraganglioma occurs most commonly in the retroperitoneum and head and neck, and the diagnosis usually is not suspected at the time of presentation. Surgery is the mainstay of treatment, and outcome is good after gross total resection. Neoadjuvant therapy can facilitate complete resection of initially unresectable tumors.

View details for DOI 10.1016/S0022-3468(03)00388-9

View details for Web of Science ID 000185741600008

View details for PubMedID 14523812

Abstract

The Ewing sarcoma family of tumors (ESFT) comprises a group of well-characterized neoplasms with aggressive behavior. Despite significant progress with the use of intensive multiagent chemotherapy and local control measures, a significant proportion of patients die of disease progression. Chemotherapy dose intensification and autologous hematopoietic stem cell transplant (HSCT) have been explored by many institutions without obvious benefit in high-risk patients. Our current understanding in the biology and treatment of ESFT suggests that a more rational approach to the development of risk-adapted therapy should be undertaken.We performed a review of the most relevant data regarding the current status in the treatment of ESFT. The results of the major American and European cooperative groups were analyzed, including the treatment strategies used and the prognostic factors identified for both localized and metastatic ESFT.The intensification of alkylating agents and topoisomerase-II inhibitors is feasible and has resulted in some survival improvement for selected patients. This benefit seems to be restricted to patients with localized disease, and a proportion of survivors are at risk of developing treatment-related hematologic malignancies. Nevertheless, these advances have resulted in a re-definition of prognostic factors, which may help to define risk groups based on tumor load parameters as well as biologic factors (type of fusion transcript and histologic response to chemotherapy). Patients with advanced metastatic disease may benefit from HSCT. New strategies such as immunotherapy and the use of biologic modifiers may have a role in the treatment of ESFT.Future treatment for ESFT should consider risk-adapted strategies and the inclusion of newer therapies such as biologic modifiers for the minimal residual disease. A modified risk-adapted therapy is proposed.

View details for DOI 10.1002/mpo.10240

View details for Web of Science ID 000181946200002

View details for PubMedID 12652615

View details for Web of Science ID 000181897901655

Abstract

Osteosarcoma arising in soft tissues is exceedingly rare in children. The tumor most often affects older adults, involves the lower extremity, responds poorly to chemotherapy, and carries a grave prognosis. The authors describe a 12-year-old girl with an extraosseous osteosarcoma of the left sternocleidomastoid muscle with pulmonary metastases. The patient responded well to neoadjuvant chemotherapy and remains disease-free nearly 3 years after her initial diagnosis. The authors review available information about this disease in children and adults. Children with extraosseous osteosarcoma may have a more favorable response to treatment than adults; thus, a curative approach using combined modality therapy appears warranted.

View details for Web of Science ID 000180289900014

View details for PubMedID 12544778

Abstract

The aim of this study was to determine the importance of pretreatment reexcision (PRE) of pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) after initial unplanned resection.The authors retrospectively reviewed the records of 116 consecutive patients with surgically resected NRSTS treated at their institution between February 1978 and September 1999. Ninety-four (81.0%) patients had undergone unplanned resections before referral to their institution for further therapy. Demographic data, tumor characteristics, treatment administered, and outcomes were recorded.Sixty-nine patients (73.4%) underwent PRE at a median interval after the initial unplanned resection of 29 days. Twenty-five patients were thought unsuitable for PRE because of the proximity to vital neurovascular bundles. Tumors deemed not feasible for PRE were more likely to be greater than 5 cm (P =.0094) and high grade (P =.0200). Tumor was found in 33 (47.8%) of the PRE specimens, and 24 of these patients (72.7%) were deemed disease free after achieving negative surgical margins. Residual tumor was more likely to be found after PRE in head and neck primary tumors than in trunk wall or extremity primary tumors (P =.0128). There were no local failures in the 60 PRE patients who achieved clear margins. The estimated 5-year event-free and 5-year overall survival rates in these 60 patients were 98.3% +/- 2.0% and 98.2% +/- 2.1%, respectively.Pretreatment reexcision should be performed whenever feasible in pediatric patients with NRSTS who had an initial unplanned resection. The proportion of patients with residual tumor in the PRE specimen is high, and negative microscopic margins can be achieved after PRE in most patients with residual tumor. Despite delay in obtaining a complete surgical resection, no local recurrences were seen. The possibility of NRSTS should be considered when resecting a soft tissue mass in children, and diagnostic incisional biopsy followed by wide local excision with negative microscopic margins should be the surgical goal.

