BACKGROUND:In many pediatric malignant germ cell tumor (MGCT) protocols, patients who do not achieve a complete response (CR; normal tumor markers, no radiological/histological residual) after three cisplatin-etoposide-bleomycin (PEb) cycles receive two to three "consolidation" cycles of the same regimen. Evidence for this practice is limited, and historical outcomes for non‑CR patients remain poor. METHODS:We retrospectively reviewed patients diagnosed with intermediate-risk MGCT, enrolled in AGCT0132, between 2003 and 2011. All patients received three cycles of PEb and underwent response assessment at the end of induction. Patients not in CR were prescribed three additional cycles of PEb as consolidation. We compared event-free survival (EFS) and overall survival (OS) for patients who did and did not receive consolidation. RESULTS:Among 210 patients enrolled, two patients were excluded from analyses: one without complete information, and one had rapid progressive disease (PD) and did not complete induction therapy. Out of 208 patients, 193 had a CR after three cycles of induction chemotherapy, and their post-induction 4-year EFS and OS were 93% and 99%. Fifteen patients were not in CR at the end of the first three cycles. Twelve received consolidated chemotherapy as mandated per protocol, and their 4-year EFS and OS were 61% and 65%, respectively. Three patients were deemed to have progressive disease at the end of induction and received second-line therapy. CONCLUSION:Children with MGCTs who did not achieve CR after the first three cycles of chemotherapy had an inferior outcome compared to those with a CR, despite receiving additional cycles of PEb chemotherapy. We conclude that consolidation is of unclear benefit. We suggest that pediatric MGCT patients who fail to achieve a CR after standard induction chemotherapy may receive a salvage regimen with different agents rather than consolidation with more of the same chemotherapy.

ABSTRACTBackgroundDifferentiated thyroid carcinoma (DTC) is the most common pediatric thyroid malignancy, with papillary thyroid carcinoma (PTC) representing 90% of the cases. In 2015, the American Thyroid Association (ATA) developed management guidelines for pediatric DTC.ProcedurePatients less than 21 years of age diagnosed with DTC between 2000 and 2015 at Texas Children's Hospital, Seattle Children's Hospital, Children's Healthcare of Atlanta, Children's Hospital Colorado, and Nationwide Children's Hospital were retrospectively analyzed to evaluate treatment practices before the implementation of the ATA guidelines.ResultsWe included 216 pediatric patients with DTC. A majority were female (76%) with a median age at diagnosis of 14.8 years. Neck swelling (56%) and palpable nodules (49%) were common presenting symptoms. Diagnostic evaluations typically included thyroid ultrasound, with common features being microcalcifications (47.7%) and hypoechogenicity (39.0%). Fine‐needle aspiration cytology confirmed diagnosis in 50.5%. The majority of patients underwent total thyroidectomy (78.7%) and lymph node dissection (75.5%). ATA risk stratification was low, intermediate, and high risk in 111 (51.4%), 29 (13.4%), and 76 patients (35.2%), respectively. Upfront radioactive iodine (RAI) was administered in 83%. At 1‐year follow‐up, 46% were disease‐free (66% low risk, 59% intermediate risk, and 13% high risk). The 5‐year progression‐free survival for low, intermediate, and high risk were 86%, 53%, and 43%, respectively. The disease‐related overall survival was 100%.ConclusionsPrior to the introduction of the ATA guidelines, a majority of patients underwent total thyroidectomy with lymph node dissection followed by RAI. Selective use of RAI for low‐risk disease as recommended in the current guidelines may be appropriate.

