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10022 Background: Adolescents with extracranial malignant germ cell tumors (GCTs) are often treated on the same regimens developed for children, but more closely resemble the clinical characteristics of young adult patients. We sought to determine whether event-free survival (EFS) for adolescents with GCTs was more like that of children or young adults. Methods: We assembled an individual patient database of ten GCT trials: seven conducted by pediatric cooperative groups and three by an adult group. We selected male patients aged 0-30 years old treated with platinum-based chemotherapy for non-seminomatous malignant GCTs of the testis, retroperitoneum, or mediastinum. We categorized age-group as children (0 to < 11 years), adolescents (11 to < 18 years), or young adults (18 to < 30 years old). We compared EFS among age groups, and adjusted for calculated IGCCCG risk-group using Cox proportional hazards analysis. Results: 593 patients met inclusion criteria, of whom 90 were children, 109 were adolescents, and 394 were young adults. The 5-year EFS for adolescents (72%; CI = 62-79%) was significantly lower than for children (90%; CI = 81-95%, p = 0.003) and for young adults (88%; CI = 84-91%, p < 0.001). Risk-group was significantly associated with EFS in the adolescent age-group (p = 0.002). In a Cox multivariable analysis, the difference between adolescents and children remained statistically significant (HR = 0.30, p = 0.001), but the difference between adolescents and young adults did not (HR 0.66, p = 0.114). Conclusions: EFS for adolescent patients with extracranial malignant GCTs was similar to young adults but significantly worse than children. This finding may have important implications for how adolescent patients are treated.

10036 Background: There are several studies describing the correlation between unsatisfactory tumor marker decline and poor prognosis in adult patients treated for germ cell tumors. In pediatric patients the data is limited. We therefore retrospectively analyzed data collected from pediatric patients treated on the Children’s Oncology Group (COG) Protocol AGCT0132 to determine whether a relationship exists between AFP decline and outcome. Methods: One hundred and thirty-one patients with germ cell tumors enrolled on Children’s Oncology Group Protocol AGCT0132 were eligible for analysis of AFP decline. Serum AFP half-life was calculated from levels collected post-operatively and after the start of chemotherapy, excluding values in the first 7 days of chemotherapy to accommodate unpredictable increases in the initial days of treatment. AFP decline was defined as automatically satisfactory (AFP normalized within the first two AFP measures following the start of chemotherapy), calculated satisfactory (AFP half-life ≤7 days following the start of chemotherapy), and unsatisfactory. Results: The 3-year event-free survival (EFS) was 87 % (95% confidence interval-CI: 79-92 %) for patients with a satisfactory decline and 62 % (95% CI: 31-82 %) for patients with an unsatisfactory decline (p = 0.006). In stratified analyses, this effect was limited to patients ≥11 years of age and with standard risk (SR2) disease ((p = 0.002 and p = 0.004, respectively). Three-year overall survival for patients with satisfactory versus unsatisfactory decline was not statistically significant. Conclusions: This study is the first to show an association between AFP decline and EFS in pediatric patients. Although there is no statistically significant association between tumor marker decline and overall survival, recognition of patients at high-risk of relapse may allow for early intensification of therapy and impact the rationale for future clinical trial design.

Background Reports of responses and toxicities of salvage therapies for relapsed neuroblastoma are rare and often confounded by effects of additional treatments. Our objective was to describe the outcomes and toxicities for a topotecan and cyclophosphamide (TOPO/CTX) regimen for first relapse or progression of high-risk neuroblastoma. Methods We retrospectively reviewed charts of relapsed or refractory neuroblastoma patients treated between 1999 and 2009 with our standard-of-care outpatient TOPO/CTX (0.75 and 250 mg/m2/day × 5 days q3–4 weeks). Results Twenty-seven patients received 343 cycles of TOPO/CTX (median 10 cycles per patient, range 1–32). Most patients (N = 25) had undergone autologous stem cell transplantation. Seventeen (63%) patients had an objective response (CR + PR + MR). The 3-year progression-free survival (PFS) after relapse was 11 ± 6% and 3-year overall survival (OS) after relapse was 33 ± 9%. The median PFS was 1.2 years and the median OS was 2.3 years. Five patients are alive with follow-up of 3.1–5.5 years. Shorter time from diagnosis to relapse (6–18 months) was associated with shorter OS. The majority of patients experienced chemotherapy delays, transfusions, and febrile neutropenia, including eight bacterial infections. The mean number of hospitalized days was less than one per cycle. Conclusions TOPO/CTX was well tolerated and resulted in response rates and PFS similar to those reported for patients treated on COG 9462. Our study provides additional toxicity, historical endpoints, and time-to-progression data against which new agents and combination therapies using TOPO/CTX as a backbone can be measured. Pediatr Blood Cancer 2013;60:1636–1641. © 2013 Wiley Periodicals, Inc.

