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Florette Gray Hazard, MD

  • Florette Kimberly Gray Hazard


Anatomic & Clinical Pathology

Work and Education

Professional Education

Georgetown University Internal Medicine Residency, Washington, DC, 06/30/2002


Stanford Hospital and Clinics, Stanford, CA, 06/30/2003


Stanford Hospital and Clinics, Stanford, CA, 06/30/2006


Childrens Hospital of Philadelphia Pediatric Pathology, Philadelphia, PA, 06/30/2008

Stanford Hospital and Clinics, Stanford, CA, 06/30/2007

Board Certifications

Anatomic & Clinical Pathology, American Board of Pathology

Pediatric Pathology, American Board of Pathology

All Publications

Sclerosing Epithelioid Fibrosarcoma of the Kidney: First Reported Case in a Young Child. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society Kurtz, J. L., Tan, S. Y., Hazard, F. K. 2021: 1093526620977738


Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma primarily arising in the deep soft tissue of the extremities and trunk. Despite having the morphologic appearance of a low-grade sarcoma, it generally has an aggressive clinical course with frequent local recurrences and distant metastases. It typically occurs in middle aged adults and is characterized by immunoexpression of MUC4 and recurrent gene fusions, most commonly EWSR1-CREB3L1. We report a primary renal SEF in a 4-year-old male. To our knowledge, this is the youngest patient reported with SEF and the second case of SEF in a pre-adolescent child. It is the eleventh reported case of primary renal SEF in the literature. While SEF arising in visceral organs is rare, the kidney is the most common primary site of any visceral organ. This case demonstrates SEF can occur in pre-adolescents, is an important consideration when evaluating sarcomas in young children, and should be considered in the differential diagnosis for primary renal tumors.

View details for DOI 10.1177/1093526620977738

View details for PubMedID 33470922

ALK-positive compound Spitz nevus with extensive perineural and intraneural neurotropism. Journal of cutaneous pathology Brown, R. A., Wang, J. Y., Raghavan, S. S., Zhang, J., Wan, D. C., Born, D., Koo, M., Hazard, F. K., Novoa, R. A., Rieger, K. E. 2020

View details for DOI 10.1111/cup.13890

View details for PubMedID 33034114

Integrative analysis of whole-genome and RNA sequencing in high-risk pediatric malignancies Shah, A. T., Breese, M. R., Lee, A. G., Martell, H. J., Tanasa, B., Leung, S. G., Spillingeer, A., Liu, H., Behroozfard, I., Phuong Dinh, Hazard, F. K., Cho, S., Rangaswami, A., Lacayo, N. J., Spunt, S. L., Cooney, T., Michlitsch, J. G., Agarwaal, A. K., Sweet-Cordero, A. AMER ASSOC CANCER RESEARCH. 2020: 9091
The Role of the Clinical Laboratory in the Diagnosis of Neuroblastoma JOURNAL OF APPLIED LABORATORY MEDICINE Hazard, F. K., Shimada, H. 2020; 5 (2): 25456
EPIGENETIC TARGETING OF TERT-ASSOCIATED GENE EXPRESSION SIGNATURE IN HUMAN NEUROBLASTOMA WITH TERT OVEREXPRESSION. Cancer research Huang, M. n., Zeki, J. n., Sumarsono, N. n., Coles, G. L., Taylor, J. S., Danzer, E. n., Bruzoni, M. n., Hazard, F. K., Lacayo, N. J., Sakamoto, K. M., Dunn, J. C., Spunt, S. L., Chiu, B. n. 2020


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

Three Infants with Pathogenic Variants in the ABCA3 Gene: Presentation, Treatment and Clinical Course. The Journal of pediatrics Si, n. n., X, n. n., Steffes, n. n., L C, n. n., Schymick, n. n., J C, n. n., Hazard, n. n., F K, n. n., Tracy, n. n., M C, n. n., Cornfield, n. n., D N, n. n. 2020

View details for DOI 10.1016/j.jpeds.2020.12.055

View details for PubMedID 33359301

Differentiation of benign and malignant lymph nodes in pediatric patients on ferumoxytol-enhanced PET/MRI THERANOSTICS Muehe, A., Siedek, F., Theruvath, A., Seekins, J., Spunt, S. L., Pribnow, A., Hazard, F., Liang, T., Daldrup-Link, H. 2020; 10 (8): 361221


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

Impact of a deep learning assistant on the histopathologic classification of liver cancer. NPJ digital medicine Kiani, A. n., Uyumazturk, B. n., Rajpurkar, P. n., Wang, A. n., Gao, R. n., Jones, E. n., Yu, Y. n., Langlotz, C. P., Ball, R. L., Montine, T. J., Martin, B. A., Berry, G. J., Ozawa, M. G., Hazard, F. K., Brown, R. A., Chen, S. B., Wood, M. n., Allard, L. S., Ylagan, L. n., Ng, A. Y., Shen, J. n. 2020; 3: 23


Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p=0.184, OR=1.281), it significantly improved the accuracy (p=0.045, OR=1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p=0.000, OR=4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p=0.000, OR=0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

View details for DOI 10.1038/s41746-020-0232-8

View details for PubMedID 32140566

View details for PubMedCentralID PMC7044422

Pathological overlap of Arrhythmogenic Right Ventricular Cardiomyopathy and Cardiac Sarcoidosis. Circulation. Genomic and precision medicine Kerkar, A., Hazard, F., Caleshu, C. A., Shah, R. L., Reuter, C., Ashley, E. A., Parikh, V. N. 2019


A previously healthy 50-year-old female long-distance runner initially presented to the emergency room with sustained palpitations and was found to be in a hemodynamically stable wide complex tachycardia at 220 bpm. Initial electrocardiogram (ECG) demonstrated monomorphic tachycardia with a right inferoapical ventricular origin (Figure 1A). Echocardiogram revealed normal left ventricular (LV) size and moderately reduced function, but severe right ventricular (RV) enlargement and systolic dysfunction in the absence of elevated pulmonary pressures (Figure 1B). Her ECG in normal sinus rhythm showed T wave inversions in V1-V4 (Figure 1C) and her signal averaged ECG was abnormal with a filtered QRS duration of 150 msec, root mean square amplitude of the last 40 msec of late potentials (RMS40) of 2.16 mV and duration of low amplitude signal (LAS) of 92.5msec. Electrophysiology study confirmed inducible ventricular arrhythmias from the RV, and internal cardiac defibrillator (ICD) was placed.

