Amy Gallo, MD

Abstract

High tacrolimus intrapatient variability has been associated with inferior graft outcomes in patients with kidney transplants. We studied baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants and examined these patterns in relation to C1q-binding de novo donor-specific antibodies.All tacrolimus levels in participants who underwent kidney-only transplantation at a single pediatric center from 2004 to 2018 (with at least 12-month follow-up, followed until 2019) were analyzed to determine baseline variability. Intrapatient variability was defined using the coefficient of variation (SD/mean 100%) of all samples in a 6-month moving window. Routine de novo donor-specific antibody measurements were available for a subgroup of patients transplanted in 2010-2018. Cox proportional hazards models using tacrolimus intrapatient variability as a time-varying variable were used to examine the association between intrapatient variability and graft outcomes. The primary outcome of interest was C1q-binding de novo donor-specific antibody formation.Tacrolimus intrapatient variability developed a steady-state baseline of 30% at 10 months post-transplant in 426 patients with a combined 31,125 tacrolimus levels. Included in the outcomes study were 220 patients, of whom 51 developed C1q-binding de novo donor-specific antibodies. De novo donor-specific antibody formers had higher intrapatient variability, with a median of 38% (interquartile range, 28%-48%) compared with 28% (interquartile range, 20%-38%) for nondonor-specific antibody formers (P<0.001). Patients with high tacrolimus intrapatient variability (coefficient of variation >30%) had higher risk of de novo donor-specific antibody formation (hazard ratio, 5.35; 95% confidence interval, 2.45 to 11.68). Patients in the top quartile of tacrolimus intrapatient variability (coefficient of variation >41%) had the strongest association with C1q-binding de novo donor-specific antibody formation (hazard ratio, 11.81; 95% confidence interval, 4.76 to 29.27).High tacrolimus intrapatient variability was strongly associated with de novo donor-specific antibody formation.

View details for DOI 10.2215/CJN.16421221

View details for PubMedID 35882506

Abstract

BACKGROUND: During the donor hepatectomy time (dHT), defined as the time from the start of cold perfusion to the end of the hepatectomy, liver grafts have a suboptimal temperature. The aim of this study was to analyze the impact of prolonged dHT on outcomes in donation after circulatory death (DCD) liver transplantation (LT).METHODS: Using the US national registry data between 2012 and 2020, DCD LT patients were separated into 2 groups based on their dHT: standard dHT (<42 min) and prolonged dHT (42 min).RESULTS: There were 3810 DCD LTs during the study period. Median dHT was 32 min (IQR 25-41 min). Kaplan- Meier graft survival curves demonstrated inferior outcomes in the prolonged dHT group at 1-year after DCD LT compared to those in the standard dHT group (85.3% vs 89.9%; p < 0.01). Multivariate Cox proportional hazards models for 1-year graft survival identified that prolonged dHT [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.19 - 1.79], recipient age 64 years (HR 1.40, 95% CI 1.14 - 1.72), and MELD score 24 (HR 1.43, 95% CI 1.16 - 1.76) were significant predictors of 1-year graft loss. Spline analysis shows that the dHT effects on the risk for 1-year graft loss with an increase in the slope after median dHT of 32 min.CONCLUSION: Prolonged dHTs significantly reduced graft and patient survival after DCD LT. Because dHT is a modifiable factor, donor surgeons should take on cases with caution by setting the dHT target of < 32 min. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/ctr.14778

View details for PubMedID 35866342

Abstract

Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of alphabeta T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.).

View details for DOI 10.1056/NEJMoa2117028

View details for PubMedID 35704481

Abstract

We report 4 cases of our institutional experience with liver transplantation that illustrate the high risk of heart failure and cardiogenic shock in the setting of cardiac iron overload. We then discuss a pragmatic approach to assess the cardiovascular risk in liver transplantation candidates with cardiac iron overload. (Level of Difficulty: Advanced.).

