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Germ cell tumors (GCTs) are rare in childhood, representing only 3.5% of childhood cancers, but a common malignancy in adolescents and young adults (AYAs), accounting for 13.9% of neoplasms in adolescents between age 15 and 19 years. The overall outcomes of patients treated for GCTs are excellent. However, as seen in other cancers, outcomes for AYA patients are significantly worse. Understanding the reasons for this observation has led to different approaches to diagnosis, staging, and treatment. The Malignant Germ Cell International Consortium was created to bring together pediatric, gynecologic, and testicular cancer specialists to promote research initiatives and provide evidence-based approaches in the management of GCTs across different age groups. Collaboration between multiple subspecialties is essential to further understand the disease continuum, the underlying biologic characteristics, and the development of appropriate therapeutic approaches. This review focuses on the unique characteristics of patients with extracranial GCTs in the AYA group.

Background There are several studies describing the correlation between unsatisfactory tumor marker decline and a poor prognosis for adult patients treated for germ cell tumors. In pediatric patients, the data are limited. Therefore, this study retrospectively analyzed data from Children's Oncology Group (COG) protocol AGCT0132 to determine whether a relationship exists between α-fetoprotein (AFP) decline and outcome. Methods One hundred thirty-one patients with germ cell tumors who were enrolled in COG protocol AGCT0132 were eligible for this analysis of AFP decline. The serum AFP half-life was calculated from levels collected postoperatively as a baseline and after the start of chemotherapy. AFP decline was defined as automatically satisfactory (AFP normalized within the first 2 AFP measures after the start of chemotherapy), calculated satisfactory (AFP half-life ≤7 days after the start of chemotherapy), and unsatisfactory. Results The 3-year cumulative incidence of relapse was 11% (95% confidence interval [CI], 6.0%-18%) for patients with a satisfactory decline and 38% (95% CI, 13%-64%) for patients with an unsatisfactory decline (P = .006). In stratified analyses, this effect was limited to patients who were 11 years of age or older and had standard risk 2 (SR2) disease (P = .004 and P = .007, respectively). Three-year overall survival (OS) for patients with a satisfactory decline versus an unsatisfactory decline was not statistically significant. Conclusions This study is the first to show an association between AFP decline and the cumulative incidence of relapse in pediatric patients treated for germ cell tumors. Recognition of patients at high risk for relapse may allow for early intensification of therapy, which could affect future clinical trial design.

PURPOSE To investigate relapse detection methods among children and adolescents with nongerminomatous malignant germ cell tumors (MGCTs) and to determine whether tumor markers alone might be sufficient for surveillance. METHODS We retrospectively reviewed all patients enrolled in a phase III, single-arm trial for low-risk and intermediate-risk MGCTs. The method used to detect relapse was assessed based on case report forms, tumor markers, imaging, and pathology reports. Relapses were classified into one of two categories on the basis of whether they were (1) detectable by tumor marker elevation or (2) not detectable by tumor markers. RESULTS A total of 302 patients were enrolled, and 284 patients had complete data for review. Seven patients had normal tumor markers at initial diagnosis, and none experienced a relapse. At a median follow-up of 5.3 years, 48 patients (16.9%) had experienced a relapse. After central review, 47 of 48 relapses (98%) were detected by tumor marker elevation. Of the 47 patients, 16 (33.3%) had abnormal tumor markers with normal/unknown imaging, 31 patients (64.6%) had abnormal tumor markers with abnormal imaging, and one patient (2.1%) had abnormal imaging with unknown marker levels at relapse. CONCLUSION Tumor marker elevation is a highly sensitive method of relapse surveillance, at least among children and adolescents with tumor marker elevation at initial diagnosis. Eliminating exposure to imaging with ionizing radiation may enhance the safety of relapse surveillance in patients treated for MGCT.