View details for DOI 10.1161/CIRCGEN.119.002638

View details for PubMedID 31542937

Integrative analysis of whole-genome and RNA sequencing in high-risk pediatric malignancies Breese, M. R., Shah, A. T., Lee, A. G., Tanasa, B., Leung, S. G., Spillinger, A., Liu, H., Behroozfard, I., Phuong Dinh, Hazard, F. K., Rangaswami, A., Spunt, S. L., Lacayo, N. J., Cooney, T., Michlitsch, J. G., Agrawal, A. K., Sweet-Cordero, E. AMER ASSOC CANCER RESEARCH. 2019
Delayed appearance of mature ganglia in an infant with an atypical presentation of total colonic and small bowel aganglionosis: a case report. BMC pediatrics Salimi Jazi, F., Chandler, J. M., Thorson, C. M., Sinclair, T. J., Hazard, F. K., Kerner, J. A., Dutta, S., Dunn, J. C., Chao, S. D. 2019; 19 (1): 93


BACKGROUND: Total colonic and small bowel aganglionosis (TCSA) occurs in less than 1% of all Hirschsprung's disease patients. Currently, the mainstay of treatment is surgery. However, in patients with TCSA, functional outcomes are often poor. A characteristic transition zone in TCSA can be difficult to identify which may complicate surgery and may often require multiple operations.CASE PRESENTATION: We present the case of a male infant who was diagnosed with biopsy-proven total colonic aganglionosis with extensive small bowel involvement as a neonate. The patient was diverted at one month of age based on leveling biopsies at 10cm from the Ligament of Treitz. At 7months of age, during stoma revision for a prolapsed stoma, intra-operative peristalsis was observed in nearly the entire length of the previously aganglionic bowel, and subsequent biopsies demonstrated the appearance of mature ganglion cells in a previously aganglionic segment.CONCLUSIONS: TCSA remains a major challenge for pediatric surgeons. Our case introduces new controversy to our understanding of aganglionosis. Our observations warrant further research into the possibility of post-natal ganglion maturation and encourage surgeons to consider a more conservative surgical approach.

View details for PubMedID 30953480

Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints MOLECULAR IMAGING AND BIOLOGY Chapelin, F., Khurana, A., Moneeb, M., Hazard, F., Chan, C., Nejadnik, H., Gratzinger, D., Messing, S., Erdmann, J., Gaur, A., Daldrup-Link, H. E. 2019; 21 (1): 95104
Genome-Informed Targeted Therapy for Osteosarcoma CANCER DISCOVERY Sayles, L. C., Breese, M. R., Koehne, A. L., Leung, S. G., Lee, A. G., Liu, H., Spillinger, A., Shah, A. T., Tanasa, B., Straessler, K., Hazard, F. K., Spunt, S. L., Marina, N., Kim, G. E., Cho, S., Avedian, R. S., Mohler, D. G., Kim, M., DuBois, S. G., Hawkins, D. S., Sweet-Cordero, E. 2019; 9 (1): 4663
Obstetric and neonatal outcomes in pregnancies complicated by fetal lung masses: does final histology matter? The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians Anderson, J. N., Girsen, A. I., Hintz, S. R., El-Sayed, Y. Y., Davis, A. S., Barth, R. A., Halabi, S. n., Hazard, F. K., Sylvester, K. G., Bruzoni, M. n., Blumenfeld, Y. J. 2019: 17


Purpose: Fetal lung masses complicate approximately 1 in 2000 live births. Our aim was to determine whether obstetric and neonatal outcomes differ by final fetal lung mass histology.Materials and methods: A review of all pregnancies complicated by a prenatally diagnosed fetal lung mass between 2009 and 2017 at a single academic center was conducted. All cases included in the final analysis underwent surgical resection and histology diagnosis was determined by a trained pathologist. Clinical data were obtained from review of stored electronic medical records which contained linked maternal and neonatal records. Imaging records included both prenatal ultrasound and magnetic resonance imaging. Fisher's exact test was used for categorical variables and the Kruskal-Wallis test was used for continuous variables. The level of significance was p<.05.Results: Of 61 pregnancies complicated by fetal lung mass during the study period, 45 cases underwent both prenatal care and postnatal resection. Final histology revealed 10 cases of congenital pulmonary airway malformation (CPAM) type 1, nine cases of CPAM type 2, and 16 cases of bronchopulmonary sequestration. There was no difference in initial, maximal, or final CPAM volume ratio between groups, with median final CPAM volume ratio of 0.6 for CPAM type 1, 0.7 for CPAM type 2, and 0.3 for bronchopulmonary sequestration (p=.12). There were no differences in any of the maternal or obstetric outcomes including gestational age at delivery and mode of delivery between the groups. The primary outcome of neonatal respiratory distress was not statistically different between groups (p=.66). Median neonatal length of stay following delivery ranged from 3 to 4days, and time to postnatal resection was similar as well, with a median of 126days for CPAM type 1, 122days for CPAM type 2, and 132days for bronchopulmonary sequestration (p=.76).Conclusions: In our cohort, there was no significant association between histologic lung mass subtypes and any obstetric or neonatal morbidity including respiratory distress.