View details for DOI 10.1016/j.jaccas.2021.12.012

View details for PubMedID 35677787

View details for Web of Science ID 000783167500235

View details for Web of Science ID 000783167500111

View details for Web of Science ID 000783167500202

View details for Web of Science ID 000783167500234

View details for Web of Science ID 000783167500064

View details for Web of Science ID 000783167500017

View details for Web of Science ID 000783167500145

View details for Web of Science ID 000783167500041

View details for Web of Science ID 000783167500071

Abstract

BACKGROUND: Currently, there is no consensus among pediatric kidney transplant centers regarding the use and regimen for immunosuppressive induction therapy.METHODS: In this single center, retrospective cohort study, pediatric kidney transplant recipients transplanted between 1 May 2013 and 1 May 2018 with rabbit antithymocyte globulin (rATG) induction were included. We stratified patients based on immunological risk, with high risk defined as those with repeat transplant, preformed donor specific antibody, current panel-reactive antibodies>20%, 0 antigen match and/or African-American heritage. Outcome of interest was the incidence of biopsy proven acute rejection by 1year.RESULTS: A total of 166 patients met inclusion criteria. Age of patients was 12years (11 mo-21 y), (median, range), 21.5% received a living donor transplant and 50.6% were female. Low-immunologic-risk patients were divided into 2 groups, those who received the lower cumulative rATG dose of3.5mg/kg (n=52) versus the higher cumulative dose of>3.5mg/kg (n=47). The median total dose in the lower dose group was 3.1 (IQR 0.3) and 4.4 (IQR 0.8) in the higher dose group, P<0.001. Rejection rate did not differ significantly between the 2 treatment groups (7/52 vs. 6/47). None in the lower dose group developed BK nephropathy versus 3 in the higher dose group. Graft loss due to BK nephropathy occurred in 1 patient in the higher dose group. Graft loss in the whole cohort at 12months was a rare event (n=1) with 99.5% graft survival and 100% patient survival.CONCLUSIONS: Reduced rATG dosing (3.5mg/kg) when compared to higher dosing (>3.5mg/kg) is safe and effective in low-risk pediatric kidney transplant recipients without increasing risk of rejection. A higher resolution version of the Graphical abstract is available as Supplementary information.

View details for DOI 10.1007/s00467-021-05407-y

View details for PubMedID 35006359

View details for Web of Science ID 000739470700158

View details for DOI 10.3389/ti.2021.10158

View details for Web of Science ID 000739470700182

Abstract

Liver transplantation (LT) is definitive treatment for end-stage liver disease. This study evaluated factors predicting successful evaluation in patients transferred for urgent inpatient LT evaluation. Eighty-two patients with cirrhosis were transferred for urgent LT evaluation from January 2016 to December 2018. Alcohol-associated liver disease was the common etiology of liver disease (42/82). Of these 82 patients, 35 (43%) were declined for LT, 27 (33%) were wait-listed for LT, 5 (6%) improved, and 15 (18%) died. Psychosocial factors were the most common reasons for being declined for LT (49%). Predictors for listing and receiving LT on multivariate analysis included Hispanic race (odds ratio [OR], 1.89; P=0.003), Asian race (OR, 1.52; P=0.02), non-Hispanic ethnicity (OR, 1.49; P=0.04), hyponatremia (OR, 1.38; P=0.04), serum albumin (OR, 1.13; P=0.01), and Model for End-Stage Liver Disease (MELD)-Na (OR, 1.02; P=0.003). Public insurance (i.e., Medicaid) was a predictor of not being listed for LT on multivariate analysis (OR, 0.77; P=0.02). Excluding patients declined for psychosocial reasons, predictors of being declined for LT on multivariate analysis included Chronic Liver Failure Consortium (CLIF-C) score >51.5 (OR, 1.26; P=0.03), acute-on-chronic liver failure (ACLF) grade 3 (OR, 1.41; P=0.01), hepatorenal syndrome (HRS) (OR, 1.38; P=0.01), and respiratory failure (OR, 1.51; P=0.01). Predictors of 3-month mortality included CLIF-C score >51.5 (hazard ratio [HR], 2.52; P=0.04) and intensive care unit (HR, 8.25; P<0.001). Conclusion: MELD-Na, albumin, hyponatremia, ACLF grade 3, HRS, respiratory failure, public insurance, Hispanic race, Asian race, and non-Hispanic ethnicity predicted liver transplant outcome. Lack of psychosocial support was a major reason for being declined for LT. The CLIF-C score predicted being declined for LT and mortality.