11530 Background: Survival after relapse in osteosarcoma (OST), Ewing Sarcoma (ES) and chondrosarcoma (CS) remains dismal. Recent reports suggest a role of tyrosine kinase inhibitors (TKI) including regorafenib (R) and cabozantinib (C). We conducted a retrospective multi-centre pan-Canadian study to assess real-word outcomes with these novel treatments in recurrent BT. Methods: After ethics approval, data from pts treated in 7 different institutions was extracted from the CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) Database. Pt characteristics, treatment and outcomes were analyzed. Response was assessed per RECIST 1.1. PFS, OS were estimated using Kaplan-Meier. TTP was defined as time from TKI start to progression. Results: From June 2018-Dec 2021, 44 pts received R or C and best response by histology are listed in Table, with an overall clinical benefit rate of 63.6%. Median time to best response was 2.3 mo (range 1 – 17). 15 pts (34.1%) required dose reduction; most common reasons were hand-foot syndrome (13.6%), mucositis (9.1%) and hypertension (9.1%). At median FU of 6.4 mo (range 1.6 – 29), 25 pts (56.8%) died, 19 (43.2%) were alive with disease (AWD). Median PFS was 4.1 mo (95%CI 2.9 – 5.7), for OST was 5.0 (N = 25, 95%CI 2.6 – 10.6), for ES was 4.1 (N = 10, 95%CI 2-5.9), and for CS 4.0 (N = 9, 1 Progressed). Median OS was 10.5 mo (95%CI 7 – 14). By univariate analysis, age, line of therapy, gender, location of primary, or R vs. C did not correlate with PFS. Conclusions: Consistent with previous published studies, our pan-country real-world analysis shows that TKI have meaningful activity in the setting of recurrent BT with acceptable toxicities. Inclusion in earlier lines of treatment and/or maintenance therapy could be questions for future research. [Table: see text]

BACKGROUND Ultrasound assistance improves success rates and reduces adverse outcomes of lumbar punctures (LPs) among adult patients in the emergency room and the operating room, but has not been evaluated in pediatric patients with cancer. Our objectives were (1) to determine whether pediatric oncologists could perform ultrasound-assisted LPs following a structured teaching curriculum, and (2) to determine the feasibility of recruiting pediatric cancer patients to a clinical trial of this procedure. METHODS Three pediatric oncologists completed a curriculum composed of didactic teaching followed by hands-on workshops. Each learner was evaluated during 20 attempts at three ultrasound tasks using the cumulative sum method. The three pediatric oncologists then performed ultrasound assessments prior to routinely scheduled LPs. Feasibility was defined as ability to perform at least 30 ultrasound-assisted LPs within 6 months. Secondary outcomes were the proportion of successful, bloody, or traumatic LPs, time required, and perceived helpfulness of ultrasound. RESULTS All three pediatric oncologists achieved competence in the three tasks of ultrasound scanning within 20 evaluated attempts. We recruited 62 patients within 1 month, and 58 underwent an ultrasound-assisted LP. All LPs were successful. Two LPs (4%) had ≥500 red blood cells (RBCs)/μl, and nine (16%) had ≥10 RBCs/μl. Median time to conduct the scan was 1.9 minutes (range 0.8-4.0 minutes). In 37 (64%) of the LPs, ultrasound assistance was considered helpful or very helpful. CONCLUSIONS Pediatric oncologists readily achieved competence in ultrasound-assisted LPs, and ultrasound was commonly perceived as helpful. It is feasible to proceed to a randomized trial of this procedure in pediatric cancer.

BACKGROUND Adolescents with extracranial metastatic germ cell tumors (GCTs) are often treated with regimens developed for children, but their clinical characteristics more closely resemble those of young adult patients. This study was designed to determine event-free survival (EFS) for adolescents with GCTs and compared them with children and young adults. METHODS An individual patient database of 11 GCT trials was assembled: 8 conducted by pediatric cooperative groups and 3 conducted by an adult group. Male patients aged 0 to 30 years with metastatic, nonseminomatous, malignant GCTs of the testis, retroperitoneum, or mediastinum who were treated with platinum-based chemotherapy were included. The age groups were categorized as children (0 to