View details for DOI 10.1080/14767058.2019.1689559

View details for PubMedID 31722592

Comparative RNA-seq analysis aids in diagnosis of a rare pediatric tumor. Cold Spring Harbor molecular case studies Sanders, L. M., Rangaswami, A. n., Bjork, I. n., Lam, D. L., Beale, H. C., Kephart, E. T., Durbin, A. n., Learned, K. n., Currie, R. n., Lyle, A. G., Pfeil, J. n., Shah, A. T., Lee, A. G., Leung, S. G., Behroozfard, I. H., Breese, M. R., Peralez, J. n., Hazard, F. K., Lacayo, N. n., Spunt, S. L., Haussler, D. n., Salama, S. R., Sweet-Cordero, E. A., Vaske, O. M. 2019; 5 (5)


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

Adrenal Incidentaloma: Challenges in Diagnosing Adrenal Myelolipoma. Journal of investigative medicine high impact case reports Adapa, S., Naramala, S., Gayam, V., Gavini, F., Dhingra, H., Hazard, F. K., Aeddula, N. R., Konala, V. M. 2019; 7: 2324709619870311


Adrenal myelolipomas (AMLs) are rare benign adrenal tumors, containing adipose and hematopoietic tissue, a result of reticuloendothelial cell metaplasia. Incidence on autopsy has been reported from 0.08% to 0.4%. AMLs are generally considered nonsecretory. The functional aspect of adrenal incidentaloma should be evaluated. In this article, we report a case of a 40-year-old male, who presented with uncontrolled hypertension and renal failure, with imaging revealing an adrenal incidentaloma. He was started on dialysis for acute fluid overload, and workup for pheochromocytoma revealed an elevated serum norepinephrine level of 1181 pg/mL. Free metanephrine and normetanephrine levels were low when checked pre- and post-dialysis. Complete resection of the encapsulated right adrenal mass was performed. Pathology of the adrenal tumor demonstrates an 11.5 * 9.5 * 7.5 cm well-circumscribed, partially encapsulated proliferation of mature adipose tissue with admixed hemopoietic elements consistent with myelolipoma weighing 29.3 g. This case highlights the inclusion of a full metabolic workup for all adrenal incidentalomas, including AML.

View details for DOI 10.1177/2324709619870311

View details for PubMedID 31434506

OncoKids A Comprehensive Next-Generation Sequencing Panel for Pediatric Malignancies JOURNAL OF MOLECULAR DIAGNOSTICS Hiemenz, M. C., Ostrow, D. G., Busse, T. M., Buckley, J., Maglinte, D. T., Bootwalla, M., Done, J., Ji, J., Raca, G., Ryutov, A., Xu, X., Zhen, C., Conroy, J. M., Hazard, F. K., Deignan, J. L., Rogers, B. B., Treece, A. L., Parham, D. M., Gai, X., Judkins, A. R., Triche, T. J., Biegel, J. A. 2018; 20 (6): 76576


The OncoKids panel is an amplification-based next-generation sequencing assay designed to detect diagnostic, prognostic, and therapeutic markers across the spectrum of pediatric malignancies, including leukemias, sarcomas, brain tumors, and embryonal tumors. This panel uses low input amounts of DNA (20 ng) and RNA (20 ng) and is compatible with formalin-fixed, paraffin-embedded and frozen tissue, bone marrow, and peripheral blood. The DNA content of this panel covers the full coding regions of 44 cancer predisposition loci, tumor suppressor genes, and oncogenes; hotspots for mutations in 82 genes; and amplification events in 24 genes. The RNA content includes 1421 targeted gene fusions. We describe the validation of this panel by using a large cohort of 192 unique clinical samples that included a wide range of tumor types and alterations. Robust performance was observed for analytical sensitivity, reproducibility, and limit of detection studies. The results from this study support the use of OncoKidsfor routine clinical testing of a wide variety of pediatric malignancies.

View details for PubMedID 30138724

Integrative analysis of whole-genome and RNA sequencing in high-risk pediatric malignancies Breese, M. R., Shah, A. T., Tanasa, B., Lee, A. G., Leung, S. G., Spillinger, A., Liu, H., Hazard, F. K., Sweet-Cordero, A. AMER ASSOC CANCER RESEARCH. 2018
Genome-Informed Targeted Therapy for Osteosarcoma. Cancer discovery Sayles, L. C., Breese, M. R., Koehne, A. L., Leung, S. G., Lee, A. G., Liu, H., Spillinger, A., Shah, A. T., Tanasa, B., Straessler, K., Hazard, F. K., Spunt, S. L., Marina, N., Kim, G. E., Cho, S., Avedian, R. S., Mohler, D. G., Kim, M., Dubois, S. G., Hawkins, D. S., Sweet-Cordero, E. A. 2018


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

Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation CLINICAL CANCER RESEARCH Aghighi, M., Theruvath, A. J., Pareek, A., Pisani, L. L., Alford, R., Muehe, A. M., Sethi, T. K., Holdsworth, S. J., Hazard, F. K., Gratzinger, D., Luna-Fineman, S., Advani, R., Spunt, S. L., Daldrup-Link, H. E. 2018; 24 (17): 411018
Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Chapelin, F. n., Khurana, A. n., Moneeb, M. n., Gray Hazard, F. K., Chan, C. F., Nejadnik, H. n., Gratzinger, D. n., Messing, S. n., Erdmann, J. n., Gaur, A. n., Daldrup-Link, H. E. 2018


While imaging matrix-associated stem cell transplants aimed for cartilage repair in a rodent arthritis model, we noticed that some transplants formed locally destructive tumors. The purpose of this study was to determine the cause for this tumor formation in order to avoid this complication for future transplants.Adipose-derived stem cells (ADSC) isolated from subcutaneous adipose tissue were implanted into 24 osteochondral defects of the distal femur inten athymic rats and two immunocompetent control rats. All transplants underwent serial magnetic resonance imaging (MRI) up to 6weeks post-transplantation to monitor joint defect repair. Nine transplants showed an increasing size over time that caused local bone destruction (group 1), while 11 transplants in athymic rats (group 2) and 4 transplants in immunocompetent rats did not. We compared the ADSC implant size and growth rate on MR images, macroscopic features, histopathologic features, surface markers, and karyotypes of these presumed neoplastic transplants with non-neoplastic ADSC transplants.Implants in group 1 showed a significantly increased two-dimensional areaat week 2 (p=0.0092), 4 (p=0.003), and 6 (p=0.0205) compared to week 0, as determined by MRI. Histopathological correlations confirmed neoplastic features in group 1 with significantly increased size, cellularity, mitoses, and cytological atypia compared to group 2. Six transplants in group 1were identified as malignant chondrosarcomas and three transplants as fibromyxoid sarcomas. Transplants in group 2 and immunocompetent controls exhibited normal cartilage features. Both groups showed a normal ADSC phenotype; however, neoplastic ADSC demonstrated a mixed population of diploid and tetraploid cells without genetic imbalance.ADSC transplants can form tumors in vivo. Preventive actions to avoid in vivo tumor formations may include karyotyping of culture-expanded ADSC before transplantation. In addition, serial imaging of ADSC transplants in vivo may enable early detection of abnormally proliferating cell transplants.