View details for DOI 10.1002/hep4.1644

View details for PubMedID 33681683

View details for PubMedCentralID PMC7917272

View details for DOI 10.1002/hep4.1644

View details for Web of Science ID 000602465100001

Abstract

Infections following orthotopic liver transplant (OLT) result in significant morbidity and mortality, warranting careful consideration of risks associated with antibiotic overuse and benefits of infection prevention. In the absence of specific guidelines for antimicrobial prophylaxis in pediatric OLT, we developed a standardized approach to post-operative (post-op) antimicrobial therapy including 48 hours of antibiotics, no vancomycin for post-op fever within the first 48 hours, and caspofungin only for certain situations. The goal was to reduce antimicrobial utilization and adverse outcomes associated with longer duration of and broader treatment while maintaining good outcomes. The impact of this standardization on antimicrobial utilization and clinical outcomes at the largest pediatric liver transplant center in the United States is described. All individuals receiving an OLT from 1/1/17-9/30/17 (N=38) and 3/14/18-12/13/18 (N=27) were included in the pre-intervention (PreI) and post-intervention (PostI) groups, respectively. The intervention resulted in a significant reduction in individuals receiving post-op broad-spectrum gram-negative antibiotics for > 48 hours (76% PreI vs 44% PostI OLT recipients, P = 0.01) and post-op vancomycin use (50% PreI, vs 7.4% PostI, P < 0.001). There were no statistically significant differences between groups for post-op fever, positive pre-/post-operative cultures, receipt of massive transfusion, or hospital length of stay. In conclusion, following the implementation of a standardized approach to post-op prophylaxis, antimicrobial exposure was significantly reduced without affecting OLT recipient outcomes.

View details for DOI 10.1111/tid.13538

View details for PubMedID 33252820

View details for Web of Science ID 000618872101244

View details for Web of Science ID 000618872101233

Abstract

INTRODUCTION: Transfusion protocols are not well-studied for pediatric patients with acute liver failure (ALF). This study evaluates the utility of an international normalized ratio (INR)-based transfusion threshold for these patients.METHODS: Forty-four ALF pediatric patients from 2009 to 2018 were reviewed and divided into two groups: (1) a threshold group including patients between 2009-2015 who were transfused for an INR above 3.0, per institutional policy (n=30), and (2) a post-threshold group including patients after 2015 through 2018 who were transfused based on clinical judgment (n=14). Preoperative INRs, preoperative transfusions, intraoperative transfusions, early reoperation, renal function, graft function and deaths were compared.RESULTS: Liver failure severity was similar between threshold and post-threshold groups. Threshold patients had a lower average INR prior to transplantation, 2.8 (range 1.8-3.8) versus 4.4 (range 2.1-9.0), respectively (p=0.01). Twenty-six threshold patients (87%) received preoperative FFP compared to seven post-threshold patients (50%, p=0.0088). Two threshold patients (7%) received preoperative cryoprecipitate compared to five post-threshold patients (36%, p=0.014). The incidence of pre-transplant bleeding, operative transfusions and one-year patient and graft survival did not differ significantly.CONCLUSION: Clinical judgment versus an INR-based threshold for transfusions did not increase perioperative complications in children with ALF.

View details for DOI 10.1111/ctr.13819

View details for PubMedID 32037570

Abstract

INTRODUCTION: Urinary diversion in pediatric renal transplant candidates with bladders not amenable to primary reconstruction can be achieved by pre-transplant ileal conduit creation. We performed cutaneous ureterostomies to limit pre-transplant surgery, protect the peritoneum for dialysis, transplant patients sooner, and preserve ureter length for future surgical reconstruction.METHODS: We compared four pediatric transplant recipients with ureterostomies to four recipients with ileal conduits from 2009-2017.RESULTS: All patients with ileal conduits developed at least one urinary tract infection (UTI) within one year of transplant and three of four patients had recurrent UTIs within the first year. Two patients required ileal conduit revisions for redundant conduits and recurrent UTIs. Of the four ureterostomy patients, two patients had UTIs within one year of transplant. Two patients developed ureterostomy strictures requiring revision at the fascial level; one was associated with a UTI.CONCLUSION: In our small case series, ureterostomy allowed for a single operative intervention with preservation of ureter length for later reconstruction. Ureterostomy is safe and recurrent UTI may be lower in the ureterostomy group. Long-term evaluation of ureterostomy for urinary diversion in pediatric kidney transplant is warranted.

View details for DOI 10.1111/ctr.13777

View details for PubMedID 31904131

View details for Web of Science ID 000505634300148

View details for Web of Science ID 000488653502295

View details for DOI 10.1093/infdis/jiz114

View details for Web of Science ID 000477595700005

Abstract

Bilateral renal agenesis is associated with severe oligohydramnios and was considered incompatible with postnatal life due to severe pulmonary hypoplasia. The use of renal replacement therapy was limited by significant morbidity and mortality associated with dialysis in very young infants with major pulmonary pathology. In the United States, there is a tremendous controversy about whether or not the use of prenatal amniotic fluid infusions provides a benefit to fetuses with bilateral renal agenesis. One of the critical issues identified is that there are, as yet, no children reported who had achieved long-term survival. Previous reports all indicated these children died shortly after birth or after unsuccessful peritoneal dialysis. We present two infants with a prenatal diagnosis of bilateral renal agenesis whose mothers elected to undergo prenatal amnioinfusions. One was born at 28weeks with a birthweight of 1230g and the other born at 34weeks with a birthweight of 1940g. We present the details of both cases, with initial management on chronic peritoneal dialysis, which started shortly after birth, as a bridge to living related kidney transplants.