View details for DOI 10.1053/jpsu.2002.35405

View details for Web of Science ID 000178353600008

View details for PubMedID 12378447

View details for Web of Science ID 000177574600045

View details for PubMedID 12185067

View details for DOI 10.1002/mpo.10099

View details for Web of Science ID 000176535100007

View details for PubMedID 12116060

Abstract

To describe the clinical features, response to therapy, and outcome of pediatric patients with initially unresected nonmetastatic nonrhabdomyosarcoma soft tissue sarcoma (NRSTS).We retrospectively reviewed the presenting clinical features and tumor characteristics of all 40 pediatric patients with initially unresected nonmetastatic NRSTS who were seen at our institution between March 1962 and December 1996. A subset of 27 patients for whom complete treatment information was available was analyzed to determine whether response to therapy was associated with local disease control and event-free and overall survival.More than 70% of the 40 patients had tumors with high-risk features (tumor size > 5 cm, high grade, invasiveness). For the 27 patients included in the outcome analysis, 5-year event-free survival and survival estimates were 33% +/- 9% and 56% +/- 10%, respectively. Ten (37%) of these patients had a complete or partial response to neoadjuvant chemotherapy and/or radiotherapy, and only two of the 10 had residual tumor after surgery. Combined chemotherapy and radiotherapy seemed more effective than either modality alone in inducing a response, but the response to neoadjuvant therapy did not predict outcome. Most treatment failures were local, and postrelapse survival was poor (19% +/- 10%).Initially unresected NRSTS constitutes a unique subgroup of pediatric sarcomas that commonly present with high-risk features and respond poorly to neoadjuvant therapy. Only about one third of patients treated with multimodal therapy remain disease-free, and local control is the major limiting factor in achieving cure. More effective risk-directed treatments are needed for this unique subgroup of patients.

View details for DOI 10.1200/JCO.2002.06.066

View details for Web of Science ID 000177286100010

View details for PubMedID 12149295

Abstract

Synovial sarcoma is the most common nonrhabdomyosarcomatous soft-tissue sarcoma in children and young adults. It is characterized by the common t(X;18)(p11.2;q11.2) that results in the fusion of SYT on chromosome 18 to one of two closely related and adjacent genes on the X chromosome, SSX1 or SSX2. Here we describe a poorly differentiated, monophasic synovial sarcoma in a 17-year-old adolescent boy. Hyperdiploidy, a t(X;18)(q13;q11), and other structural abnormalities were detected by conventional cytogenetic analysis. Fluorescence in situ hybridization with the PAC probe RP3-519N18, which is specific for the Xp11 region, resulted in a signal on the der(Xq), a finding consistent with a pericentric inversion of the X chromosome that resulted in a t(X;18)(p11.2;q11.2)inv(X)(p11.2q13). Real-time polymerase chain reaction using primer sets specific for SYT-SSX1 and SYT-SSX2 confirmed the presence of an SYT-SSX1 fusion transcript. Our finding of this unique and complex translocation in synovial sarcoma demonstrates the utility of molecular methods in confirming the diagnosis of synovial sarcoma.

View details for Web of Science ID 000174032900009

View details for PubMedID 11850075

View details for Web of Science ID 000172915000019

Abstract

To the authors' knowledge, the incidence of brain metastases at the time of diagnosis in children with metastatic rhabdomyosarcoma (RMS) arising outside the head and neck region is unknown, and routine imaging to identify metastatic brain involvement is costly.The authors retrospectively reviewed the results of computed tomography (CT) or magnetic resonance imaging (MRI) scans of the head, which was mandated by protocol, in patients with metastatic RMS arising outside the head and neck region who were enrolled on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV; 1991--1997).Of 100 eligible patients with metastatic RMS arising outside the head and neck region, 56 (56%) underwent head CT (n = 51) and/or MRI (n = 11) scans. Seven of these 56 patients (12.5%) had abnormal scans. Three patients with physical findings suggesting head or neck pathology underwent imaging that confirmed the presence of metastases in bone (one patient), orbit (one patient), or lymph nodes (one patient). One patient who presented with seizures had imaging findings consistent with cerebral embolic infarctions. Of three asymptomatic patients, one had bone metastases that also were identified on skeletal survey and one had bone metastases in the base of the skull that were not identified on bone scan. The remaining asymptomatic patient had a retroperitoneal paraspinal tumor with spinal canal extension and subsequently developed leptomeningeal disease dissemination.Brain metastases are uncommon at the time of initial diagnosis of metastatic RMS arising outside the head and neck region, and the majority of abnormalities detected on head CT or MRI scans are evident clinically or on other imaging studies. Patients with clinical findings suggesting intracranial pathology and those with paraspinal tumors may benefit from brain imaging, but cost savings may be realized by foregoing imaging in patients without these features.