View details for PubMedID 29869062

CD47 is not Over-Expressed in Fibrolamellar Hepatocellular Carcinoma ANNALS OF CLINICAL AND LABORATORY SCIENCE Cooney, T., Wei, M. C., Rangaswami, A., Xu, L., Sage, J., Hazard, F. K. 2017; 47 (4): 395402


CD47 is a transmembrane receptor that inhibits phagocytosis. Over-expression of CD47 is associated with an increased risk of tumor growth and metastasis. Clinical trials based on anti-CD47 therapy in adults are underway in a variety of malignancies. CD47 has been shown to be over-expressed in conventional hepatocellular carcinoma (HCC), a common liver tumor in adults. To our knowledge, there have been no studies to evaluate CD47 expression in the fibrolamellar subtype of HCC (FL-HCC), common in children and young adults. This study will evaluate CD47 expression in FL-HCC and shed light on its suitability for anti-CD47 therapy.Using immunohistochemistry, 10 samples of FL-HCC from 8 patients were evaluated for CD47 (anti-phagocytic) and calreticulin (pro-phagocytic) expression. By direct comparison, CD47 and calreticulin expression were evaluated in 21 samples of conventional HCC. Additionally, transcriptome sequencing to detect CD47 mRNA expression was performed on fresh tissue from 1 FL-HCC institutional patient and previously published sequencing data from 20 additional samples was reviewed.Immunohistochemistry showed only weak CD47 expression in 20% of FL-HCC samples. In contrast, 57% of conventional HCC samples showed CD47 expression. All (100%) FL-HCC samples showed moderate or strong calreticulin expression. The difference between CD47 and calreticulin expression in FL-HCC is statistically significant (p=0.0007). Transcriptome sequencing revealed no difference in CD47 expression between FL-HCC and normal liver samples.CD47 is not over-expressed in FL-HCC. Our studies provide no support for expanding ongoing clinical trials in adults to include children and young adults with FL-HCC.

View details for PubMedID 28801364

Mesenteric lipoma simulating an ovarian teratoma JOURNAL OF PEDIATRIC SURGERY CASE REPORTS Deshmukh, S., Hazard, F. K., Mueller, C. M. 2017; 21: 3638
Hepatoblastoma Arising in a Pigmented -catenin-activated Hepatocellular Adenoma: Case Report and Review of the Literature. American journal of surgical pathology Louie, C. Y., Concepcion, W., Park, J. K., Rangaswami, A., Finegold, M. J., Hazard, F. K. 2016; 40 (7): 998-1003


Hepatoblastoma is the most common malignant liver tumor in childhood. It has been associated with a variety of constitutional syndromes and gene mutations. However, there are very few reports of associations with pediatric hepatocellular adenomas (HCAs) and no reported associations with pigmented HCAs (P-HCAs). We present a unique case of hepatoblastoma arising in a background of 2 -catenin-activated HCAs, one of which is pigmented, in a 4-year-old child. The gross, histologic, and immunohistochemical features are described for each tumor. In addition, the literature is reviewed with specific emphasis on the clinical and pathologic features of B-HCAs. Although the potential of -catenin-activated HCAs to progress to hepatocellular carcinoma has been well documented, there are very few reports of their potential to progress to hepatoblastoma. We not only present such a case, but, to our knowledge, we also present the first case of a P-HCA in a child.

View details for DOI 10.1097/PAS.0000000000000652

View details for PubMedID 27096257

Synchronous Hepatoblastoma, Neuroblastoma, and Cutaneous Capillary Hemangiomas: A Case Report. Pediatric and developmental pathology Ozawa, M. G., Cooney, T., Rangaswami, A., Hazard, F. K. 2016; 19 (1): 74-79


Multiple synchronous tumors presenting in infancy raise concern for inherited or sporadic cancer predisposition syndromes, which include Beckwith-Wiedemann syndrome, familial adenomatous polyposis syndrome, and Li-Fraumeni syndrome. We report a case of a 7-month-old previously healthy male born following an in vitro fertilization-assisted twin pregnancy who presented with new-onset refractory shock, severe acidosis, and rapid decline over several hours. An autopsy revealed a ruptured liver involved by hepatoblastoma, an adrenal gland involved by neuroblastoma, and multiple cutaneous capillary hemangiomas. Standard genetic testing demonstrated that both twins were Gaucher disease (GD) carriers without evidence of other known cancer predisposition syndromes. This report describes a unique association of multiple synchronous tumors, which underscores the utility and importance of the pediatric autopsy. Moreover, given that the reported child was a GD carrier, the possibility the tumors were the result of a GD-mediated cancer-associated phenotype or an unrecognized sporadic clinical syndrome remains an unanswered, but intriguing, question worthy of further investigation.