Extracranial germ cell tumors are an uncommon pediatric malignancy with limited information on the clinical impact ofThe purpose of this study was to evaluate and compare the clinical impact on management ofThe list ofDuring the study period, 9 children (5 males and 4 females; age range: 1.6-17 years, mode age: 14 years) had 11

OBJECTIVES Surveillance of hepatic nodules for malignant transformation to hepatocellular carcinoma is important in the monitoring of patients with biliary atresia (BA). To date, only 2 published case reports describe the finding of hepatoblastoma (HB) in this setting. The present study aimed to investigate this association of HB and BA, and to assess the utility of alpha-fetoprotein (aFP) as a marker in the diagnosis. METHODS A retrospective study of all patients who underwent isolated liver transplantation (LTx) for the primary diagnosis of BA at a single center, between January 1999 and June 2014, was conducted. Patient demographics, pre-LTx aFP levels, and histologic examination of native liver explants were reviewed. RESULTS One hundred two (44% men, median age 11 months) patients underwent LTx for BA. Two (2%) explants examinations were confirmatory for concomitant HB; both patients had abnormally elevated aFP. Overall, 56 (55%) patients had available pre-LTx aFP levels. Recipients with persistently abnormal aFP levels (n = 20, 36%) were older at hepatoportoenterostomy (107 vs 68 days, P = 0.02) and younger at LTx surgery (359 vs 1713 days, P

Translocation-associated renal cell carcinoma (RCC) is a distinct subtype of RCC with gene rearrangements of the TFE3 or TFEB loci. The TFE3 gene is located at Xp11 and can fuse to a number of translocation partners, resulting in high nuclear expression of TFE3 protein. TFE3 immunostaining is often used as a surrogate marker for a TFE3 translocation. We report a case of an RCC that expressed TFE3 but showed only gain of TFE3 rather than a translocation. Moreover, this case had a t(1;2) translocation fusing ALK and TMP3, identical to that seen in inflammatory myofibroblastic tumour. There was resulting overexpression of ALK protein in a cytoplasmic and membranous pattern. The patient was not treated with chemotherapy but following regional nodal recurrence, an ALK inhibitor was added and the patient remains alive one year later. There are only rare reports of RCC with an ALK-TMP3 fusion, and these tumours can express TFE3 on some unknown basis not related to a TFE3 translocation. Any RCC positive for TFE3 and lacking a translocation should be tested for ALK expression and translocation. Recognition of this subtype of RCC will allow ALK inhibitor therapy to be added, in the hope of improving patient outcome.

The pediatric ocular tumor retinoblastoma readily metastasizes, but these lesions can masquerade as histologically similar pediatric small round blue cell tumors. Since 98% of retinoblastomas have RB1 mutations and a characteristic genomic copy number "signature", genetic analysis is an appealing adjunct to histopathology to distinguish retinoblastoma metastasis from second primary cancer in retinoblastoma patients. Here, we describe such an approach in two retinoblastoma cases. In patient one, allele-specific (AS)-PCR for a somatic nonsense mutation confirmed that a temple mass was metastatic retinoblastoma. In a second patient, a rib mass shared somatic copy number gains and losses with the primary tumor. For definitive diagnosis, however, an RB1 mutation was needed, but heterozygous promoter→exon 11 deletion was the only RB1 mutation detected in the primary tumor. We used a novel application of inverse PCR to identify the deletion breakpoint. Subsequently, AS-PCR designed for the breakpoint confirmed that the rib mass was metastatic retinoblastoma. These cases demonstrate that personalized molecular testing can confirm retinoblastoma metastases and rule out a second primary cancer, thereby helping to direct the clinical management.

Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.

Background While cisplatin is considered superior to carboplatin for the treatment of malignant germ cell tumors (MGCTs) in adults, pediatric oncology collaborative groups still remain concerned about the late effects of cisplatin in children. Methods We performed a literature search to identify randomized controlled trials (RCTs) that used carboplatin for MGCTs in adults. Since no RCTs were available in children, we identified cohort studies of pediatric MGCTs treated with carboplatin. We compared the adult and pediatric studies in terms of characteristics, doses of chemotherapy, and outcomes. Results Of 2,131 publications retrieved, five RCTs in adults (1,340 patients) and four cohort studies in children (219 patients) met criteria for inclusion. All adult RCTs evaluated carboplatin versus cisplatin regimens in men with good-prognosis metastatic MGCTs. Carboplatin regimens had a higher risk of events (RR 2.51, P

Purpose In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development. Patients and methods Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies-yolk sac tumor, embryonal carcinoma, or choriocarcinoma-were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS). Results Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2-87.8%) and for non-GD patients was 88.8% (95% CI 80.2-93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7-98.1%) and for non-GD patients was 97.6% (95% CI of 90.6-99.4%). Conclusion Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen.

During the past 35 years, survival rates for children with extracranial malignant germ cell tumors (GCTs) have increased significantly. Success has been achieved primarily through the application of platinum-based chemotherapy regimens; however, clinical challenges in GCTs remain. Excellent outcomes are not distributed uniformly across the heterogeneous distribution of age, histologic features, and primary tumor site. Despite good outcomes overall, the likelihood of a cure for certain sites and histologic conditions is less than 50%. In addition, there are considerable long-term treatment-related effects for survivors. Even modest cisplatin dosing can cause significant long-term morbidities. A particular challenge in designing new therapies for GCT is that a variety of specialists use different risk stratifications, staging systems, and treatment approaches for three distinct age groups (childhood, adolescence, and young adulthood). Traditionally, pediatric cancer patients younger than 15 years have been treated by pediatric oncologists in collaboration with their surgical specialty colleagues. Adolescents and young adults with GCTs often are treated by medical oncologists, urologists, or gynecologic oncologists. The therapeutic dilemma for all is how to best define disease risk so that therapy and toxicity can be appropriately reduced for some patients and intensified for others. Further clinical and biologic insights can only be achieved through collaborations that do not set limitations by age, sex, and primary tumor site. Therefore, international collaborations, spanning different cooperative groups and disciplines, have been developed to address these challenges.

Children with Langerhans cell histiocytosis (LCH) and single-bone CNS-risk lesions have been reported to be at increased risk of diabetes insipidus (DI), central nervous system neurodegeneration (CNS-ND), and recurrence of disease. However, it is unknown whether the addition of chemotherapy or radiotherapy changes outcomes in these patients.Ten pediatric institutions across North America and Europe contributed data of their patients with LCH and single-bone CNS-risk lesions. Clinical information on age, sex, specific craniofacial site involvement, and intracranial extension at diagnosis, therapy, and disease course was collected for all eligible patients.The final analysis included 93 eligible children who were either treated with systemic therapy (chemotherapy, chemo-radiotherapy, or radiotherapy) or local therapy (biopsy, curettage, and/or intralesional steroids). Fifty-nine patients had systemic and 34 had local therapy. The 5-year event-free survival (EFS) and overall survival (OS) were 80 ± 5% and 98 ± 2% in the systemic therapy group versus 85 ± 6% and 95 ± 5% in the local therapy group. There was no statistically significant difference between either group with regard to EFS (P = 0.26) and OS (P = 0.78). On multivariable analysis, there was no significant difference among the two treatment groups after adjusting for site and intracranial soft tissue extension, nor any trend favoring systemic therapy (HR = 2.26, 95% CI = 0.77-6.70; P = 0.14).Systemic therapy may not reduce the risk of recurrence or late sequelae in children with LCH and single-bone CNS-risk lesions as compared to local treatment.

