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PURPOSE AREN0321 evaluated the activity of vincristine and irinotecan (VI) in patients with newly diagnosed diffuse anaplastic Wilms tumor (DAWT) and whether a regimen containing carboplatin (regimen UH1) in addition to regimen I agents used in the National Wilms Tumor Study 5 (NWTS-5; vincristine, doxorubicin, cyclophosphamide, and etoposide plus radiotherapy) would improve patient outcomes. PATIENTS AND METHODS Patients with stage II to IV DAWT without measurable disease received regimen UH1. Patients with stage IV measurable disease were eligible to receive VI (vincristine, 1.5 mg/m2 per day intravenously on days 1 and 8; irinotecan, 20 mg/m2 per day intravenously on days 1-5 and 8-12 of a 21-day cycle) in an upfront window; those with complete (CR) or partial response (PR) had VI incorporated into regimen UH1 (regimen UH2). The study was designed to detect improvement in outcomes of patients with stage II to IV DAWT compared with historical controls treated with regimen I. RESULTS Sixty-six eligible patients were enrolled. Of 14 patients with stage IV measurable disease who received VI, 11 (79%) achieved CR (n = 1) or PR (n = 10) after 2 cycles. Doses of doxorubicin, cyclophosphamide, and etoposide were reduced midstudy because of nonhematologic toxicity. Four patients (6%) died as a result of toxicity. Four-year event-free survival, relapse-free survival, and overall survival rates were 67.7% (95% CI, 55.9% to 79.4%), 72.9% (95% CI, 61.5% to 84.4%), and 73.7% (95% CI, 62.7% to 84.8%), respectively, compared with 57.5% (95% CI, 47.6% to 67.4%; P = .26), 57.5% (95% CI, 47.6% to 67.4%; P = .048), and 59.2% (95% CI, 49.4% to 69.0%; P = .08), respectively, in NWTS-5. CONCLUSION VI produced a high response rate in patients with metastatic DAWT. AREN0321 treatment seemed to improve outcomes for patients with stage II to IV DAWT compared with NWTS-5, but with increased toxicity. The UH2 regimen warrants further investigation with modifications to reduce toxicity.

Background In the fifth National Wilms Tumor Study (NWTS-5), the 4-year event-free survival (EFS) and overall survival (OS) estimates for 29 patients with stage I focal (n = 10) or diffuse (n = 19) anaplastic Wilms' tumour (AWT) treated with vincristine and dactinomycin without flank radiation were 69.5% and 82.6%, respectively. The Children's Oncology Group AREN0321 study evaluated whether adding doxorubicin and flank radiation improves survival for these patients. Patients and methods Tumour histology and stage were confirmed by real-time central pathology, surgery and radiology review. The patients received 25 weeks of vincristine, dactinomycin and doxorubicin (cumulative dose 150 mg/m2) with flank radiation (1080 cGy). We retrospectively analysed outcomes of all patients with stage I AWT enrolled in NWTSs 1–5 and AREN0321 with respect to treatment regimens. Results Eighteen patients with stage I AWT (8 focal and 10 diffuse) were enrolled on AREN0321. With a median follow-up of 4.6 years, the 4-year EFS and OS were 100%. One patient with diffuse AWT had pulmonary relapse 4.12 years after diagnosis. In the 112 patients with stage I AWT treated in NWTSs 1–5 and AREN0321, the EFS was significantly improved with doxorubicin treatment (p = 0.01; 4-year EFS: 97.2% [95% confidence interval {CI}: 91.3–100] vs. 77.5% [95% CI: 67.6–87.4]) but not by flank radiation (p = 0.15). Conclusions Treatment of stage I AWT with vincristine, dactinomycin, doxorubicin and flank radiation in AREN0321 yielded excellent survival outcomes. Retrospective analysis of AREN0321 and NWTS patients suggests that doxorubicin had a greater contribution to the excellent outcomes than radiation.