View details for DOI 10.2350/14-11-1573-CR.1

View details for PubMedID 26368548

Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertility and sterility McQueen, D. B., Perfetto, C. O., Hazard, F. K., Lathi, R. B. 2015; 104 (4): 927-931


To evaluate the prevalence of chronic endometritis (CE) in women with recurrent pregnancy loss (RPL) and compare pregnancy outcomes in women with and without CE.Case-control observational study.Academic fertility practice.Women with two or more pregnancy losses.Hematoxylin and eosin (H & E) staining was performed on all endometrial biopsies and plasma cells were identified by morphology. Immunohistochemical (IHC) staining for CD138 was later applied to all tissue samples. Charts were reviewed to evaluate the outcome of the next clinical intrauterine pregnancy.Miscarriage rate and live birth rate.A total of 107 women met inclusion criteria. The use of CD138 IHC staining resulted in a significantly higher prevalence of CE compared with the use of H & E staining and morphological assessment alone (56% [60/107] vs. 13% [14/107]). The 51 women with untreated CE were compared with the 45 women without CE by CD138 staining. Among those women with a subsequent pregnancy, the live birth rate in the next clinical intrauterine pregnancy after endometrial evaluation was 67.6% (23/34) in women with untreated CE and 87.1% (27/31) in women without CE. Age, body mass index (BMI), results of RPL evaluation, and number of prior losses were not significantly different between the two groups.CD138 IHC staining of endometrial biopsies in women with RPL provides increased sensitivity when screening for CE compared with H & E staining and morphological assessment alone. Untreated CE may contribute to poor pregnancy outcomes and deserves further investigation in a larger cohort.

View details for DOI 10.1016/j.fertnstert.2015.06.044

View details for PubMedID 26207958

Genomic analysis of fibrolamellar hepatocellular carcinoma. Human molecular genetics Xu, L., Hazard, F. K., Zmoos, A., Jahchan, N., Chaib, H., Garfin, P. M., Rangaswami, A., Snyder, M. P., Sage, J. 2015; 24 (1): 50-63


Pediatric tumors are relatively infrequent but are often associated with significant lethality and lifelong morbidity. A major goal of pediatric cancer research has been to identify key drivers of tumorigenesis to eventually develop targeted therapies to enhance cure rate and minimize acute and long-term toxic effects. Here we used genomics approaches to identify biomarkers and candidate drivers for fibrolamellar hepatocellular carcinoma (FL-HCC), a very rare subtype of pediatric liver cancer for which limited therapeutic options exist. In-depth genomics analyses of one tumor followed by immunohistochemistry validation on seven other tumors showed expression of neuroendocrine markers in FL-HCC. DNA and RNA sequencing data further showed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. The first, a 400kb deletion, results in a DNAJ1-PRKCA fusion transcript, which leads to increased PKA activity in the index tumor case and other FL-HCC cases compared to normal liver. This PKA fusion protein is oncogenic in HCC cells. The second gene fusion event, a translocation between the CLPTML1 and GLIS3 genes, generates a transcript whose product also promotes cancer phenotypes in HCC cell lines. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.

View details for DOI 10.1093/hmg/ddu418

View details for PubMedID 25122662

Congenital peribronchial myofibroblastic tumor: case report of an asymptomatic infant with a rapidly enlarging pulmonary mass and review of the literature. Annals of clinical and laboratory science Brock, K. E., Wall, J., Esquivel, M., Newman, B., Marina, N., Albanese, C., Hazard, F. K. 2015; 45 (1): 83-89


Congenital peribronchial myofibroblastic tumor (CPMT) is a rare, benign lung tumor of infants, with only 19 reported cases worldwide. It is often diagnosed by prenatal imaging or in the immediate postnatal period due to co-morbidities like polyhydramnios, fetal hydrops, respiratory distress, and heart failure.We report the oldest known infant (8 weeks old) diagnosed with CPMT, and present his clinical course including the relevant radiographic and histopathologic findings.CPMT is a rare tumor that should be considered among other primary lung tumors of infancy (developmental, benign, and malignant) even if not detected prenatally or in the immediate postnatal period.

View details for PubMedID 25696016

Features of Gastric and Colonic Mucosa in Congenital Enteropathies A Study in Histology and Immunohistochemistry AMERICAN JOURNAL OF SURGICAL PATHOLOGY Treetipsatit, J., Hazard, F. K. 2014; 38 (12): 1697-1706


Congenital enteropathies comprise a constellation of rare clinicopathologic diagnoses characterized by intractable watery diarrhea and failure to thrive in infants. These diagnoses include, but are not limited to, tufting enteropathy (TE), microvillous inclusion disease (MID), and enteroendocrine cell dysgenesis (EED). Commonly, the diagnosis is based on identification of their characteristic histologic and/or ultrastructural features in small intestinal mucosa. In cases in which the changes in the small intestine are inconclusive or a small intestine biopsy is not performed, the diagnosis can be hampered or significantly delayed. We describe the histologic features and immunohistochemical staining patterns of gastric and colonic mucosa in patients with confirmed TE (3), MID (2), and EED (1). Specifically, focal epithelial tufts were found in the gastric mucosa of one TE patient and multifocally in the colonic mucosa of another. All TE patients showed complete loss of membranous epithelial EpCAM expression in gastric and colonic mucosa, characteristic of the diagnosis. Gastric biopsies were available in 1 patient with MID; this showed focal disruption of the gastric glandular architecture. Three colon biopsies and 1 resection from 2 patients with MID showed characteristic cytoplasmic vacuoles and periodic acid-Schiff/villin-positive cytoplasmic inclusions. Chromogranin stains showed complete absence of enteroendocrine cells within the colon and a normal distribution in the gastric mucosa of the EED patient. On the basis of our findings, we conclude that the characteristic histologic and immunohistochemical features associated with the small intestine can be confirmed within the gastric and/or colonic mucosa by careful histologic examination and immunohistochemistry.

View details for Web of Science ID 000345131700015

Evaluation of intestinal biopsies for pediatric enteropathy: a proposed immunohistochemical panel approach. American journal of surgical pathology Martin, B. A., Kerner, J. A., Hazard, F. K., Longacre, T. A. 2014; 38 (10): 1387-1395