Purpose To risk stratify malignant extracranial pediatric germ cell tumors (GCTs). Patients and Methods Data from seven GCT trials conducted by the Children's Oncology Group (United States) or the Children's Cancer and Leukemia Group (United Kingdom) between 1985 and 2009 were merged to create a data set of patients with stage II to IV disease treated with platinum-based therapy. A parametric cure model was used to evaluate the prognostic importance of age, tumor site, stage, histology, tumor markers, and treatment regimen and estimate the percentage of patients who achieved long-term disease-free (LTDF) survival in each subgroup of the final model. Validation of the model was conducted using the bootstrap method. Results In multivariable analysis of 519 patients with GCTs, stage IV disease (P = .001), age ≥ 11 years (P < .001), and tumor site (P < .001) were significant predictors of worse LTDF survival. Elevated alpha-fetoprotein (AFP) ≥ 10,000 ng/mL was associated with worse outcome, whereas pure yolk sac tumor (YST) was associated with better outcome, although neither met criteria for statistical significance. The analysis identified a group of patients age > 11 years with either stage III to IV extragonadal tumors or stage IV ovarian tumors with predicted LTDF survival < 70%. A bootstrap procedure showed retention of age, tumor site, and stage in > 94%, AFP in 12%, and YST in 27% of the replications. Conclusion Clinical trial data from two large national pediatric clinical trial organizations have produced a new evidence-based risk stratification of malignant pediatric GCTs that identifies a poor-risk group warranting intensified therapy.

The lumbar puncture (LP) and the bone marrow aspiration and trephine biopsy (BMAT) are the most common procedures performed by doctors working in pediatric oncology. These procedures are integral components of the diagnosis and management of several childhood cancers. The knowledge, skills, resources, and support for the optimal performance of these procedures are therefore vital to the provision of childhood cancer care. Abnormal fluid may accumulate in the pleural and abdominal cavities as a first manifestation of childhood cancer. Tapping fluid from the pleural cavity (thoracentesis) and from the peritoneal cavity (paracentesis) affords the clinician the opportunity to examine the fluid for malignant disease as well as drain the fluid to relieve symptoms and discomfort. Vascular access is required for infusion of intravenous fluids, chemotherapy, and blood products. This chapter is a practical guide on the indications, contraindications, methods, and complications of procedures in pediatric oncology.

The development of effective treatments for germ cell tumors (GCTs) has been one of the major success stories of medical and pediatric oncology. While building on the results of studies in adult testicular GCTs, pediatric oncology treatment approaches have developed and evolved in their own ways. This chapter reviews the evolution and outcomes of trials for childhood GCTs conducted by pediatric oncology cooperative groups in North America, the United Kingdom, Germany, France, and Brazil. It outlines how each group has explored strategies to maintain high cure rates while minimizing the late effects of treatment for children with low-intermediate-risk tumors or to intensify treatment for those with high-risk disease. Building on this global view, the chapter highlights the importance of international collaboration for further progress in the treatment of pediatric GCTs.

Importance Intra-arterial chemotherapy has emerged as a treatment for intraocular retinoblastoma and has been quickly adopted by centers worldwide. Objective To conduct a systematic review and attempt a meta-analysis to summarize the reported outcomes of intra-arterial chemotherapy. Evidence Review In January 2015, we performed comprehensive searches in Medline, Embase, Cochrane, and Web of Science from inception through January 2015, including any peer-reviewed English-language publication that described outcomes related to toxicity or efficacy in at least 4 patients. Findings From a total of 208 identified publications, 28 met inclusion criteria. Twelve reports with discernable nonduplicative information were included, reporting 655 patients, 757 eyes, and 2350 catheterizations. All were single-arm case series, and 67% (8 of 12) were retrospective. Across all studies, globe salvage was achieved for 502 (66%) of all eyes. Most common reported toxicities were chorioretinal atrophy and vascular occlusions. There were at least 13 reports of children with metastases. After publication, 7 additional children had metastases. The 4 different classification systems used challenged the comparison of disease severity at presentation. Visual outcome was not addressed in most studies. Meta-analyses were not possible because no study had a comparative group. Assessment of risk of bias was not possible because no validated tool for single-arm studies was available. Conclusions and Relevance Intra-arterial chemotherapy is a promising new treatment associated with high rates of globe salvage. However, the literature is limited by the predominance of retrospective case series, absence of comparison groups, short median follow-up, heterogeneous definitions and tumor classifications, and frequent duplicate reporting. Metastases have been observed, and long-term follow-up is needed. Until the results of clinical, prospective studies are available, it is recommended that intra-arterial chemotherapy be offered selectively among other options, with fully informed discussion about all possible risks, benefits, and uncertainties.