Purpose: To compare the outcomes of paediatric and adolescent extracranial malignant germ cell tumour (GCT) patients treated with either carboplatin or cisplatin on clinical trials conducted by the Children's Oncology Group (COG) and the Children's Cancer and Leukaemia Group (CCLG).\ud \ud \ud \ud Methods: The Malignant Germ Cell International Consortium (MaGIC) has created a database of the GCT clinical trials conducted since 1983 by COG (United States, Canada and Australia), which used cisplatin-based regimens, and by CCLG (United Kingdom), which used carboplatin-based regimens. Using the parametric cure model, this study compared the overall 4-year event-free survival (EFS), stratified by age, stage, site and the a-priori defined MaGIC ‘risk’ groups: standard risk ((SR) 1 (EFS >80%; age 80%, age ≥ 11y) and poor risk (PR) (EFS ≤ 70%, age ≥ 11y).\ud \ud \ud \ud Results: Cisplatin-based therapy was used in 620 patients; carboplatin was used in 163 patients. In the overall multivariate cure model, the two regimens did not differ significantly (cisplatin: 4-year EFS 86%; 95% confidence interval (CI) 83–89% versus carboplatin 4-year EFS 86%; 95% CI 79–90%; p = 0.87). No significant differences were noted in stratified analyses by site, stage, age and MaGIC risk groups: SR1 (p = 0.20), SR2 (p = 0.55) or PR (p = 0.72) patients.\ud \ud \ud \ud Conclusions: In these trials conducted contemporaneously, there is no significant difference in outcome observed overall, or any subset of patients, who were treated with regimens containing cisplatin versus carboplatin These results suggested sufficient equipoise to justify a randomised trial to evaluate the effectiveness of carboplatin versus cisplatin in the treatment of children, adolescents and young adults with standard risk GCT, which is currently underway.

Introduction Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms that arise in the gastrointestinal tract. While most GISTs are driven by mutations in cKIT or PDGFR, approximately 10% lack these variants and are referred to as ‘wild-type’. Wild-type GISTs are commonly succinate dehydrogenase (SDH)-deficient and are characterized by indolent, multi-focal disease at presentation. On occasion, patients experience symptomatic disease progression warranting treatment ; imatinib or sunitinib offer minimal benefit. PIK3CA mutations have recently been described in a small proportion of GIST. Case report A previously healthy 16-year-old female presented with a five-month history of vomiting and weight loss, compatible with gastric outlet obstruction. Computerized tomography demonstrated a large gastric mass, and multiple liver and peritoneal metastases. Biopsy showed nests of epithelioid cells with round nuclei, vesicular chromatin, and eosinophilic cytoplasm. The lesional cells were immunoreactive for CD117, DOG1, CD34, and smooth muscle actin, while negative for SDH-B immunohistochemistry, in keeping with SDH-deficient GIST. Germline and somatic panel sequencing were performed through the SickKids Cancer Sequencing Program along with RNA sequencing by Illumina TruSight RNA Pan-Cancer NGS analysis. Somatic analysis revealed a PIK3CA p.Glu545Lys (E545K) mutation at 0.12 variant allele fraction (VAF). The patient was also found to have germline heterozygous pathogenic splice variant in the SDHB gene c.75+1 G>T (p?). In the light of the molecular findings and no alternative curative options, compassionate access to alpelisib was sought. The patient started drug at the recommended adult dose of 300 mg by mouth daily, and after completing two 28-day cycles, showed marked improvement in her abdominal distension and discomfort. Her appetite improved with documented nutritional weight gain. Reimaging at this time showed a 20% reduction in the sum of maximum dimensions of target lesions (per RECIST 1.1). Repeat imaging after five months on treatment confirmed continued improvement with 25% reduction compared to baseline.The patient did not experience hypersensitivity, severe cutaneous adverse reactions, hyperglycemia or pneumonitis. She currently continues on alpelisib monotherapy. Conclusion We describe the first report of a clinically meaningful response to a PIK3CA inhibitor in an adolescent patient with advanced metastatic SDH-deficient GIST harbouring a somatic activating PIK3CA hotspot mutation. There is still much to be learned about the biology of pediatric/wild-type GIST. In these rare cases, we recommend referral to specialized centers and incorporation of comprehensive next generation sequencing into care. Sequencing should be performed both on germline and somatic DNA to evaluate for a cancer predisposition syndrome, along with possible druggable targets in PIK3CA, cKIT or PDGFRA. We believe that the lack of routine comprehensive genomic analysis may underestimate the frequency of such rare variants. Citation Format: Sarah Cohen-Gogo, Nisha Kanwar, Furqan Shaikh, Reto M. Baertschiger, Adam Shlien, David Malkin, Juan Putra, Ailish Coblentz, Anita Villani, Abha A. Gupta, Daniel A. Morgenstern. Response to alpelisib in an adolescent with PIK3CA-mutated metastatic gastrointestinal stromal tumour [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P136.