View details for Web of Science ID 000169666200016

View details for PubMedID 11443617

View details for Web of Science ID 000168929900039

View details for PubMedID 11373233

Abstract

The benefit of whole-lung irradiation (WLI) for patients who have pulmonary metastases (PM) of Ewing sarcoma family tumors (ESFT) is unclear. At our institution, WLI is reserved for patients with PM that do not respond completely to induction chemotherapy. We reviewed our experience to assess the impact of WLI on clinical outcome.Twenty-eight patients with ESFT and PM were treated in three consecutive institutional trials (1979-1996). Extent of pulmonary involvement at diagnosis, response of PM after induction chemotherapy, local treatment of PM thereafter, and clinical outcome were recorded. Treatment included primary tumor surgery and/or radiotherapy and 42 to 58 weeks of multiagent chemotherapy.Only eight patients (29%) received WLI. For the entire study group, the estimated 5-year event-free survival was 22.9% +/- 9.0%; the 5-year survival was 37.3% +/- 9.8%. Complete resolution of PM after induction chemotherapy was not correlated with survival (P = 0.53), nor was treatment with WLI (P = 0.87).The comparable survival of patients with poor and good response of PM to induction chemotherapy suggests that WLI may benefit poor responders. The use of WLI in good responders may provide similar benefit and merits further study.

View details for Web of Science ID 000166903000004

View details for PubMedID 11216713

Abstract

Brain metastases in children with cancer are rare and their incidence is significantly lower (5-10%) than that reported in adults. The development of metastatic brain tumours in children is usually a manifestation of advanced disease and commonly occur after, or at the time of progression at other sites. This review summarises the salient clinical features of the most common paediatric solid tumours that metastasize to the brain including neuroblastoma, musculoskeletal sarcomas, germ cell tumours and melanoma.

View details for PubMedID 11734866

View details for DOI 10.1200/JCO.2000.18.21.3741

View details for Web of Science ID 000165135800023

View details for PubMedID 11054452

Abstract

To better characterize childhood carcinoid tumors, the authors reviewed the clinical presentation, treatment, and outcomes of pediatric patients with these rare tumors.A retrospective review was conducted of medical records and pathologic materials of all children with carcinoid tumors treated at St Jude Children's Research Hospital between December 1977 and March 1999.Eight patients (median age, 12.7 years) were identified; 2 were boys, and 7 were white. Primary tumor sites were the appendix (n = 5), small intestine (n = 1), bronchus (n = 1), and 1 unknown site. In 7 cases, carcinoid tumor was not suspected at the time the tumor was identified. Seven patients had localized disease; 5 remain disease-free after complete resection, and 2, whose carcinoid tumors were identified incidentally, died of metastatic mucinous adenocarcinoma of the colon. One patient who presented with symptoms of carcinoid syndrome had metastatic disease that responded poorly to cytotoxic chemotherapy and remains alive with active disease.Although most pediatric carcinoid tumors arise in the appendix, these tumors also occur in other primary sites. Clinical awareness and early diagnosis are important factors in preventing morbidity and mortality. Outcomes are excellent for patients with localized disease that is completely resected, but those with metastatic disease fare poorly. New therapeutic strategies are needed for these patients.

View details for Web of Science ID 000089146600002

View details for PubMedID 10999679

Abstract

The associations between age at diagnosis, tumor characteristics, and outcome in children diagnosed with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) were studied.Retrospective review was conducted of 192 children from 1962 through 1996. Patients were divided into groups: birth to 1 year (n = 13), 1 to 5 years (n = 26), 5 to 10 years (n = 49), 10 to 15 years (n = 55), and older than 15 years (n = 49) of age at diagnosis. Characteristics including IRS group, histological grade and pattern, tumor size, and invasiveness were investigated. Survival rate was estimated by age group. The median follow-up was 8.8 years (range, 2 to 28 years).There were 81 group I patients, 40 group II, 41 group III, and 30 group IV. A significant difference of IRS groups among the age groups was seen (P = .034). There were no IRS group IV patients less than 1 year of age; 50% of IRS group IV patients were older than 15 years. A significant difference in the distribution of histological grade among the age groups (P = .032) was seen. Ten of 13 (77%) children less than 1 year of age had low-grade tumors, whereas 42%, 45%, 60%, and 37% of patients aged 1 to 5, 5 to 10, 10 to 15, and older than 15 years, respectively, had low-grade tumors. Patients older than 15 years had the highest incidence of invasive tumors (59%). Histological pattern also varied with age. The most prevalent histology in the less-than-1-year age group was infantile fibrosarcoma. No predominant histology was seen in the 1- to 5-year age group. Malignant fibrous histiocytoma was the most frequent histological subtype in children between 5 and 10 years of age. In the 10- to 15-year age group and children older than 15 years the malignant peripheral nerve sheath tumor and synovial sarcoma were the most prevalent subtypes. Without adjusting for any other factors, age group was prognostic of survival (P = .007). Patients less than 1 year at diagnosis had the best outcome, with a 5-year survival rate of 92% +/- 9%. Five-year estimates were lowest for patients older than 15 years (49% +/- 7%).Significant differences in IRS group, histological grade, and histological subtype were observed in different age groups. Infants with NRSTS were more likely to have low grade, less invasive, and lower stage tumors. These characteristics may account for their improved prognosis.