Reports of responses and toxicities of salvage therapies for relapsed neuroblastoma are rare and often confounded by effects of additional treatments. Our objective was to describe the outcomes and toxicities for a topotecan and cyclophosphamide (TOPO/CTX) regimen for first relapse or progression of high-risk neuroblastoma.We retrospectively reviewed charts of relapsed or refractory neuroblastoma patients treated between 1999 and 2009 with our standard-of-care outpatient TOPO/CTX (0.75 and 250 mg/m(2) /day × 5 days q3-4 weeks).Twenty-seven patients received 343 cycles of TOPO/CTX (median 10 cycles per patient, range 1-32). Most patients (N = 25) had undergone autologous stem cell transplantation. Seventeen (63%) patients had an objective response (CR + PR + MR). The 3-year progression-free survival (PFS) after relapse was 11 ± 6% and 3-year overall survival (OS) after relapse was 33 ± 9%. The median PFS was 1.2 years and the median OS was 2.3 years. Five patients are alive with follow-up of 3.1-5.5 years. Shorter time from diagnosis to relapse (6-18 months) was associated with shorter OS. The majority of patients experienced chemotherapy delays, transfusions, and febrile neutropenia, including eight bacterial infections. The mean number of hospitalized days was less than one per cycle.TOPO/CTX was well tolerated and resulted in response rates and PFS similar to those reported for patients treated on COG 9462. Our study provides additional toxicity, historical endpoints, and time-to-progression data against which new agents and combination therapies using TOPO/CTX as a backbone can be measured.

Background The clinical implications of a diagnosis of progressive transformation of germinal centers (PTGC) in children are not well known. Methods To better understand this entity, we conducted a retrospective review of all patients aged 0–18 years diagnosed with PTGC at our center between 1998 and 2010. Results Twenty-nine patients were identified. Median age at diagnosis was 11.5 years, and median duration of follow-up was 2.8 years. Thirteen patients (45%) had a single episode of PTGC with no other associated features. Five patients (17%) had recurrent PTGC. Four patients (14%) had PTGC associated with Hodgkin lymphoma (HL): one preceding, two concurrent, and one subsequently developed HL. The most commonly associated HL was nodular lymphocyte-predominant HL. Seven patients (24%) had PTGC associated with immune disorders, including lupus, Castleman disease, and probable autoimmune lymphoproliferative syndrome. Overall, 15 patients (52%) had more than one lymph node biopsy. The cumulative incidence of a second biopsy after a diagnosis of PTGC was 42.3% ± 12.2% at 4 years. PTGC was PET-avid in all four patients tested. Conclusions PTGC is a nonspecific manifestation of a variety of associated conditions. There is a small risk of subsequent HL, and a larger risk of requiring multiple biopsies for recurrent PTGC. The presence of an immune disorder should be considered in patients who present with generalized lymphadenopathy, splenomegaly, immune cytopenias, and/or progression to HL. Routine surveillance imaging may not be required. Future research should determine the optimal surveillance strategy for patients with PTGC and the indications for repeat biopsies. Pediatr Blood Cancer 2013; 60: 26–30. © 2012 Wiley Periodicals, Inc.

Primary myelofibrosis (PMF) is rare in children. An allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for severe cases. Here, we report the case of a female infant with PMF treated with allogeneic HSCT using an unrelated cord blood unit. She had successful reversal of her disease, but experienced complications related to transplant. This is the seventh reported case of HSCT for PMF in children, and the second using umbilical cord blood. We conclude that cord HSCT is a useful curative treatment option in children with PMF, but that efforts must be taken to reduce complications.