Congenital enteropathies are rare disorders with significant clinical consequences; however, definitive diagnosis based on morphologic assessment of duodenal biopsies with routine stains alone is often impossible. To determine the role of immunohistochemistry (IHC) in the evaluation for microvillous inclusion disease, congenital tufting enteropathy (intestinal epithelial dysplasia), and enteroendocrine cell dysgenesis, a series of duodenal biopsies from 26 pediatric patients with chronic/intractable diarrhea was retrospectively reviewed. IHC stains for CD10, EpCAM, chromogranin, and villin were performed on all biopsies, and the results were correlated with hematoxylin and eosin and ultrastructural findings using electron microscopy, when available. Biopsies from 2 patients diagnosed with microvillous inclusion disease at the time of original biopsy demonstrated diffuse CD10-positive cytoplasmic inclusions within enterocytes and normal expression of EpCAM and chromogranin. Biopsies from 3 patients, including 2 siblings with confirmed EPCAM mutations, demonstrated complete loss of EpCAM expression and normal expression of CD10 and chromogranin; electron microscopic evaluation revealed characteristic ultrastructural findings of tufting enteropathy. Biopsies from 1 patient with a confirmed NEUROG3 mutation demonstrated an absence of intestinal enteroendocrine cells by chromogranin staining, consistent with enteroendocrine cell dysgenesis. Four patients' biopsies displayed nonspecific staining patterns for CD10 and/or EpCAM with normal expression of chromogranin, and 16 patients' biopsies exhibited normal expression for all 3 markers. Villin stains demonstrated heterogenous brush border labeling with nonspecific cytoplasmic reactivity, a pattern variably present throughout the biopsy series. In conclusion, the routine use of an IHC panel of CD10, EpCAM, and chromogranin is warranted in patients meeting specific age and/or clinical criteria, as the morphologic findings of congenital enteropathies may be subtle, focal, or inapparent on routine stains.

View details for DOI 10.1097/PAS.0000000000000314

View details for PubMedID 25188866

Successful Treatment with Temozolomide Combined with Chemoradiotherapy and Surgery of a Metastatic Undifferentiated Soft Tissue Sarcoma with Relapse in the Central Nervous System of a Young Adult JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY Hsu, C. H., Daldrup-Link, H. E., Yeom, K. W., Donaldson, S. S., Million, L., Hazard, F. K., Rangaswami, A. 2014; 3 (2): 100-103
Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small Ansari, C., Tikhomirov, G. A., Hong, S. H., Falconer, R. A., Loadman, P. M., Gill, J. H., Castaneda, R., Hazard, F. K., Tong, L., Lenkov, O. D., Felsher, D. W., Rao, J., Daldrup-Link, H. E. 2014; 10 (3): 566-?


A major drawback with current cancer therapy is the prevalence of unrequired dose-limiting toxicity to non-cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, the design and characterization of novel multifunctional "theranostic" nanoparticles (TNPs) is described for enzyme-specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs are synthesized by conjugation of FDA-approved iron oxide nanoparticles ferumoxytol to an MMP-activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIO-ICTs (TNPs). Significant cell death is observed in TNP-treated MMP-14 positive MMTV-PyMT breast cancer cells in vitro, but not MMP-14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrates significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO-ICTs induces a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death is observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol. These findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme-activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.

View details for DOI 10.1002/smll.201301456

View details for PubMedID 24038954

Cancer therapy: development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy (small 3/2014). Small Ansari, C., Tikhomirov, G. A., Hong, S. H., Falconer, R. A., Loadman, P. M., Gill, J. H., Castaneda, R., Hazard, F. K., Tong, L., Lenkov, O. D., Felsher, D. W., Rao, J., Daldrup-Link, H. E. 2014; 10 (3): 417-?


Cancer cells overexpress matrix-type metalloproteinases (MMPs, shown as pacmen). MMPs cleave the peptide linker connecting anticancer prodrug to the dextran coated magnetic nanoparticle. After the cleavage, the drug becomes toxic (active drug shown in purple). As J. Rao, H. E. Daldrup-Link, and co-workers describe on page 566, this tumor specific drug release reduces the side-effects of cancer therapy. The magnetic core of the nanoparticles allows for MRI monitoring of their distribution in the body.

View details for DOI 10.1002/smll.201470016

View details for PubMedID 24497471

Comparison of Latino and Non-Latino Patients With Ewing Sarcoma PEDIATRIC BLOOD & CANCER Sharib, J., Horvai, A., Hazard, F. K., Daldrup-Link, H., Goldsby, R., Marina, N., DuBois, S. G. 2014; 61 (2): 233-237


Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES.Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing.Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54).Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.

View details for DOI 10.1002/pbc.24745

View details for Web of Science ID 000328694300016

View details for PubMedID 23970433

Features of gastric and colonic mucosa in congenital enteropathies: a study in histology and immunohistochemistry. The American journal of surgical pathology Treetipsatit, J. n., Hazard, F. K. 2014; 38 (12): 16971706


Congenital enteropathies comprise a constellation of rare clinicopathologic diagnoses characterized by intractable watery diarrhea and failure to thrive in infants. These diagnoses include, but are not limited to, tufting enteropathy (TE), microvillous inclusion disease (MID), and enteroendocrine cell dysgenesis (EED). Commonly, the diagnosis is based on identification of their characteristic histologic and/or ultrastructural features in small intestinal mucosa. In cases in which the changes in the small intestine are inconclusive or a small intestine biopsy is not performed, the diagnosis can be hampered or significantly delayed. We describe the histologic features and immunohistochemical staining patterns of gastric and colonic mucosa in patients with confirmed TE (3), MID (2), and EED (1). Specifically, focal epithelial tufts were found in the gastric mucosa of one TE patient and multifocally in the colonic mucosa of another. All TE patients showed complete loss of membranous epithelial EpCAM expression in gastric and colonic mucosa, characteristic of the diagnosis. Gastric biopsies were available in 1 patient with MID; this showed focal disruption of the gastric glandular architecture. Three colon biopsies and 1 resection from 2 patients with MID showed characteristic cytoplasmic vacuoles and periodic acid-Schiff/villin-positive cytoplasmic inclusions. Chromogranin stains showed complete absence of enteroendocrine cells within the colon and a normal distribution in the gastric mucosa of the EED patient. On the basis of our findings, we conclude that the characteristic histologic and immunohistochemical features associated with the small intestine can be confirmed within the gastric and/or colonic mucosa by careful histologic examination and immunohistochemistry.