418 Background: Patients with clinical stage I (CS I: cN0M0) germ cell tumors (GCT) exhibit favorable oncologic outcomes. While prognostic features can help inform treatment in adults with CS I GCT, we lack reliable means to predict relapse among pediatric patients. We sought to identify predictors of relapse in children with CS I GCT. Methods: We performed a pooled post hoc analysis on pediatric CS I GCT patients enrolled in 3 prospective trials: INT-0097 (phase II), INT-0106 (phase III), and AGCT0132 (phase III). Pathology was centrally reviewed. Patient demographics, pT stage, serum tumor markers, margin status, histology, relapse, and survival were compiled. Cox regression analyses were used to identify predictors of outcomes. Results: 88 patients were identified with histologic data available. Most patients were pT1-2 stage. Yolk sac tumor was present in 75%, while 16% had embryonal carcinoma, and 9% had choriocarcinoma. When evaluable, lymphovascular invasion (LVI) was present in 36/66 (55%) of patients. Over a median follow-up of 5.0 years, no patients died and 24 patients (27%) relapsed (median relapse-free survival not reached). Predictors of relapse included presence of choriocarcinoma (HR 4.3, p=0.004), embryonal carcinoma (HR 3.8, p=0.002), pT3 stage (HR 6.9, p=0.027), and age >12 years (HR 3.1, p=0.011). LVI (HR 2.4, p=0.072), serum tumor markers, and dominant tumor size did not reach significance. Pediatric CS I GCT patients exhibit remarkable 5-year survival. Conclusions: Using combined data from multiple prospective trials, our study identifies clinicopathologic features that predict relapse and potentially inform personalized treatment for these patients.

Objective Dysgerminoma is the most common malignant ovarian germ cell tumor (GCT) with peak incidence during adolescence and young adulthood. Current standard of care for patients with disease that has spread outside of the ovary (advanced-stage) utilizes platin-based chemotherapy regimens. The study objective was to compare clinical outcomes between platin-based (carboplatin versus cisplatin) strategies across all age groups (children 25 y) for advanced-stage dysgerminoma. Methods The Malignant Germ Cell Tumor International Consortium (MaGIC) pooled data from six GCT trials (3 = pediatric, 3 = adult) conducted internationally by pediatric and gynecologic oncology clinical trial organizations (CTOs) between 1983 and 2009. Newly diagnosed patients, with advanced-stage (FIGO IC–IV) dysgerminoma, who received either carboplatin- or cisplatin-based chemotherapy were eligible for analysis. Results 126 eligible patients were identified; 56 patients (38 = pediatric, 18 = adult) received carboplatin-based and 70 patients (50 = pediatric, 20 = adult) received cisplatin-based chemotherapy. Mean age was 20 y (range = 6–46 y). The median follow-up was 10.3 y (range = 0.17–21.7 y). The five-year event-free survival (EFS5) and overall survival (OS5) was 0.94 (95%CI, 0.88–0.97) and 0.96 (95%CI, 0.91–0.99) respectively. Survival outcomes were comparable between carboplatin-(EFS5 = 0.96 (95%CI, 0.85–0.99), OS5 = 0.96 (95%CI, 0.85–0.99)) and cisplatin-(EFS5 = 0.93 (95%CI, 0.83–0.97), OS5 = 0.96 (95%CI, 0.87–0.99)) based regimens. Across three age groups, comparison of the EFS5 ( 25 y = 0.97 (95%CI, 0.81–0.99)) and OS5 ( 25 y = 0.97 (95%CI, 0.81–0.99)) did not demonstrate any statistically significant differences in outcomes. Conclusions Patients diagnosed with dysgerminoma have an excellent OS, across all ages, even in the context of metastatic disease. Data from three large CTOs supports the investigation of carboplatin-based regimens in the frontline treatment of all patients with advanced-stage dysgerminoma to minimize treatment-related toxicities.

Hepatoblastoma is the most common hepatic malignancy of childhood with known genetic predispositions and perinatal risk factors, with rare case reports occurring in the setting of cirrhosis. This case describes a young patient with cirrhosis attributed to early-onset hereditary hemochromatosis who was diagnosed with hepatoblastoma with uncommon histologic findings, evidence of chemotherapy resistance who ultimately succumbed to her disease. It is important to consider diagnoses beyond hepatocellular carcinoma in this scenario and consider early biopsy. With atypical histology, the tumor may respond poorly to conventional treatment and aggressive surgery or intensive therapy should be contemplated.

INTRODUCTION AND OBJECTIVE:Patients with clinical stage I (CS I: cN0M0) germ cell tumors (GCT) exhibit favorable oncologic outcomes. While prognostic features can help inform treatment in adults wi...