Introduction: 6-Mercaptopurine (6-MP) is the most frequently used chemotherapy agent in the management of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Skewed drug metabolism can decrease the effectiveness of 6-MP while also resulting in unnecessary toxicities. Each individual's ability to metabolize 6-MP into the desired therapeutic product, 6-thioguanine nucleotide (6-TGN), is directly opposed by the development of the hepatotoxic byproduct, 6-methyl-mercaptopurine (6-MMPN). Certain individuals, referred to as 'shunters,' preferentially generate high levels of 6-MMPN resulting in decreased production of 6-TGN. Current guidelines suggest holding or lowering 6-MP doses in the setting of toxicity. However this approach results in decreased intensity of 6-MP treatment, potentially risking an increase in disease relapse. Allopurinol, a drug used to manage hyperuricemia, can alter 6-MP metabolism to maximize 6-TGN production while reducing the hepatotoxic metabolite, 6-MMPN. Methods: We performed a single institution, IRB approved, retrospective cohort study to quantify and characterize the rate of shunters treated in our center. Chart review was conducted of ALL and LL patients treated for at least one year of maintenance therapy at our center over a 10 year period from January 1, 2009 to June 1, 2019. Incidents of hypoglycemia (glucose 123), and hypogammaglobulinemia (IgG Results: We performed a chart review on 42 eligible patients and included demographic information (Table 1). Using lab data, we documented potential markers of toxicity (Table 2). Seventy four percent of patients had a least one episode of documented hypoglycemia, and 88% had at least one episode of elevated ALT > 3 times the upper limit of normal. Metabolites were checked in 66% (28/42) of our patients. 6-MMPN levels were > 10,000 in 82.1% (23/28). Shunting was observed in 54% of the patients; meaning one half of the patients were eligible for allopurinol combination therapy. Allopurinol was initiated by the primary team for metabolite and laboratory derangements in 12 of 23 patients. All patients who received allopurinol had normalization of laboratory values with combined treatment. Discussion: In our population of pediatric and young adults treated for leukemia and lymphoblastic lymphoma, over half of the patients were shunters with metabolite derangements and associated signs of toxicity. Current guidelines in the Children's Oncology Group (COG) leukemia protocols recommend checking metabolites in the context of increased sensitivity to 6-MP, as in the case of TPMT and NUDT15 deficient patients, but do not specifically address the more common problem of skewed metabolism. Previous gastroenterology publications suggest there may be as many as 15% of shunters in their population of patients being prescribed 6MP. We found a much higher incidence of shunters among our leukemia population, many of whom had concurrent toxicities. The patients who received allopurinol during their treatment period showed adequate count suppression with reversal of undesired toxicities, suggesting that combination therapy may be beneficial for many more patients in the future. All of these patients remain in remission through 1 Jun 2019, the longest being 6 years post-treatment. Based on our institutional experience, we propose an algorithm for the use of allopurinol in conjunction with chemotherapy for patients with ALL or LL who have inappropriate 6-MP metabolism (Figure 1) to optimize their treatment while decreasing 6-MP associated toxicities. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Allopurinol inhibits the enzyme, xanthine oxidase, and is commonly used for prevention of tumor lysis syndrome and gout. However, it is understood that allopurinol also affects the metabolism of 6-Mercaptopurine. Allopurinol directs 6MP metabolism towards 6-TGN, the desired product, and away from 6-MMPN. 6-MMPN is associated with increased toxicity in patients. We describe in our abstract the incorporation of allopurinol therapy in many of our patients with abnormal 6-MP metabolism

Background We sought to compare survival outcomes of sarcomas in the pediatric and adolescent/young adult populations with universal care access in the Military Health System (MHS) to those from the United States general population. Methods We compared data from the Department of Defense's (DoD) Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program on the overall survival of patients 24 years or younger with histologically or microscopically confirmed sarcoma between diagnosed between January 1, 1987, and December 31, 2013. The Kaplan-Meier survival curves were used to compare survival between the 2 patient populations. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) comparing ACTUR relative to SEER. Results The final analysis included 309 and 1236 bone sarcoma cases and 465 and 1860 soft tissue sarcoma cases from ACTUR and SEER, respectively. Cox proportional hazards analysis showed soft tissue sarcoma patients in ACTUR had significantly better overall (HR=0.73, 95% CI=0.55-0.98) and 5-year overall (HR=0.63, 95% CI=0.46-0.86) survival compared with SEER patients, but no significant difference in overall or 5-year overall survival between ACTUR and SEER patients with bone sarcoma. Conclusion Survival data from the ACTUR database demonstrated significantly improved overall survival for soft tissue sarcomas and equivalent survival in bone sarcomas compared with that reported by SEER.