Optic pathway gliomas (OPG) in neurofibromatosis type 1 (NF1) usually remain localized to the anterior visual pathway. However, a small number can demonstrate widespread dissemination. We describe three children with NF1 OPGs and extensive central nervous system involvement. In one case, a postmortem examination revealed tumor cells extending continuously from the optic nerves to the conus medullaris. This is the most widespread NF1 OPG reported in the literature. We suggest that rapid visual deterioration in the absence of radiographic changes or increased intracranial pressure can be caused by increasing tumor infiltration within the central nervous system.

Background: Several randomized controlled trials (RCTs) have demonstrated that dexrazoxane reduces anthracycline cardiotoxicity in adults, but use in children has been hindered by lack of direct evidence of cardioprotection and concerns regarding second malignant neoplasms (SMNs). This study aimed to systematically review the evidence regarding dexrazoxane in children. Methods: We searched Medline, Embase, the Cochrane Library, and abstracts for RCTs and nonrandomized studies (NRSs) that compared dexrazoxane to no cardioprotection among children. We combined findings using random-effects models. All statistical tests were two-sided. Results: Eleven eligible publications reported results from five RCTs (1254 patients), and 15 publications reported results from 12 NRSs (3385 patients). Dexrazoxane did not impact clinical cardiotoxicity in RCTs because of a low cardiotoxic event rate (three events among all patients) but was associated with a reduction in subclinical cardiotoxicity. Among NRSs, dexrazoxane was associated with a reduction in clinical cardiotoxicity (relative risk (RR) = 0.29, P = .001) and clinical+subclinical cardiotoxicity (RR = 0.43, P < .001). Among RCTs, 17 of 635 (2.7%) patients treated with dexrazoxane developed an SMN compared with seven of 619 (1.1%) who did not receive dexrazoxane (RR = 2.37, P = .06). Two RCTs that used concurrent etoposide reported an increased risk of acute myeloid leukemia, while one that used cranial radiation reported an increased risk of brain tumors. Event-free survival did not differ ( P = .91). Conclusion: Dexrazoxane is associated with a statistically significant risk reduction for most cardiotoxic outcomes. Dexrazoxane is associated with a statistically borderline increase in SMNs, possibly because of an interaction with concurrent cancer therapies. The decision to use dexrazoxane in children should balance the risks of cardiotoxicity and SMNs specific to each treatment protocol.

Background Allele-specific (AS)-PCR for known point mutations is a high-sensitivity method to monitor for minimal residual disease (MRD) in metastatic retinoblastoma. However, this approach is difficult to apply to large RB1 gene deletions. Objective We describe a novel, high sensitivity molecular assay for MRD monitoring of a large RB1 deletion. Method The proband’s retinoblastoma RB1 deletion was identified using quantitative multiplex (QM)-PCR. Array comparative genomic hybridization (aCGH) was used to map the boundaries of the tumour RB1 deletion. Inverse PCR was then applied to capture the unique deletion breakpoint, and AS primers were optimised for high sensitivity surveillance for MRD. Result Full RB1 gene testing revealed no mutation in blood of this patient. Using QM-PCR, we found one RB1 mutation in the retinoblastoma tumour (del P- >11). aCGH confirmed an ~238 kb hemizygous deletion extending centromeric from RB1. The precise deletion breakpoint was determined using inverse PCR to amplify from the known two-copy flanking sequence to identify a PCR product in tumour DNA that was absent from the patient’s blood DNA. AS primers based on the breakpoint detected a tumour-specific PCR product with a sensitivity of 1 in 1000 cells. The original bone marrow (BM) prior to therapy was strongly positive, but all subsequent BM, CSF, and cells harvested for stem cell transplant have been negative for the tumour-specific marker. Conclusion aCGH followed by inverse PCR provides a cost- and time-effective way to map QM-PCR detected RB1 breakpoints for high sensitivity molecular surveillance for MRD.