BackgroundWhereas among pediatric oncologists, ovarian yolk sac tumor (O-YST) is considered a chemosensitive tumor, it is often cited as an adverse prognostic factor in adult women with ovarian germ cell tumors.MethodsThe Malignant Germ Cell International Consortium data set included 6 pediatric clinical trials (United States, United Kingdom, and France) and 2 adult gynecology clinical trials (United States). Any patient with an O-YST that was International Federation of Gynecology and Obstetrics stage IC or higher and treated with a platinum-based chemotherapy was eligible. Age was modeled as a continuous and a categorical variable (children, 0-10 years; adolescents, 11–17 years; and adults, ≥18 years). In addition, analyses to establish the optimal cut point for age were conducted. Tumors were coded as pure YST (YST +/− teratoma), mixed YST (YST + other malignant germ cell component), or putative YST (“mixed” germ cell tumor + alpha-fetoprotein >1000 ng/mL). Histology, stage (II/III vs IV), preoperative alpha-fetoprotein levels (10,000 ng/mL), and chemotherapeutic regimen (carboplatin vs cisplatin) were analyzed as covariates.ResultsTwo hundred fifty-one patients (median age, 13 years; range, 0–38 years) were identified (78 children, 139 adolescents, and 34 adults). Histology was pure, mixed, and putative in 129, 56, and 66 cases, respectively. Twenty-six patients had stage IV disease, similarly distributed in the 3 age groups. Median follow-up was 5.8 years. The overall 5-year event-free survival and overall survival was 91% (95% confidence interval, 87%–94%) and 96% (92%–98%), respectively. Age did not affect risk of event or death, modeled either as a categorical or continuous variable. Analysis failed to identify an age cut point that affected risk. None of the other covariates investigated had a prognostic impact on event-free survival or overall survival.ConclusionsOvarian yolk sac tumors have an excellent outcome across all age-groups. Age has no apparent impact on the probability of event or death, allowing pediatric and gynecologic oncologists to enroll patients onto joint pediatric and adult trials.

BACKGROUND There is a debate regarding the management of ovarian immature teratomas (ITs). In adult women, postoperative chemotherapy is standard except for stage I, grade 1 disease, whereas surgery alone is standard in pediatric patients. To determine the role of chemotherapy, a pooled analysis of pediatric and adult clinical trials was conducted. METHODS Data from 7 pediatric trials and 2 adult trials were merged in the Malignant Germ Cell International Collaborative data set. Four trials included patients with newly diagnosed pure ovarian ITs and were selected (Pediatric Oncology Group/Children's Cancer Group Intergroup Study (INT 0106), Second UKCCSG Germ Cell Tumor Study (GC2), Gynecologic Oncology Group (GOG 0078 and GOG 0090). Adult and pediatric trials were analyzed separately. The primary outcome measures were event-free survival (EFS) and overall survival (OS). RESULTS One hundred seventy-nine patients were included (98 pediatric patients and 81 adult patients). Ninety pediatric patients were treated with surgery alone, whereas all adult patients received chemotherapy. The 5-year EFS and OS were 91% and 99%, respectively, for the pediatric cohort and 87% and 93%, respectively, for the adults. There were no relapses in grade 1 patients, regardless of the stage or age. Only 1 adult patient with a grade 2 IT relapsed. Among grade 3 patients, the 5-year EFS was 0.92 (0.72-0.98) for stage I/II and 0.52 (0.22-0.75) for stage III in the pediatric cohort (P = .005) and 0.91 (0.69-0.98) for stage I/II and 0.65 (0.39-0.83) for stage III/IV in the adult cohort (P = .01). Postoperative chemotherapy did not decrease relapses in the pediatric cohort. CONCLUSIONS The grade was the most important risk factor for relapse in ovarian ITs. Among grade 3 patients, the stage was significantly associated with relapse. Adjuvant chemotherapy did not decrease relapses in the pediatric cohort; its role in adults remains unresolved. Cancer 2016;122:230–237. © 2015 American Cancer Society.