Background Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods 9028 recipients of hematopoietic cell autotransplants (1995–2010) for Hodgkin lymphoma (HL; n = 916), non-Hodgkin lymphoma (NHL; n = 3546) and plasma cell myeloma (PCM; n = 4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS. Results 335 MDS/AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR = 4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR = 2.5 [1.1, 2.5]); (2) ≥3 versus 1 line of chemotherapy for NHL (HR = 1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005–2010 versus 1995–1999 (HR = 2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/MDS in HL, NHL and PCM to be 5–10 times the background rate. In contrast, relative risks were 10–50 for AML and approximately 100 for MDS in the autotransplant cohort. Conclusions There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and non-malignant diseases. Despite increasing survival rates, long-term morbidity following HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction following HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction following HCT. In this review, we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and to help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Lastly, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae following HCT.

BACKGROUND Autologous hematopoietic cell transplantation (auto-HCT) is a standard therapy for relapsed classic Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL); however, long-term outcomes are not well described. METHODS This study analyzed survival, nonrelapse mortality, late effects, and subsequent malignant neoplasms (SMNs) in 1617 patients who survived progression-free for ≥2 years after auto-HCT for cHL or DLBCL between 1990 and 2008. The median age at auto-HCT was 40 years; the median follow-up was 10.6 years. RESULTS The 5-year overall survival rate was 90% (95% confidence interval [CI], 87%-92%) for patients with cHL and 89% (95% CI, 87%-91%) for patients with DLBCL. The risk of late mortality in comparison with the general population was 9.6-fold higher for patients with cHL (standardized mortality ratio [SMR], 9.6) and 3.4-fold higher for patients with DLBCL (SMR, 3.4). Relapse accounted for 44% of late deaths. At least 1 late effect was reported for 9% of the patients. A total of 105 SMNs were confirmed: 44 in the cHL group and 61 in the DLBCL group. According to a multivariate analysis, older age, male sex, a Karnofsky score < 90, total body irradiation (TBI) exposure, and a higher number of lines of chemotherapy before auto-HCT were risk factors for overall mortality in cHL. Risk factors in DLBCL were older age and TBI exposure. A subanalysis of 798 adolescent and young adult patients mirrored the outcomes of the overall study population. CONCLUSIONS Despite generally favorable outcomes, 2-year survivors of auto-HCT for cHL or DLBCL have an excess late-mortality risk in comparison with the general population and experience an assortment of late complications. Cancer 2018;124:816-25. © 2017 American Cancer Society.

Very young children undergoing hematopoietic cell transplantation (HCT) are a unique and vulnerable population. We analyzed outcomes of 717 patients from 117 centers who survived relapse free for year after allogeneic myeloablative HCT for hematologic malignancy at = 1 organ toxicity/late effect >1 year after HCT. The most frequent late effects included growth hormone deficiency/growth disturbance (10-year cumulative incidence, 23%; 95% CI, 19% to 28%), cataracts (18%; 95% CI, 15% to 22%), hypothyroidism (13%; 95% CI, 10% to 16%), gonadal dysfunction/infertility requiring hormone replacement (3%; 95% CI, 2% to 5%), and stroke/seizure (3%; 95% CI, 2% to 5%). Subsequent malignancy was reported in 3.6%. In multivariable analysis, total body irradiation (TBI) was predictive of increased risk of cataracts (HR, 17.2; 95% CI, 7.4 to 39.8; P