View details for DOI 10.1111/petr.13532

View details for PubMedID 31259459

View details for Web of Science ID 000485482200280

View details for Web of Science ID 000485482200254

View details for Web of Science ID 000485482200137

Abstract

BACKGROUND: BK virus (BKV) is a significant cause of nephropathy in kidney transplantation. The goal of this study was to characterize the course and source of BKV in kidney transplant recipients.METHODS: We prospectively collected pre-transplant plasma and urine samples from living and deceased kidney donors and performed BKV PCR and IgG testing on pre-transplant and serially collected post-transplant samples in kidney transplant recipients.RESULTS: Among deceased donors, 8.1%(17/208) had detectable BKV DNA in urine prior to organ procurement. BK viruria was observed in 15.4%(6/39) of living donors and 8.5%(4/47) of deceased donors of recipients at our institution (p=0.50). BKV VP1 sequencing revealed identical virus between donor-recipient pairs to suggest donor transmission of virus. Recipients of BK viruric donors were more likely to develop BK viruria (66.6%vs.7.8%, p<0.001) and viremia (66.6%vs.8.9%, p<0.001) with a shorter time to onset (log-rank, p<0.001). Though donor BKV IgG titers were higher in recipients who developed BK viremia, pre-transplant donor, recipient, and combined donor/recipient serology status was not associated with BK viremia (p=0.31,0.75,0.51,respectively).DISCUSSION: Donor BK viruria is associated with early BK viruria and viremia in kidney transplant recipients. BKV PCR testing of donor urine may be useful in identifying recipients at-risk for BKV complications.

View details for PubMedID 30869132

Abstract

BACKGROUND: Native nephrectomy in pediatric kidney transplant recipients is performed for multiple indications. Posttransplant hypertension requiring medical management is common, and the effect of native nephrectomy on posttransplant hypertension is poorly studied. Our aim is to evaluate the impact of native nephrectomy on posttransplant hypertension.METHODS: One hundred thirty-six consecutive pediatric kidney transplant recipients from 2007 to 2012 were studied at a single institution and divided into 2 groups: no nephrectomy and native nephrectomy (unilateral and bilateral nephrectomy). Antihypertensive medication use was evaluated before nephrectomy/transplant, at discharge from transplant and at 1, 3, and 5 years posttransplant.RESULTS: In a bivariate analysis, nephrectomy was associated with a significant reduction in the percentage of patients requiring antihypertensive medication at the time of discharge (27.3%) and 1 year posttransplant (10.7%) as compared with patients without nephrectomy (71.7%, and 50%, respectively, P < 0.05). This trend toward reduction in antihypertensive medication in the nephrectomy group as compared with the no nephrectomy group persisted at 3 (18.6% versus 43.2%) and 5 years (19.7% versus 37.5%) posttransplant. Multivariable logistic regression demonstrated that patients without native nephrectomy had higher odds of requiring antihypertensive medication at the time of discharge (3.3) and 1 year (5.2) as compared with patients who underwent native nephrectomy (P = 0.036 and P = 0.013, respectively).CONCLUSIONS: Native nephrectomy reduces the odds of needing antihypertensive medication after transplant. The impact of native nephrectomy is crucial to the comprehensive management of pediatric transplant recipients where medication compliance is challenging and lifelong hypertension is known to negatively impact cardiovascular health.

View details for PubMedID 29953422

View details for Web of Science ID 000444541200473

View details for PubMedID 29706006

Abstract

The kidney allocation system (KAS) altered pediatric candidate prioritization. We determined KAS's impact on pediatric kidney recipients by examining delayed graft function (DGF) rates from 2010 to 2016. A propensity score-matched pediatric recipients pre- and post-KAS. A semiparametric decomposition analysis estimated the contributions of KAS-related changes in donor characteristics and dialysis time on DGF rate. The unadjusted odds of DGF were 69% higher post-KAS for young (<10years at listing) recipients (N=1153, P=.02) but were not significantly increased for older pediatric (10-17years at listing) recipients (N=2624, P=.48). Post-KAS, young recipients received significantly fewer pediatric (<18years) donor kidneys (21% vs 32%, P<.01) and had longer median pretransplant dialysis time (603 vs 435days, P<.01). After propensity score matching, post-KAS status increased the odds of DGF in young recipients 71% (OR 1.71, 95% CI 1.01-2.46). In decomposition analysis, 24% of the higher DGF rate post-KAS was attributable to donor characteristics and 19% to increased recipient dialysis time. In a confirmatory survival analysis, DGF was associated with a 2.2 times higher risk of graft failure (aHR2.28, 95% CI 1.46-3.54). In conclusion, KAS may lead to worse graft survival outcomes in children. Allocation changes should be considered.