View details for PubMedID 25007148

Adequacy of lymph node examination in colorectal surgery: contribution of the hospital versus the surgeon. Medical care Rhoads, K. F., Ackerson, L. K., Ngo, J. V., Gray-Hazard, F. K., Subramanian, S. V., Dudley, R. A. 2013; 51 (12): 1055-1062


Examination of at least 12 lymph nodes (LNs) in the staging of colon cancer (CC) was recommended by the National Comprehensive Cancer Network in 2000; however, rates of an adequate examination remain low. This study compares the impact of the hospital contextual variance against that of the operating surgeon on delivery of an adequate LN examination.Retrospective analysis of California Cancer Registry data for all CC operations (2001-2006). Hierarchical models predicted the adequacy of LN examination as a function of patient, surgeon, and hospital characteristics. Models were created using penalized quasi-likelihood approximation with second order Taylor linearization as implemented in MLwiN 2.15.A total of 25,606 resections involving 3376 surgeons operating in 346 hospitals were analyzed. Half of cases had an adequate examination. Hierarchical models showed the median odds of an adequate examination associated with the hospital context [(MORhosp 2.05; 95% confidence interval, 1.9-2.2) was much higher than that associated with the surgeon (MORsurg 1.34; 95% confidence interval, 1.2-1.4)]. Hospital characteristics teaching and high volume predicted higher odds of an adequate examination. There was no association with hospital revenue.Approximately half of patients undergoing surgery for CC received an adequate LN examination. Hospital contextual factors had a stronger association with receipt of an adequate examination than surgeon factors. Our results suggest that quality improvement initiatives and incentives should be targeted at the hospital level to achieve the highest impact. Furthermore, we have identified nonteaching and low volume settings as rational targets for these efforts.

View details for DOI 10.1097/MLR.0b013e3182a53d72

View details for PubMedID 23969586

View details for PubMedCentralID PMC3830585

Liver Pathology in Infantile Mitochondrial DNA Depletion Syndrome PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Hazard, F. K., Ficicioglu, C. H., Ganesh, J., Ruchelli, E. D. 2013; 16 (6): 415-424


Mitochondrial DNA (mtDNA) depletion syndrome is a relatively novel cause of hepatic dysfunction in the pediatric population. It is caused by mutations in either mtDNA or nuclear DNA (nDNA) that result in a quantitative reduction in mtDNA and, in turn, dysfunctional oxidative phosphorylation. In infants, it results in the hepatocerebral phenotype, characterized by hyperbilirubinemia, coagulopathy, lactic acidosis, hypoglycemia, lethargy, encephalopathy, developmental delay, and hypotonia. Three infants diagnosed with mtDNA depletion syndrome at The Children's Hospital of Philadelphia were identified, and their clinical presentation, disease course, and histologic and ultrastructural features of liver samples (pre- and postmortem) were characterized. While a different mutant gene was identified in each child, they all showed clinical evidence of metabolic dysfunction soon after birth and expired by 1 year of age. Steatosis, cholestasis, and cytoplasmic crowding by atypical mitochondria were consistent pathologic liver findings. Other findings included hepatocyte hypereosinophilia, fibrosis, and hemosiderosis. This analysis provides insight into the important clinical signs/symptoms and histopathologic and ultrastructural features of mtDNA depletion syndrome in infants and young children. Knowledge of these characteristics will facilitate early recognition and appropriate treatment of this rare disorder. Additionally, ultrastructural evaluation of liver samples by electron microscopy is an important diagnostic component of hepatic dysfunction caused by metabolic abnormalities. This type of analysis should be routinely employed in the setting of unexplained cholestasis, especially when accompanied by steatosis and hepatocyte hypereosinophilia.

View details for DOI 10.2350/12-07-1229-OA.1

View details for Web of Science ID 000328893600003

View details for PubMedID 24050659

Ovarian Surface Epithelial Neoplasms in the Pediatric Population Incidence, Histologic Subtype, and Natural History AMERICAN JOURNAL OF SURGICAL PATHOLOGY Hazard, F. K., Longacre, T. A. 2013; 37 (4): 548-553


Surface epithelial neoplasms account for a small but significant proportion of pediatric ovarian tumors. The overall incidence, prevalence of histologic subtypes, and natural history of these neoplasms has not been thoroughly evaluated. A retrospective review of the pathology archives of Stanford University School of Medicine yielded 69 surface epithelial ovarian tumors in 64 pediatric patients 18 years of age or younger from 1974 to 2010. Tumors comprised benign (57.8%), borderline/low malignant potential (LMP) (37.5%), and malignant (4.7%) subgroups and exhibited serous, mucinous, and mixed histology; there were no clear cell, pure endometrioid, or transitional (Brenner) tumors. In addition, no high-grade carcinomas were identified. Clinical follow-up data were available in a subset of patients (maximum follow-up, 22 y). Similar numbers of recurrences were found in each of the 3 subgroups. However, overall survival was 100% for benign and borderline/LMP tumors and 50% for carcinomas. The type of surgical management and the use of chemotherapy varied; 2 patients with borderline/LMP tumors were treated by sterilizing procedures and/or chemotherapy. These data suggest that surface epithelial neoplasms comprise a small but significant proportion of ovarian tumors in the pediatric population, and they exhibit a marked preponderance for benign, borderline, and low-grade malignant subgroups. In contrast to their adult counterpart, high-grade serous carcinoma in children is extraordinarily rare and not seen in this series. Given this difference, uniform treatment modalities with consideration for ovarian conservation and fertility preservation should be rigorously adopted in any pediatric patient with a suspected ovarian surface epithelial neoplasm.

View details for DOI 10.1097/PAS.0b013e318273a9ff

View details for PubMedID 23388124

A Case of Genitourinary Crohn's Disease UROLOGY Weinberg, A. E., Hazard, F. K., Hsieh, M. H. 2012; 80 (5): 1132-1134


Scrotal swelling in young boys is a common problem. The differential diagnosis includes testicular torsion, epididymoorchitis, and idiopathic scrotal edema. We report the unusual case of a 17-year-old boy who presented with recurrent episodes of penile and scrotal edema as extraintestinal manifestations of Crohn's disease. Genitourinary complications of Crohn's disease are not uncommon; however, they more typically present in the form of nephrolithiasis, obstructive uropathy, and enterovesical fistulization. Few reports have described Crohn's disease presenting with isolated genital edema in the absence of associated intestinal or systemic symptoms.