This Center for International Blood and Marrow Transplant Research report describes the use of hematopoietic stem cell transplantation (HSCT) in pediatric patients with cancer, 4408 undergoing allogeneic (allo) and3076 undergoing autologous (auto) HSCT in the United States between 2008 and 2014. In both settings, there was a greater proportion of boys (n = 4327; 57%), children < 10 years of age (n = 4412; 59%), whites (n = 5787; 77%), and children with a performance score ≥ 90% at HSCT (n = 6187; 83%). Leukemia was the most common indication for an allo-transplant (n = 4170; 94%), and among these, acute lymphoblastic leukemia in second complete remission (n = 829; 20%) and acute myeloid leukemia in first complete remission (n = 800; 19%) werethe most common. The most frequently used donor relation, stem cell sources, and HLA match were unrelated donor (n = 2933; 67%), bone marrow (n = 2378; 54%), and matched at 8/8 HLA antigens (n = 1098; 37%) respectively. Most allo-transplants used myeloablative conditioning (n = 4070; 92%) and calcineurin inhibitors and methotrexate (n = 2245; 51%) for acute graft-versus-host disease prophylaxis. Neuroblastoma was the most common primary neoplasm for an auto-transplant (n = 1338; 44%). Tandem auto-transplants for neuroblastoma declined after 2012 (40% in 2011, 25% in 2012, and 8% in 2014), whereas tandem auto-transplants increased for brain tumors (57% in 2008 and 77% in 2014). Allo-transplants from relatives other than HLA-identical siblings doubled between 2008 and 2014 (3% in 2008 and 6% in 2014). These trends will be monitored in future reports of transplant practices in the United States.

The curative potential of autologous hematopoietic cell transplantation (autoHCT) for male germ cell tumors (GCTs) is well established. The optimal timing and number (single transplant [ST] versus tandem transplants [TT] versus triple transplants) of autoHCT are controversial, with wide practice variations. We examined survival trends among 2395 recipients of autoHCT for male GCTs between 1990 and 2015 reported to the Center for International Blood and Marrow Transplant Research. Trends and outcomes were analyzed by year of transplantation for intervals 1990 to 1994 (N = 288), 1995 to 1999 (N = 351), 2000 to 2004 (N = 376), 2005 to 2009 (N = 509), and 2010 to 2015 (N = 871). Multivariate analysis was restricted to the subset from 2000 to 2015 with research-level data (n = 267). The median duration of follow-up was 51 months. The median age at autoHCT was 31 years; 633 patients (26%) had primary extragonadal GCT, and 1167 (49%) underwent TT. The 3-year progression-free (PFS) and overall survival (OS) improved from 24% (95% confidence interval [CI], 18% to 31%) and 35% (95% CI, 29% to 40%), respectively, in 1990 to 1994 to 47% (95% CI, 43% to 50%) and 54% (95% CI, 50% to 57%), respectively, in 2010 to 2015 (P < .0001). TT recipients were more likely than ST recipients to undergo autoHCT as first salvage treatment. The proportion of TTs increased from 38% of all autoHCTs in 2000 to 2004 to 77% in 2010 to 2015. Nonseminoma histology, residual disease at autoHCT, >1 line of pretransplantation chemotherapy, and ST versus TT were associated with inferior PFS and OS. Post-transplantation survival has improved significantly over time for relapsed/refractory male GCT and is associated with the increased use of TTs (compared with STs) and performance of autoHCT earlier in the disease course.

6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels. We suggest that this combination therapy can be used safely to change the metabolite production in patients who develop excessive hepatotoxicity.

We analyzed the outcomes of patients who survived disease-free for 1 year or more after a second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant after disease relapse; among these, 325 were relapse free at 1 year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplantation in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least 1 year was 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status before second HCT was significantly associated with higher risk for overall mortality (hazard ratio, 1.71 for patients with disease not in complete remission before second HCT, P

Purpose This non-randomized, patient-access protocol, assessed both safety and efficacy outcomes following liposomal muramyl-tripeptide-phosphatidylethanolamine (L-MTP-PE; mifamurtide) in patients with high-risk, recurrent and/or metastatic osteosarcoma. Methods Patients received mifamurtide 2 mg/m2 intravenously twice-weekly ×12 weeks, then weekly ×24 weeks with and without chemotherapy. Serum concentration-time profiles were collected. Adverse events within 24 hours of drug administration were classified as infusion-related adverse events (IRAE); other AEs and overall survival (OS) were assessed. Results The study began therapy in January 2008; the last patient completed therapy in October 2012. Two hundred five patients were enrolled; median age was 16.0 years and 146/205 (71%) had active disease. Mifamurtide serum concentrations declined rapidly in the first 30 minutes post-infusion, then in a log-linear manner 2–6 hours post-dose; t1/2 was 2 hours. There were no readily apparent relationships between age and BSA-normalized clearance, half-life, or pharmacodynamic effects, supporting the dose of 2 mg/m2 mifamurtide across the age range. Patients reported 3,679 IRAE after 7,482 mifamurtide infusions. These were very rarely grade 3 or 4 and most commonly included chills + fever or headache + fatigue symptom clusters. One- and 2-year OS was 71.7% and 45.9%. Patients with initial metastatic disease or progression approximated by within 9 months of diagnosis (N = 40) had similar 2-year OS (39.9%) as the entire cohort (45.9%) Conclusions Mifamurtide had a manageable safety profile; PK/PD of mifamurtide in this patient access study was consistent with prior studies. Two-year OS was 45.9%. A randomized clinical trial would be required to definitively determine impact on patient outcomes. Pediatr Blood Cancer 2014;61:238–244. © 2013 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.