To assess the needs, awareness and barriers to diabetes education for self management and to facilitate the initiation of an education programme promoting self care among diabetics and their families.A qualitative study was conducted among adult diabetics attending outpatient clinics in a tertiary care teaching hospital in Karachi, Pakistan. Semi-structured interviews were conducted on 27 subjects (11 men; 16 women) to identify dominant themes and priority issues.Participants displayed great deal of variation with respect to level of knowledge and motivation for education. Most believed that diabetes was caused by stress. Family was perceived to be a source of positive support. Relative ease of adherence to pharmacological regimens as compared to diet and exercise was reported. Participants expressed frustration at chronicity of disease and fear of developing certain specific complications and inheritance by their children. Barriers to enhancing knowledge included 'No need for further information', distance from training institutions and other priorities.Knowledge, beliefs and fears about diabetes, family influence and accessibility of healthcare, affects management behaviours and learning. Understanding needs and expectations of people with diabetes is essential in initiating and improving the outcomes of education programme for diabetes self care.

PURPOSE: Cyclosporin (CSA) inhibits the multidrug resistance P-glycoprotein. Since 2000, we tested increased carboplatin and increased etoposide dosages in a cyclosporin-modulated carboplatin-etoposide-vincristine protocol, followed by focal laser/cryotherapy consolidation, to avoid elective radiation of newly diagnosed retinoblastoma (RB) patients, since radiation increases the secondary cancer risk in patients with heritable RB. We report the results for International Classification Groups A, B, C and D intraocular eyes (Ophthalmol Clinic North Am 2005; 18:41-53). METHOD: When Neupogen support became available, we increased the predominantly myelotoxic carboplatin to 28 mg/kg (from 18.7 mg/kg in our previous trial) and etoposide to 12 mg/kg (from 7.7 mg/kg in our previous trial), but kept the predominantly neurotoxic vincristine unchanged at 0.05 mg/kg, modulated by the same cyclosporin schedule (33 mg/kg over 3 hours on each of the 2 days per cycle). We treated 34 eyes in 23 patients: 2 A eyes, 11 B eyes, 6 C eyes and 15 D eyes. This report focuses only on the most difficult to save Group D eyes, and compares results with a non-cyclosporin carboplatin (26 mg/kg) and etoposide (10 mg/kg), vincristine (0.05 mg/kg) regimen. Radiation or enucleation for recurrence was considered failure. RESULTS: We report the long-term results of 15 Group D eyes in 10 patients, at mean followup of 11.1 years and median followup of 10.8 years (range 5.7-13.4 years). Eye event-free rate was 53% for Group D (8/15) eyes. Seven D eyes failed, and 6 were enucleated and 1 radiated. No child lost both eyes. Toxicity rates were acceptable with 15.7% fever-and-neutropenia, 0.7% bacterial sepsis, 9.7% blood transfusion and 27.6% platelet transfusion, and no long-term renotoxicity or ototoxicity. In comparison, at mean followup of 4.5 years (range 0.4-9.8 years), in a previously reported (Pediatr Blood Cancer 2013; 60:688-693) non-cyclosporin regimen, the non-radiation eye event-free rate was 47% for Group D (26/55) eyes, with 5 eyes enucleated, and 24 eyes radiated (19 irradiated eyes retained; 5 irradiated eyes required enucleation). CONCLUSION: This cyclosporin-modulated intensified-dosage protocol was well-tolerated, with a non-radiation eye salvage rate of 53%, and 60% overall if the one irradiated but retained eye was included, in the most difficult to save Group D eyes. No child lost both eyes, and most avoided radiation. This same protocol is being tested in a multicenter trial. Citation Format: Helen S.L. Chan, Elise Héon, A Linn Murphree, Paulita P. Astudillo, Helen Dimaras, Furqan Shaikh, Brenda L. Gallie. Cyclosporin-modulated intensified-dosage chemotherapy for saving eyes with Group D intraocular retinoblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 767. doi:10.1158/1538-7445.AM2014-767

10093 Background: Several randomized controlled trials (RCTs) in breast cancer have demonstrated the efficacy of dexrazoxane (DRZ) in reducing anthracycline cardiotoxicity. However, research on DRZ...

10074 Background: Post-recurrence survival (PRS) of children and adolescents with malignant germ cell tumors (MGCTs) has not previously been described, due to the limited sample size of relapsed pa...