View details for PubMedID 29457274

View details for Web of Science ID 000419034500006

Abstract

Hepatoblastoma (HBL) and hepatocellular cancer (HCC) are the most common primary hepatic malignant neoplasms in childhood. Given the rarity of these childhood tumors and their propensity to present at advanced stages, updated long-term data are needed.To determine the efficacy of liver transplant in children with HBL or HCC.This single-institution retrospective medical record review and analysis spanned from January 1, 1997, through September 17, 2014, at Stanford University School of Medicine. A total of 40 patients younger than 18 years underwent liver transplant for treatment of HBL (n=30) or HCC (n=10) during the study period, with follow-up until September 17, 2014. Patients who underwent transplant for HCC included those with tumors that were greater in size than what is proposed by the Milan (a single tumor measuring 5 cm or 3 nodules measuring 3 cm) and University of California, San Francisco (single tumor measuring 6.5 cm or 3 nodules measuring 4.5 cm and a total diameter of 8 cm), criteria.Disease-free and overall patient survival and graft survival.Using a Kaplan-Meier survival analysis, 1-, 5-, and 10-year disease-free survival after liver transplant was 93%, 82%, and 82%, respectively, for 30 patients with HBL and 90%, 78%, and 78%, respectively, for 10 patients with HCC. Risk factors associated with HBL recurrence after transplant included having pretreatment extent of disease stage IV lesions and a longer waiting list time and being older at the time of the transplant. Recurrence was found in 2 of 7 patients with HBL and pretransplant metastases, which were not found to be an independent risk factor for recurrence. Patients with HCC larger than the proposed Milan and University of California, San Francisco, criteria experienced good 5-year disease-free (82%) and overall (78%) survival after transplant. Being older at the time of transplant (18 vs 11 years; P=.04) and the presence of metastatic disease (1 patient vs none; P=.05) were associated with HCC tumor recurrence.Liver transplant combined with chemotherapy is an excellent treatment that provides long-term disease-free survival in children diagnosed with advanced HBL and HCC. Early addition to a waiting list and aggressive multimodal therapy provide excellent results. Transplant should still be considered in children with HCC larger than the Milan and University of California, San Francisco, criteria.

View details for DOI 10.1001/jamasurg.2015.1847

View details for Web of Science ID 000367990700010

Abstract

Hepatoblastoma (HBL) and hepatocellular cancer (HCC) are the most common primary hepatic malignant neoplasms in childhood. Given the rarity of these childhood tumors and their propensity to present at advanced stages, updated long-term data are needed.To determine the efficacy of liver transplant in children with HBL or HCC.This single-institution retrospective medical record review and analysis spanned from January 1, 1997, through September 17, 2014, at Stanford University School of Medicine. A total of 40 patients younger than 18 years underwent liver transplant for treatment of HBL (n=30) or HCC (n=10) during the study period, with follow-up until September 17, 2014. Patients who underwent transplant for HCC included those with tumors that were greater in size than what is proposed by the Milan (a single tumor measuring 5 cm or 3 nodules measuring 3 cm) and University of California, San Francisco (single tumor measuring 6.5 cm or 3 nodules measuring 4.5 cm and a total diameter of 8 cm), criteria.Disease-free and overall patient survival and graft survival.Using a Kaplan-Meier survival analysis, 1-, 5-, and 10-year disease-free survival after liver transplant was 93%, 82%, and 82%, respectively, for 30 patients with HBL and 90%, 78%, and 78%, respectively, for 10 patients with HCC. Risk factors associated with HBL recurrence after transplant included having pretreatment extent of disease stage IV lesions and a longer waiting list time and being older at the time of the transplant. Recurrence was found in 2 of 7 patients with HBL and pretransplant metastases, which were not found to be an independent risk factor for recurrence. Patients with HCC larger than the proposed Milan and University of California, San Francisco, criteria experienced good 5-year disease-free (82%) and overall (78%) survival after transplant. Being older at the time of transplant (18 vs 11 years; P=.04) and the presence of metastatic disease (1 patient vs none; P=.05) were associated with HCC tumor recurrence.Liver transplant combined with chemotherapy is an excellent treatment that provides long-term disease-free survival in children diagnosed with advanced HBL and HCC. Early addition to a waiting list and aggressive multimodal therapy provide excellent results. Transplant should still be considered in children with HCC larger than the Milan and University of California, San Francisco, criteria.