Physician practice variation may be a barrier to informing hematopoietic cell transplant (HCT) recipients about fertility preservation (FP) options. We surveyed HCT physicians in the United States to evaluate FP knowledge, practices, perceptions and barriers. Of the 1035 physicians invited, 185 completed a 29-item web-survey. Most respondents demonstrated knowledge of FP issues and discussed and felt comfortable discussing FP. However, only 55% referred patients to an infertility specialist. Most did not provide educational materials to patients and only 35% felt that available materials were relevant for HCT. Notable barriers to discussing FP included perception that patients were too ill to delay transplant (63%), patients were already infertile from prior therapy (92%) and time constraints (41%). Pediatric HCT physicians and physicians with access to an infertility specialist were more likely to discuss FP and to discuss FP even when prognosis was poor. On analyses that considered physician demographics, knowledge and perceptions as predictors of referral for FP, access to an infertility specialist and belief that patients were interested in FP were observed to be significant. We highlight variation in HCT physician perceptions and practices regarding FP. Physicians are generally interested in discussing fertility issues with their patients but lack educational materials.

Many medical institutions have moved forward with curricular objectives aimed at teaching professionalism, but the question remains: are we teaching the most appropriate content at the most opportune times to maximize sustained learning? The students' point of view of professionalism is helpful in addressing this question.To describe the views of professionalism held by students and faculty at the Uniformed Services University of the Health Sciences.In e-mailed surveys, students and faculty free-texted the three most important characteristics of a professional. Qualitative analysis was used to analyze the results. Data were compared on the basis of the percentage of each group affirming one of the characteristics.Fourteen characteristics of professionalism were found. There were significant differences across all participant groups in the characteristics that each indicated were most important.Differences emerge between definitions of professionalism that appear to relate to training and experience. Students' views of professionalism reflect the immediate context of their educational environment. Curricula targeted to the students' foci are relevant in teaching professionalism.

Background Pemetrexed is a multi-targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile. Procedure Pemetrexed, at a dose of 1910 mg/m2, was administered as a 10-minute intravenous infusion every 21 days. Patients also received vitamin B12, daily multivitamin supplementation, and dexamethasone. A two-stage design (10 + 10) was employed in each of the following disease strata: osteosarcoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, and non-brainstem high-grade glioma. Results Seventy-two eligible subjects (39 males) were enrolled. Median age was 11 years (range 3–23). Sixty-eight were evaluable for response. The median number of cycles administered was 2 (range 1–13). No complete or partial responses were observed. Stable disease, for a median of 5 (range 4–13) cycles, was observed in five patients (ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma; n = 1 each). Neutropenia (44%), anemia (35%), and elevated alanine transaminase (35%) attributable to pemetrexed were the most commonly recurring toxicities observed in patients receiving multiple cycles. Other toxicities attributed to pemetrexed occurring in ≥10% of cycles included thrombocytopenia (30%), fatigue (18%), nausea (14), hyperglycemia (13%), rash (11%), vomiting (13%), and hypophosphatemia (11%). Conclusions Pemetrexed, administered as an intravenous infusion every 21 days, was tolerable in children and adolescents with refractory solid tumors, including CNS tumors, but did not show evidence of objective anti-tumor activity in the childhood tumors studied. Pediatr Blood Cancer 2013;60:237–241. © 2012 Wiley Periodicals, Inc.