Background 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. Methods 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. Results 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). Conclusion 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 investigate whether event-free survival (EFS) can be maintained among children and adolescents with intermediate-risk (IR) malignant germ cell tumors (MGCT) if the administration of cisplatin, etoposide, and bleomycin (PEb) is reduced from four to three cycles and compressed from 5 to 3 days per cycle. Patients and Methods In a phase 3, single-arm trial, patients with IR MGCT (stage II-IV testicular, II-III ovarian, I-II extragonadal, or stage I gonadal tumors with subsequent recurrence) received three cycles of PEb. A parametric comparator model specified that the observed EFS rate should not be significantly < 92%. As recommended for trials that test a reduction of therapy, a one-sided P value ≤ .10 was used to indicate statistical significance. In a post hoc analysis, we also compared results to the EFS rate of comparable patients treated with four cycles of PEb in two prior studies. Results Among 210 eligible patients enrolled from 2003 to 2011, 4-year EFS (EFS4) rate was 89% (95% confidence interval, 83% to 92%), which was significantly lower than the 92% threshold of the comparison model ( P = .08). Among 181 newly diagnosed patients, the EFS4 rate was 87%, compared with 92% for 92 comparable children in the historical cohort ( P = .15). The EFS4 rate was significantly associated with stage (stage I, 100%; stage II, 92%; stage III, 85%; and stage IV, 54%; P < .001). Conclusion The EFS rate for children with IR MGCT observed after three cycles of PEb was less than that of a prespecified parametric model, particularly for patients with higher-stage tumors. These data do not support a reduction in the number of cycles of PEb from four to three. However, further investigation of a reduction in the number of cycles for patients with lower-stage tumors is warranted.

Background Orthotopic liver transplantation (OLT) is considered the standard for children with hepatoblastoma (HB) in whom complete surgical resection is not possible. However, OLT is not always available or feasible. Objective To describe the outcome of children with HB who were initially deemed unresectable and underwent complex hepatectomy with planned close margins, and ultimately avoided OLT. Methods Demographic data, surgical and pathologic details, and survival information were collected from children treated for HB between January 2010 to December 2015. Results Among six children (median age 12 months (3-41 months)), PRETEXT classification was III (n = 2), III/IV (n = 1), and IV (n = 3). Patients received a median of six cycles (range 4-7) of platinum-based induction chemotherapy; five received doxorubicin. Experienced pediatric surgeons performed extended right and left hepatectomy in five and one patients, respectively, with assistance of an experienced liver transplant surgeon (n = 4). Microscopic margins were positive (n = 2) and negative but close (n = 4; 2-5 mm). Two patients required vascular reconstruction of the vena cava. At median follow-up of 3.3 years (1.7-4.6 years), there was no evidence of local recurrence. One patient had recurrence of pulmonary disease 3 months after surgery. Conclusions Patients with advanced HB treated with complex surgical resections with positive or close negative margins had good outcomes without OLT. We suggest that planned positive or close microscopic margins in highly selected HB patients may spare the morbidity of OLT and offer an alternative for those ineligible for OLT. Our experience illustrates the importance of a multidisciplinary team specialized in the management of liver tumors.

Traumatic lumbar punctures with blasts (TLP+) in children with acute lymphoblastic leukaemia (ALL) obscure central nervous system status and are associated with a poorer event-free survival (EFS).We conducted a retrospective cohort study of all lumbar punctures (LPs) for children with ALL diagnosed at our institution from 2005 to 2009. We utilised random-effects and fixed-effects repeated-measures logistic regression analyses to identify risk factors for TLPs. Fixed-effects models use each patient as his or her own control. We used survival analysis to describe outcomes after a TLP+.264 children underwent 5267 evaluable lumbar punctures (LPs), of which 944 (17.9%) were traumatic. In the multivariable random-effects model, variables significantly associated with TLPs were age1year (odds ratio (OR) 3.46, 95% confidence interval (CI) 2.06-5.81) or age ⩾10years (OR 2.00, CI 1.66-2.40); body mass index percentile ⩾95 (OR 1.44, CI 1.19-1.75); platelet count100×10(3)/μL (OR 1.49, CI 1.08-20.7); fewer days since previous LP (OR 5.13, CI 2.34-11.25 for ⩾16days versus 0-3days); and a preceding TLP (OR 1.43, CI 1.19-1.73). In the fixed-effects model, image-guidance reduced the odds of TLP (OR 0.55, CI 0.32-0.95). The 5-year EFS (±SE) for children with TLP+ (77±8%) was significantly lower than for children with CNS1 status (93±2%; p=0.002).The frequency of TLP remains high. Consistent with previous studies, a TLP+ at diagnosis was associated with a poorer EFS. These risk factors can allow identifying interventions to reduce TLPs and directing interventions to those at highest risk.

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.

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.

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 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.

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.

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.

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...