View details for DOI 10.1001/jamasurg.2015.1847

View details for PubMedID 26308249

Abstract

Allocation of deceased donor kidneys is based on several criteria; however, the final decision to accept or reject the offered kidney is made by the potential recipient's transplant team (surgeon/nephrologist). Several considerations including assessment of the donor quality, the HLA match between the donor and the recipient, several recipient factors, the geographical location of the recipient, and the organ all affect the decision of whether or not to finally accept the organ for a particular recipient. This decision needs to be made quickly, often on the spot. Maximizing the benefit from this scarce resource raises difficult ethical issues. The philosophies of equity and utility are often competing. This article will discuss the several considerations for the pediatric nephrologist while accepting a deceased donor kidney for a particular pediatric patient.

View details for DOI 10.1111/petr.12582

View details for Web of Science ID 000362580100025

View details for PubMedID 26426405

Abstract

Renal transplantation is the treatment of choice for children with end-stage renal disease. More than 50% of children receive a deceased donor renal transplant. Marked disparity between the number of children on the renal transplant wait list and the supply has prompted numerous advances to increase supply as well as maximize the utility of donor organs. Allocation of deceased donor kidneys is based on several criteria. The organ allocation system policy is continually evaluated and changed incrementally to optimize allocation. We, in the United Sates, are in the process of transitioning into a new kidney allocation system to enhance post-transplant survival benefit, increase utilization of donated kidneys, and increase transplant access for biologically disadvantaged candidates. This review will provide a brief overview of the organ sharing system in the United States, compare the "old" and the "new" allocation system, and discuss the considerations for the pediatric nephrologist while accepting a deceased donor kidney for a particular pediatric patient.

View details for DOI 10.1111/petr.12569

View details for Web of Science ID 000362580100024

View details for PubMedID 26426316

Abstract

Inflammation is associated with the formation of aortic aneurysm. This study investigates the role of inducible Cys-X-Cys chemokine receptor 3 and its ligands in the pathogenesis of arterial aneurysms.Plasma samples from patients with or without a diagnosis of thoracic aortic aneurysms were analyzed by enzyme-linked immunosorbent assay for the T-helper 1 cytokine interferon- and the interferon--inducible chemokine receptor 3 ligands: interferon-inducible protein-10, interferon-inducible T-cell alpha chemoattractant, and monokine induced by interferon gamma. Patient charts were reviewed for demographics, initial aortic diameter, and growth rates. Aneurysm diameter and growth rates were correlated with plasma cytokine and chemokine levels using linear regression analysis. We used an animal model of aneurysm formation, where calcium chloride is applied topically to the carotid arteries of wild-type and Cys-X-Cys chemokine receptor 3(-/-) mice. After 10 weeks, the arteries were harvested and analyzed by histology and immunohistochemistry.Patients with thoracic aortic aneurysms had significant elevations in circulating interferon-, interferon-inducible protein-10, interferon-inducible T-cell alpha chemoattractant, and monokine induced by interferon gamma compared with referent patients (P<.001). Cytokine and chemokine plasma levels did not correlate with aneurysm size or growth rates. Cys-X-Cys chemokine receptor 3(-/-) mice were protected from aneurysm formation and showed decreased vascular infiltration by CD45(+) leukocytes.Elevated plasma levels of interferon- and Cys-X-Cys chemokine receptor 3-binding chemokines are present in patients with thoracic aortic aneurysms. The Cys-X-Cys chemokine receptor 3 receptor is necessary for vascular inflammation and the formation of arterial aneurysms in mice.

View details for DOI 10.1016/j.jtcvs.2011.08.036

View details for PubMedID 21962843

View details for DOI 10.1007/s10620-011-1776-x

View details for Web of Science ID 000295164600020

View details for PubMedID 21695402

View details for DOI 10.1007/s10620-010-1471-3

View details for PubMedID 21063775

Abstract

Atherosclerosis is an inflammatory disease in which interferon (IFN)-gamma, the signature cytokine of Th1 cells, plays a central role. We investigated whether interleukin (IL)-17, the signature cytokine of Th17 cells, is also associated with human coronary atherosclerosis.Circulating IL-17 and IFN-gamma were detected in a subset of patients with coronary atherosclerosis and in referent outpatients of similar age without cardiac disease but not in young healthy individuals. IL-17 plasma levels correlated closely with those of the IL-12/IFN-gamma/CXCL10 cytokine axis but not with known Th17 inducers such as IL-1beta, IL-6, and IL-23. Both IL-17 and IFN-gamma were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Combinations of proinflammatory cytokines induced IFN-gamma but not IL-17 secretion. Blockade of IFN-gamma signaling increased IL-17 synthesis, whereas neutralization of IL-17 responses decreased IFN-gamma synthesis; production of both cytokines was inhibited by transforming growth factor-beta1. Approximately 10-fold fewer coronary artery-infiltrating T helper cells were IL-17 producers than IFN-gamma producers, and unexpectedly, IL-17/IFN-gamma double producers were readily detectable within the artery wall. Although IL-17 did not modulate the growth or survival of cultured vascular smooth muscle cells, IL-17 interacted cooperatively with IFN-gamma to enhance IL-6, CXCL8, and CXCL10 secretion.Our findings demonstrate that IL-17 is produced concomitantly with IFN-gamma by coronary artery-infiltrating T cells and that these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells.