Since Wilms' tumor occurs rarely in adults, there are no standard treatments available. Most adult patients will be diagnosed unexpectedly following nephrectomy for presumed renal cell carcinoma. Outcome for adults is inferior compared with children, although better results are reported when treated within pediatric trials. Multiple factors, including the unfamiliarity of adult oncologists and pathologists with Wilms' tumors, lack of standardized treatment and consequent delays in initiating the appropriate risk-adapted therapy, may contribute to the poor outcome. A standardized approach for the management of adult Wilms' tumors is proposed with the aim to limit treatment delay after surgery and encourage a uniform approach for this rare disease and thereby improve survival. These recommendations are based on discussions held with representatives of the renal tumor committees of the Society of Paediatric Oncology and Children's Oncology Group, and have been updated with a review of more recently published institutional and trial experience of adults treated on pediatric protocols. They provide a critical evaluation of the current evidence for the management of adult Wilms' tumors and propose details of how current pediatric therapeutic guidelines could be adapted for use in adults.

Children who have undergone bone marrow transplantation (BMT) often have decreased growth. Growth is a multifactorial process, and the factors that influence growth after BMT are not completely understood. The authors hypothesized that donor type may be a factor influencing growth. Sixty-five children and adolescents who underwent BMT (32 related matched, 33 unrelated matched) were evaluated. Growth velocity (height standard deviation) was assessed prior to and 2 years following BMT. The results indicated that children and adolescents who underwent unrelated matched transplants had lower growth velocity (P < .059) than those with related matched transplants. Those who received the standard conditioning regimen that included total body irradiation (TBI) had a significantly lower growth velocity (P < .045) than those with chemotherapy-only regimens. Significant correlates of growth velocity included younger age at BMT and pre-BMT growth velocity. Thus, donor type, age at BMT, prior treatment, and BMT conditioning regimens that include TBI may all affect growth post-BMT. Careful monitoring of growth velocity is required for patients who have received an unrelated donor BMT.

We report a case of a catheter-related bloodstream infection with Mycobacterium frederiksbergense in an immunocompromised child with acute lymphoblastic leukemia. Nontuberculous mycobacteria have been implicated in central venous catheter infections in immunosuppressed individuals, however, to our knowledge this is the first reported case of invasive infection with this organism.

International audience; With broadening indications, more options for hematopoietic cell transplantation (HCT) and improvement in survival, the number of long-term HCT survivors is expected to increase steadily. Infertility is a frequent problem that long-term HCT survivors and their partners face and it can negatively impact on the quality of life. The most optimal time to address fertility issues is before the onset of therapy for the underlying disease; however, fertility preservation should also be addressed before HCT in all children and patients of reproductive age, with referral to a reproductive specialist for patients interested in fertility preservation. In vitro fertilization (IVF) and embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking are acceptable methods for fertility preservation in adult women/pubertal females. Sperm banking is the preferred method for adult men/pubertal males. Frequent barriers to fertility preservation in HCT recipients may include the perception of lack of time to preserve fertility given an urgency to move ahead with transplant, lack of patient-physician discussion because of several factors (for example, time constraints, lack of knowledge), inadequate access to reproductive specialists, and costs and lack of insurance coverage for fertility preservation. There is a need to raise awareness in the medical community about fertility preservation in HCT recipients.

Severe aplastic anemia (SAA) is a frequent complication of orthotopic liver transplantation for non-typeable viral hepatitis. Allogeneic bone marrow transplantation (BMT) may successfully reconstitute hematopoiesis but the optimal conditioning regimen and graft-versus-host disease (GVHD) prophylaxis in such patients are unknown. Allogeneic BMT was undertaken in an 8-year-old male patient who developed SAA 6 weeks after cadaveric orthotopic liver transplantation for fulminant hepatic failure secondary to presumed non-typeable viral hepatitis. The preparative regimen for his HLA genotypically identical sibling BMT consisted of cytoxan and anti-thymocyte globulin. Tacrolimus (FK506) and prednisone, used to prevent liver graft rejection, were supplemented with methotrexate on post-BMT days, 1, 3, 6 and 11 for GVHD prophylaxis. Engraftment proceeded promptly and without complications. Transfusion dependence resolved 6 weeks after BMT. The patient is alive and well 1 year after his BMT on FK506 and prednisone without any signs of GVHD or liver allograft rejection. This case is the first demonstration of the feasibility of continuing FK506 used for prevention of liver graft rejection as GVHD prophylaxis for allogeneic BMT.