View details for Web of Science ID 000087429900043

View details for PubMedID 10873042

Abstract

Rhabdomyosarcoma (RMS) of the biliary tract is rare, and, in addition to multiagent chemotherapy with or without radiotherapy (RT), some investigators recommend aggressive surgery. To assess the role of surgery, records of all 25 eligible patients with biliary RMS enrolled in IRSG studies I through IV from 1972 to 1998 were reviewed.Treatment included surgery with or without vincristine, dactinomycin, cyclophosphamide, doxorubicin, cisplatin, etoposide, ifosfamide, and with or without RT. Data evaluated included clinical presentation, treatment, complications, and outcome.Diagnostic imaging identified the primary tumor but failed to identify regional metastases. Despite aggressive surgery, gross total resection at diagnosis was possible in only 6 cases, 2 of which had negative surgical margins. Although only 6 (29%) patients without distant metastases underwent gross total resection, estimated 5-year survival rate was 78% (95% CI 58%, 97%). Infectious complications were common and frequently associated with external biliary drains. Five (20%) died within the first 2 months, 3 of sepsis.Surgery is critical for establishing an accurate diagnosis and determining the extent of regional disease. Gross total resection is rarely possible despite aggressive surgery, and outcome is good despite residual disease after surgery. External biliary drains increase the risk of postoperative infectious complications.

View details for Web of Science ID 000085128700056

View details for PubMedID 10693686

Abstract

The rarity and heterogeneity of pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) has precluded meaningful analysis of prognostic factors associated with surgically resected disease. To define a population of patients at high risk of treatment failure who might benefit from adjuvant therapies, we evaluated the relationship between various clinicopathologic factors and clinical outcome of children and adolescents with resected NRSTS over a 27-year period at our institution.We analyzed the records of 121 consecutive patients with NRSTS who underwent surgical resection between August 1969 and December 1996. Demographic data, tumor characteristics, treatment, and outcomes were recorded. Univariate and multivariate analyses of prognostic factors for survival, event-free survival (EFS), and local and distant recurrence were performed.At a median follow-up of 9.2 years, 5-year survival and EFS rates for the entire cohort were 89% +/- 3% and 77% +/- 4%, respectively. In univariate models, positive surgical margins (P =.004), tumor size > or = 5 cm (P <.001), invasivene (P =.002), high grade (P =.028), and intra-abdominal primary tumor site (P =.055) adversely affected EFS. All of these factors except invasiveness remained prognostic of EFS and survival in multivariate models. Positive surgical margins (P =.003), intra-abdominal primary tumor site (P =.028), and the omission of radiation therapy (P =.043) predicted local recurrence, whereas tumor size > or = 5 cm (P <.001), invasiveness (P <.001), and high grade (P =.004) predicted distant recurrence.In this largest single-institution analysis of pediatric patients with surgically resected NRSTS, we identified clinicopathologic features predictive of poor outcome. These variables should be prospectively evaluated as risk-adapted therapies are developed.

View details for Web of Science ID 000084043300002

View details for PubMedID 10577841

View details for Web of Science ID 000082999600291

Abstract

The human TSG101 gene was cloned and mapped to chromosome 11p15, a site suspected to contain a tumor suppressor gene involved in a variety of human cancers. Subsequent investigation described the presence of abnormally spliced transcripts and point mutations of TSG101 in breast cancer. Thus, we performed RT-PCR amplification of the entire open reading frame of TSG101 to test for aberrant transcripts in various human tumor cell lines derived from breast, bladder, head and neck, and lung cancer. In addition, we performed RT-PCR on cDNA from primary human breast and Wilms' tumor tissue. We found a single band of the expected size in 10 of 11 breast cancers and 6 of 6 Wilms' tumor samples after the first round of PCR. The remaining breast cancer sample displayed a barely visible smaller band. However, aberrant bands appeared in most cases after performing nested PCR casting doubt on the physiologic relevance of these spliced variants. We then searched for small intragenic mutations by complete sequence analysis of TSG101 in breast cancer cell lines and tumors, as well as in Wilms' tumors and normal fetal and adult kidney. No point mutations were found in any of the samples, including four breast tumors with chromosomal loss at 11p15. We found no consistent evidence of aberrant splicing or point mutations in breast cancer or Wilms' tumor suggesting that TSG101 is not a primary target of inactivation in human cancer.

View details for Web of Science ID 000073812200014

View details for PubMedID 9652749