View details for DOI 10.1161/CIRCULATIONAHA.108.827618

View details for Web of Science ID 000264243700011

View details for PubMedID 19255340

Abstract

Stage III, locally advanced non-small-cell lung cancer represents an incredibly heterogeneous group of patients. The majority of patients are treated with curative intent, but optimal therapy is controversial and the role of surgery is not well defined. Consensus has shown that the majority of patients with IIIB disease are not amenable to resection. The exceptions are selected patients with tumor stage 4 (T4) by virtue of a satellite nodule or those with isolated invasion of the spine, superior sulcus, carina, or vena cava. Surgery is more widely used for stage IIIA disease. Patients with nodal stage 2 (N2) disease represent the largest population of patients in stage III. Increasing evidence supports the use of surgery as part of a multimodality approach for N2 disease. The impact of surgery is partially determined by the bulk of the mediastinal node involvement. Patients with micrometastatic disease and single-station nodal involvement have the greatest chance for cure, and surgery appears to play a significant role in their treatment. Patients with bulky multistation disease are frequently not amenable to complete resection and may be best approached with definitive chemotherapy and radiation. In addition, the ability to sterilize mediastinal lymph nodes with induction therapy correlates strongly with survival following resection, but the ideal induction regime that balances the safety and efficacy has yet to be determined.

View details for PubMedID 17588348

Abstract

Although type A aortic dissections represent a surgical emergency, some patients present late after the onset of symptoms. Optimal management of this cohort has not been defined.Data on 195 patients with type A dissections followed up at a single institution between 1985 and 2005 were collected prospectively. Of these, 93 patients (47.2%) presented 48 hours or later after the initial onset of pain (group A), and the remaining 102 patients underwent immediate operative repair (group B). Median follow-up was 41.8 months (range, 0 to 386 months).Patients in group A were older (68.8 versus 59.3 years, p = 0.0005) and had a higher incidence of coronary artery disease (42.5% versus 14.6%, p < 0.0001), pulmonary disease (26.6% versus 8.4%, p = 0.0023), and congestive heart failure (14.1% versus 1.0%, p = 0.0004). Long-term survival was similar, although group B showed a trend toward improved 30-day mortality (16.5% versus 8.7%, p = 0.1035). Of the 92 patients in group A, 53 (57.6%) eventually underwent operative repair a median of 8.2 days after symptom onset. There was a trend toward improved long-term survival among patients undergoing repair (p = 0.1031).Initial medical management with interval operative repair of selected patients referred greater than 2 days following an acute type A dissection is a viable option. Delayed repair after optimization of the clinical condition and detailed evaluation of concomitant diseases results in excellent long-term results.

View details for PubMedID 17462364

Abstract

Patients with bicuspid aortic valve (BAV) are at risk for valvular disease and ascending aortic aneurysms and dissections. Although others have investigated the need for concomitant repair, the natural history of aortic disease has not been addressed.A review of our institutional clinical database identified 514 patients (326 male, 188 female) with unrepaired ascending aortic aneurysms followed from 1985 to 2005. Seventy patients (13.4%) diagnosed with BAV form group A; the remaining 445 patients form group B. Growth rates and risk factors for complications were assessed.Patients in group A had a lower incidence of hypertension (p = 0.0185), carotid artery disease, and stroke (p = 0.0184), and presented at an earlier age (49.0 versus 64.2 years, p < 0.0001). Group A also had a higher rate of aortic growth (0.19 versus 0.13 cm/year, p = 0.0102). The incidence of rupture and dissection were similar. Overall survival was better among patients with BAV (p < 0.0001). Among patients with BAV, those with aortic stenosis had a higher risk of rupture, dissection, or death before operative repair than did those with normally functioning valves (odds ratio 10.475, 95% confidence interval: 1.153 to 95.155).Aortic stenosis presents a significant added risk for patients with aneurysmal disease in the face of BAV. Despite faster rates of growth, however, patients with BAV have similar rates of aortic rupture, dissection, and death and improved long-term survival. Contributing to this finding may be the lower incidence of comorbidities, the younger age at presentation, and the more attentive follow-up with earlier operative repair.