Paraneoplastic syndromes may affect the central and peripheral nervous system of adults and children with cancer. Neurological symptoms may resolve with treatment of the underlying neoplasm. We report the case of a child with Wilms tumor who presented with generalized weakness, fatigue, ptosis, hypokinesis, dysarthria, urinary retention, facial diplegia, ophthalmoplegia, and autonomic dysfunction. Routine electrodiagnostic testing, including repetitive nerve stimulation, was normal. Clinical features and stimulation single-fiber electromyogram were consistent with a neuromuscular junction transmission disorder, likely Lambert-Eaton myasthenic syndrome. The child's neurological status returned to normal with successful treatment of the tumor.

International audience; Childhood autologous hematopoietic cell transplant (auto-HCT) survivors can be at risk for secondary malignant neoplasms (SMNs). We assembled a cohort of 1487 pediatric auto-HCT recipients to investigate the incidence and risk factors for SMNs. Primary diagnoses included neuroblastoma (39%), lymphoma (26%), sarcoma (18%), central nervous system tumors (14%) and Wilms tumor (2%). Median follow-up was 8 years (range

SOCIAL MEDIA AND ITS INTERFACE WITH MEDICAL PROFESSIONALISM ARE HERE TO STAY Medical professionalism has become an increasingly important focus over the past decade. A search of the medical literature using PubMed found only 130 published articles with the term “Professionalism” in the title in the years 1970 to 1980 and over 700 articles in the years from 2000 to 2008. Attributes of medical professionalism, including compassion, altruism, respect, and duty are now outlined for trainees in the manuals of medical oversight organizations. Simultaneously, the rise of social media as an omnipresent communication tool is posing unique challenges to medical professionalism. Therefore, military medical educators and those in command in the military health care system must address the appropriate use of social media with their trainees and subordinates. Social networking’s interface with the military medical profession should be explicitly defined and understood at every level.

A 5.5-year-old asymptomatic Hispanic/African American male presented with matted lymph nodes in the neck and reticulonodular opacities in the right upper lung. An extensive diagnostic work up was performed to rule out infectious etiologies. Biopsies of the lymph node and lung tissue were diagnostic of nodular lymphocyte predominant Hodgkin lymphoma. Two weeks into the chemotherapy, gastric aspirates grew Mycobacterium avium intracellulare. This is the first case of nodular lymphocyte predominant Hodgkin lymphoma involving the lung with coexistent Mycobacterium avium intracellulare.

Purpose This analysis was undertaken to determine the cumulative risk of and risk factors for portal hypertension (PHTN) in patients with Wilms' tumor (WT). Methods and Materials Medical records were reviewed to identify cases of PHTN identified with late liver/spleen/gastric toxicities in a cohort of 5,195 patients treated with National Wilms' Tumor Studies (NWTS) protocols 1 to 4. A nested case control study (5 controls/case) was conducted to determine relationships among doxorubicin, radiation therapy (RT) dose to the liver, patient gender, and PHTN. Conditional logistic regression was used to estimate adjusted hazard ratios (HR) of PHTN associated with these factors. Results Cumulative risk of PHTN at 6 years from WT diagnosis was 0.7% for patients with right-sided tumors vs. 0.1% for those with left-sided tumors ( p = 0.002). Seventeen of 19 cases were evaluable for RT. The majority of cases (16/17 [94%]) received right-flank RT either alone or as part of whole-abdomen RT and received >15 Gy to the liver. Fifteen of 17 (88%) patients received a higher dose to the liver than they would have with modern WT protocols. Controlling for RT dose, the HR was 3.0 for patients who received doxorubicin ( p = 0.32) and 2.8 for females ( p = 0.15). Controlling for doxorubicin, the 95% lower confidence bound on the HR associating PHTN with a minimum liver RT dose of >15 Gy vs. ≤15 Gy was 2.5 ( p = 0.001); it was 2.4 for a maximum liver dose of >15 Gy vs. ≤15 Gy ( p = 0.001). Conclusions There was a strong association between higher doses of liver RT (>15 Gy) and the development of PHTN among WT patients.