View details for DOI 10.1016/j.urology.2012.07.044

View details for Web of Science ID 000310566300047

View details for PubMedID 22999453

Predictors of acute chemotherapy-associated toxicity in patients with Ewing sarcoma PEDIATRIC BLOOD & CANCER Sharib, J. M., Cyrus, J., Horvai, A., Hazard, F. K., Neuhaus, J., Matthay, K. K., Goldsby, R., Marina, N., DuBois, S. G. 2012; 59 (4): 611-616


Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue of children and young adults. Patients with ES are treated with intensive chemotherapy regimens. We describe predictors of acute chemotherapy-associated toxicity in this population.In this retrospective cohort study, records of ES patients treated at two academic medical centers between 1980 and 2010 were reviewed. Grade 3 and 4 non-hematologic chemotherapy-associated toxicities during frontline therapy were recorded for each patient, along with potential clinical and demographic predictors of toxicity. Bivariate analyses were performed using the Fisher exact test. Multivariate analysis was performed using logistic regression.The cohort included 142 patients with ES and toxicity data. In bivariate analyses, age <12 years at diagnosis, Latino ethnicity, low family income, and treatment on a clinical trial were associated with higher incidence of toxicity (P < 0.01). Tumor size, site, stage, mode of local control, body mass index, overall chemotherapy exposure and dose-intensity were not associated with toxicity. In multivariate analysis, low income (odds ratio (OR) 4.97, 95% confidence interval (CI) 1.9-13.1), clinical trial enrollment (OR 3.67, 95% CI 1.2-10.9), pelvic tumor site (OR 3.88, 95% CI 1.17-12.88), and age <12 years (OR 2.8, 95% CI 1.0-7.5) were independent predictors of toxicity.ES patients who are younger, of Latino ethnicity, have pelvic tumors or low income have higher rates of toxicity that may require increased supportive care. Treatment on a clinical trial was also associated with higher rates of toxicity, though this finding may reflect better reporting in these patients.

View details for DOI 10.1002/pbc.24031

View details for Web of Science ID 000307386300004

View details for PubMedID 22180320

View details for PubMedCentralID PMC3310949

Congenital Pancreatoblastoma: Report of an Atypical Case and Review of the Literature JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Chisholm, K. M., Hsu, C. H., Kim, M. J., Rangaswami, A., Hazard, F. K. 2012; 34 (4): 310-315


Pancreatoblastoma is a rare malignant tumor of the pancreas mostly diagnosed in childhood. The clinical presentation and outcome of infantile and congenital pancreatoblastoma have not been clearly elucidated. This report describes our recent institutional experience with an unusual case of congenital pancreatoblastoma. Review of the scientific literature identifies approximately 200 cases of pancreatoblastoma. We describe the 9 infantile (aged 3 mo and younger) and 4 congenital cases previously reported and summarize their clinical presentation and outcome. We also define the close association of infantile/congenital pancreatoblastoma and Beckwith-Wiedemann syndrome (50%) versus all affected age groups (4.5%).

View details for DOI 10.1097/MPH.0b013e318239f4f6

View details for PubMedID 22278199

First Trimester Miscarriage Evaluation SEMINARS IN REPRODUCTIVE MEDICINE Lathi, R. B., Hazard, F. K., Heerema-McKenney, A., Taylor, J., Chueh, J. T. 2011; 29 (6): 463-469


Miscarriage is a relatively common occurrence for otherwise healthy women. Despite its frequency, evaluation for cause is rare. The most common cause of miscarriage is sporadic chromosome errors. Chromosomal analysis of the miscarriage offers an explanation in at least 50% of cases. Conventional cytogenetic evaluation can only be done on fresh tissue, so it is critical that the treating physician consider genetic testing at the time of the miscarriage. Ultrasound can estimate the gestational age at the time of miscarriage and identify major abnormalities in some embryos. A careful pathological examination can add to the evaluation by ruling out rare disorders with the highest recurrence risk. A multidisciplinary approach to miscarriage evaluation is essential to understanding the cause and risk of recurrence. A thorough evaluation of a miscarriage, in combination with emotional support, can often provide the necessary reassurance and confidence as the patient prepares for her next pregnancy.

View details for DOI 10.1055/s-0031-1293200

View details for PubMedID 22161459

Gorham's disease: diagnostic utility of an autopsy for a rare bone disease. Journal of pediatric health care Wells, K., Gray Hazard, F. K. 2011; 25 (6): 391-398

View details for DOI 10.1016/j.pedhc.2011.03.003

View details for PubMedID 22018430

Tissue microarrays from bone marrow aspirates for high-throughput assessment of immunohistologic markers in pediatric acute leukemia PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Hazard, F. K., Zhao, S., Schiffman, J. D., Lacayo, N. J., Dahl, G. V., Natkunam, Y. 2008; 11 (4): 283-290


Gene expression profiling studies have been employed to investigate prognostic subgroups in pediatric acute leukemia. Tissue microarrays (TMAs) are useful for high-throughput analysis of protein expression of target genes in acute leukemia samples and for validation of gene microarray analysis. Using cryopreserved samples of pediatric acute leukemia bone marrow aspirates, we constructed TMA from as few as 1 million cells. Bone marrow core biopsies from the same patients were included on the same TMA for comparison. A panel of 15 immunohistochemical markers typically used for diagnosis as well as those targeting recently characterized, prognostically relevant molecules of interest in pediatric acute leukemia was used to evaluate protein expression. Staining results confirm that suspension cells from bone marrow aspirates can be effectively used to derive protein expression data from multiple cases simultaneously with comparable efficacy to that of biopsy tissue. This method allows for new markers of diagnostic, prognostic, or therapeutic importance to be screened on large numbers of study patients. Furthermore, this technique may facilitate the inclusion of small samples, aspirates, and body fluids in large-scale studies of protein expression in clinical trials and protocols in which tissue biopsies are often unavailable.

View details for DOI 10.2350/07-04-0253.1

View details for PubMedID 17990919