View details for DOI 10.1016/j.athoracsur.2006.10.074

View details for Web of Science ID 000245178900017

View details for PubMedID 17383337

Abstract

Inflammation is associated with the pathogenesis of coronary atherosclerosis, although the mechanisms remain unclear. We investigated whether cytokine secretion by innate immune responses could contribute to the production of proarteriosclerotic Th1-type cytokines in human coronary atherosclerosis. Cytokines were measured by ELISA in the plasma of patients with coronary atherosclerosis undergoing cardiac catheterization. IL-18 was detected in all subjects, whereas a subset of patients demonstrated a coordinated induction of other IFN-gamma-related cytokines. Specifically, elevated plasma levels of IL-12 correlated with that of IFN-gamma and IFN-gamma-inducible chemokines, defining an IFN-gamma axis that was activated independently of IL-6 or C-reactive protein. Systemic inflammation triggered by cardiopulmonary bypass increased plasma levels of the IFN-gamma axis, but not that of IL-18. Activation of the IFN-gamma axis was not associated with acute coronary syndromes, but portended increased morbidity and mortality after 1-year follow-up. IL-12 and IL-18, but not other monokines, elicited secretion of IFN-gamma and IFN-gamma-inducible chemokines in human atherosclerotic coronary arteries maintained in organ culture. T cells were the principal source of IFN-gamma in response to IL-12/IL-18 within the arterial wall. This inflammatory response did not require, but was synergistic with and primed for TCR signals. IL-12/IL-18-stimulated T cells displayed a cytokine-producing, nonproliferating, and noncytolytic phenotype, consistent with previous descriptions of lymphocytes in stable plaques. In contrast to cognate stimuli, IL-12/IL-18-dependent IFN-gamma secretion was prevented by a p38 MAPK inhibitor and not by cyclosporine. In conclusion, circulating IL-12 may provide a mechanistic link between inflammation and Th1-type cytokine production in coronary atherosclerosis.

View details for Web of Science ID 000243120900067

View details for PubMedID 17182600

Abstract

Since the first description of aortic dissection in the 1700s, the understanding and treatment of this catastrophic disease has evolved. Aortic dissections are identified as a tear in the aortic intima and inner layer of the media that allows for blood flow within the aortic wall. The area of the vessel involved determines its classification. The classification, in turn, helps to predict outcomes, which allows for appropriate treatment planning. The goal of this article is to outline the operative indications and timing for Stanford type A and type B dissections, based on prior reported data and our own clinical experience with 176 patients treated surgically at the Yale Center for Thoracic Aortic Disease. With this data we will revisit the importance of looking at each patient individually to devise an appropriate operative plan, with the knowledge that treatment for type A dissections is operative and treatment for type B dissections is medical unless patients present with actual or impending rupture, malperfusion, or failure of medical management.

View details for PubMedID 16253827

Abstract

To elucidate molecular mechanism(s) of cellular response to mercaptopurine, a widely used antileukemic agent, we assessed mercaptopurine (MP) sensitivity in mismatch repair (MMR) proficient and MMR deficient human acute lymphoblastic leukemia (ALL) cells. Sensitivity to thiopurine cytotoxicity was not dependent on MMR (i.e., MutSalpha) competence among six cell lines tested. Using electrophoretic mobility shift assay analysis, we found that the incubation of nuclear extracts from ALL cells with synthetic 34-mer DNA duplexes containing deoxythioguanosine (G(S)) within either G(S).T or G(S).C pairs, resulted in formation of a DNA-protein complex distinct from the DNA-MutSalpha complex and unaffected by ATP. Isolation and sequence analysis of proteins involved in this DNA-protein complex identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a component. Western blot analysis of nuclear extracts from a panel of human lymphoblastic leukemia cell lines revealed markedly different basal levels of GAPDH in nuclei, which was significantly related to thiopurine sensitivity (p = 0.001). Confocal analysis revealed markedly different intracellular distribution of GAPDH between nucleus and cytosol in six human ALL cell lines. Redistribution of GAPDH from cytosol to nucleus was evident after MP treatment. These findings indicate that a new DNA-protein complex containing GAPDH and distinct from known MMR protein-DNA complexes binds directly to thioguanylated DNA, suggesting that this may act as a sensor of structural alterations in DNA and serve as an interface between these DNA modifications and apoptosis.

View details for Web of Science ID 000166549200026

View details for PubMedID 11160874