Background. Intensive therapy for childhood cancer is possible in large part due to improvements in supportive care that are currently available. Blood product transfusions, including red blood cell transfusions, are supportive care measures which are important in the tolerability of this therapy, and are frequently used in the majority of patients receiving therapy for childhood cancer. Although it is well recognized that frequent red blood cell transfusions in pediatric hematological disorders, such as sickle cell disease and thalassemia major, lead to iron overload and its complications (ie, organ dysfunction), pediatric oncology patients receiving numerous red blood cell transfusions are not routinely screened or evaluated for risk of iron overload or its consequences. This study was done to identify pediatric oncology patients with iron overload in a general pediatric hematology/oncology clinic. Methods. A retrospective blood bank records review was performed of pediatric hematology/oncology patients treated in our clinic in the last 10 years (2003-2013) to identify those patients receiving >10 packed red blood cell (PRBC) transfusions. These patients’ medical records were reviewed to determine which patients had been assessed for iron overload with a serum ferritin level. If a serum ferritin was obtained and the result was >1000 ug/L, records were reviewed to determine if patients received therapy for iron overload. Results. For the time period 2003-2013, blood bank records were screened on 144 patients. Fifty patients (34.7%) were identified as receiving >10 PRBC transfusions. Of these patients, 22 (44%; M/F = 12/10; age range = 2-23 y/o) were patients who had received therapy or were on active therapy for childhood cancer; 14 with leukemia (5 AML, 9 ALL), 8 with solid tumors (5 sarcomas, 1 hepatoblastoma, 1 lymphoma). Of these 22 patients, 6 (27%) patients had a serum ferritin level that was obtained and the remaining 16 (73%) had not. All the patients (100%) with a serum ferritin result had a serum ferritin level >1000 ug/L (range 1048-22021). Only one patient (off-therapy sarcoma patient, serum ferritin =1788 ug/L) was on therapy for iron overload (Exjade and phlebotomy). Conclusions. Pediatric oncology patients receiving numerous PRBC transfusions are at risk for iron overload. Routine risk screening and assessment for iron overload should be accomplished in all pediatric oncology patients as part of their off therapy follow-up management. For those identified as having iron overload, appropriate therapy should be considered as indicated. Disclosures No relevant conflicts of interest to declare.

Background The production of cell-based cancer vaccines by gene vectors encoding proteins that stimulate the immune system has advanced rapidly in model systems. We sought to develop non-viral transfection methods that could transform patient tumor cells into cancer vaccines, paving the way for rapid production of autologous cell-based vaccines. Methods As the extended culture and expansion of most patient tumor cells is not possible, we sought to first evaluate a new technology that combines electroporation and chemical transfection in order to determine if plasmid-based gene vectors could be instantaneously delivered to the nucleus, and to determine if gene expression was possible in a cell-cycle independent manner. We tested cultured cell lines, a primary murine tumor, and primary human leukemia cells from diagnostic work-up for transgene expression, using both RFP and CD137L expression vectors. Results Combined electroporation-transfection directly delivered plasmid DNA to the nucleus of transfected cells, as demonstrated by confocal microscopy and real-time PCR analysis of isolated nuclei. Expression of protein from plasmid vectors could be detected as early as two hours post transfection. However, the kinetics of gene expression from plasmid-based vectors in tumor cell lines indicated that optimal gene expression was still dependent on cell division. We then tested to see if pediatric acute lymphocytic leukemia (ALL) would also display the rapid gene expression kinetics of tumor cells lines, determining gene expression 24 hours after transfection. Six of 12 specimens showed greater than 17% transgene expression, and all samples showed at least some transgene expression. Conclusion Given that transgene expression could be detected in a majority of primary tumor samples analyzed within hours, direct electroporation-based transfection of primary leukemia holds the potential to generate patient-specific cancer vaccines. Plasmid-based gene therapy represents a simple means to generate cell-based cancer vaccines and does not require the extensive infrastructure of a virus-based vector system.

Between 1976 and 1992, 869 patients

9535 Background: Pemetrexed is a multi-targeted antifol that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recu...