Abstract 3582 Introduction: Children with acute lymphoblastic leukemia (ALL) undergo diagnostic and therapeutic lumbar punctures (LPs) with the administration of intrathecal chemotherapy as part of their cancer treatment. Difficult LPs may result in trauma (≥ 10 RBCs/μL) or a failed attempt to obtain cerebrospinal fluid (CSF). There can be several negative consequences of a difficult LP. For patients with newly diagnosed ALL, a traumatic lumbar puncture (TLP) that contains blasts obscures the correct determination of CNS status, leads to a requirement for additional therapy, and is associated with a poorer event-free survival. A failed lumbar puncture (FLP) provides inadequate diagnostic material, can be associated with pain, and leads to a delay in administering intrathecal chemotherapy. There is a need to identify interventions that can help reduce difficult lumbar punctures. At the Hospital for Sick Children (SickKids), children with difficult LPs may be referred to undergo the procedure under image-guided therapy (IGT) with fluoroscopy. We hypothesized that the use of IGT may reduce the risk of difficult LPs. The primary objective of this study was to investigate whether the use of IGT could reduce the risk of difficult LPs defined as TLPs and FLPs in children with ALL. The secondary objective was to determine whether IGT could reduce the risk of macroscopically bloody LPs (≥ 500 RBC/μl). Methods: The health records of all children less than 18 years of age with newly diagnosed ALL at SickKids from 2005 to 2009 inclusive were retrospectively reviewed. Data was collected on patients referred for at least one IGT procedure. The proportion of difficult LPs with and without IGT were compared. We used univariate and multiple conditional logistic regression (repeated-measures) analysis to examine the association between IGT and difficult LPs. The potential covariates analyzed included age at procedure (younger vs. older than 10 years), body mass index percentile (less vs. more than 95), platelet count (less vs. more than 100 × 109/L), previous TLP (yes vs. no), days since previous LP (less vs. more than 15 days), and phase of treatment (before vs. after the start of maintenance). In order to create multiple regression models, covariates that changed the beta-coefficient of the IGT effect by more than 10% were included in the model. Results: Among 267 children diagnosed with ALL in the study period, 25 patients (9.4%) had at least one image-guided LP. Of these 25 patients, 52% were over 10 years old, 64% were female and 28% were obese. These patients had a total of 542 LPs, of which 229 (42%) were performed with image-guidance and 313 were performed using the standard palpation method. Among all LPs, 149 (28%) were traumatic and 19 (4%) were failed. In univariate analysis, the use of IGT significantly lowered the odds of a difficult LP (TLP or FLP), with an odds ratio (OR) of 0.44 (95% confidence interval (CI) 0.26 to 0.76; p=0.003). The other covariates that were significant in univariate analysis included days since previous LP (OR 0.55, 95% CI 0.36 to 0.83; p=0.005) and phase of treatment (OR 0.60, 95%CI 0.39 to 0.91; p=0.017). Multivariable analysis adjusting for days since previous LP and phase of treatment demonstrated that the effect of IGT remained significantly independently associated with a reduction in difficult LPs (OR 0.49, 95% CI 0.29 to 0.86; p=0.012). In a secondary analysis, we defined bloody lumbar punctures (BLP) as ≥ 500 RBCs/μL. The effect of IGT in reducing BLP or FLP was larger, with an OR of 0.11 (95% CI 0.04 to 0.28, p Conclusions: This retrospective cohort study suggests that image-guidance may reduce the risk of traumatic and failed LPs in children with ALL. IGT may be more effective in reducing macroscopic trauma. Therefore, IGT may be able to provide a potential intervention for children with ALL anticipated to have difficult lumbar punctures at diagnosis, or found to have difficult subsequent procedures. Future work should focus on the development of better models to identify children at highest risk of difficult LPs and non-radiation based image-guided manoeuvres to facilitate LPs in these children. Disclosures: No relevant conflicts of interest to declare.

ObjectiveAcute limb ischemia (ALI) in pediatric patients is rare but may lead to limb loss and life-long complications. This study reviewed the experience of a Canadian tertiary pediatric center with the medical and operative management of ALI.MethodsThe medical records of inpatients diagnosed with ALI of the upper or lower limb between 1999 and 2012 were reviewed. Patient demographics, arterial clot site and etiology, intervention, anticoagulation type and duration, and short-term and long-term complications were analyzed.ResultsA total of 151 patients (45% female) presented with signs of limb ischemia, of whom 38% were aged