center dot PURPOSE: To compare the clinical outcomes of children with unilateral retinoblastoma (Rb) and high-risk histopathology features (HRHF) following upfront enucleation with/without adjuvant chemotherapy, and investigate cases locally considered non-HRHF but converted to a standardized HRHF definition. center dot DESIGN: Retrospective multinational clinical cohort study. center dot METHODS: Children with Rb who presented to 21 centers from 12 countries between 2011-2020, and underwent primary enucleation were recruited. Centers retrieved clinical data and were asked to report detailed histopathology findings, as well as indicate cases defined locally as high-risk. For analysis, only unilateral cases with standardized HRHF, defined as retrolaminar optic nerve invasion, massive choroidal invasion, scleral invasion, anterior-segment involvement, and/or combined nonmassive choroidal and prelaminar/laminar optic nerve invasion, were included. Main outcome measures included orbital tumor recurrence, systemic metastasis, survival and number, and outcome of cases converted to standardized HRHF. center dot RESULTS: A total of 600 children presenting to 14 centers in 9 countries were included. Of these, 505 (84.2%) were considered locally as HRHF and received adjuvant chemotherapy. After a median follow-up period of 39.2 +/- 1.6 months (range: 0.8-60.0 months), 36 (6.0%) had orbital tumor recurrence, 49 (8.2%) metastasis, and 72 (12.0%) children died. Children not receiving adjuvant chemotherapy were at significantly increased risk of orbital tumor recurrence, metastasis, and death ( P <= .002). Of the study children, 63/600 (10.5%) were considered locally non-HRHF, but converted to standardized HRHF and included in the analysis. Of these, 6/63 (9.5%) had orbital tumor recurrence, 5/63 (7.9%) metastasis, and 6/63 (9.5%) children died. Isolated minor choroidal invasion with prelaminar/laminar optic nerve invasion was reported in 114 (19.0%) children, but considered locally as HRHF only in 68/114 (59.6%). Of these, 6/114 (5.3%) children developed metastasis and subsequently died, yielding a number needed to treat of 15. center dot CONCLUSION: Based on this multinational cohort of children with Rb, we recommend the use of adjuvant chemotherapy following upfront enucleation and diagnosis of HRHF. Variation exists worldwide among centers when defining HRHF, resulting in adverse patient outcomes, warranting standardization. (Am J Ophthalmol 2024;268: 399-408. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: To evaluate high-risk histopathological features following primary enucleation of eyes with retinoblastoma and assess the patient outcomes across continents. Methods: A retrospective study of 1,426 primarily enucleated retinoblastoma eyes from five continents. Results: Of all, 923 (65%) were from Asia (AS), 27 (2%) from Australia (AUS), 120 (8%) from Europe (EUR), 162 (11%) from North America (NA), and 194 (14%) from South America (SA). Based on the continent (AS vs. AUS vs. EUR vs. NA vs. SA), the histopathological features included massive choroidal invasion (31% vs. 7% vs. 13% vs. 19% vs. 27%, P = 0.001), postlaminar optic nerve invasion (27% vs. 0% vs. 16% vs. 21% vs. 19%, P = 0.0006), scleral infiltration (5% vs. 0% vs. 4% vs. 2% vs. 7%, P = 0.13), and microscopic extrascleral infiltration (4% vs. 0% vs. <1% vs. <1% vs. 4%, P = 0.68). Adjuvant chemotherapy with/without orbital radiotherapy was given to 761 (53%) patients. Based on Kaplan-Meier estimates in different continents (AS vs. AUS vs. EUR vs. NA vs. SA), the 6-year risk of orbital tumor recurrence was 5% versus 2% versus 0% versus 0% versus 12% (P < 0.001), systemic metastasis was reported in 8% versus 5% versus 2% versus 0% versus 13% (P = 0.001), and death in 10% versus 3% versus 2% versus 0% versus 11% (P < 0.001) patients. Conclusion: There is a wide variation in the infiltrative histopathological features of retinoblastoma across continents, resulting in variable outcomes. SA and AS had a higher risk of orbital tumor recurrence, systemic metastasis, and death compared to AUS, EUR, and NA.

Germ cell tumors (GCTs) are a heterogeneous group of tumors presenting in a wide range of age groups, locations, and histological types. This diversity contributes to the wide range of specialists who care for these patients. In particular, collaborations between pediatric oncologists, medical oncologists, gynecological oncologists, surgeons, and urologists are essential for the development of stratification systems. This chapter describes the current diagnosis, staging, and treatment of GCTs and highlights the challenges moving forward.

10046 Background: Retinoblastoma (RB) is the most common tumor of the eye in childhood. Intraocular RB cure rates approach 100%. Therefore, treatment now focuses on globe salvage preserving functional vision. The Research Into Visual Endpoints and RB Health Outcomes After Treatment (RIVERBOAT) consortium was established to examine patient health outcomes, including vision, in the contemporary therapy era. Methods: Patients with RB treated at consortium centers from 2007 to present were identified. Medical record abstraction was performed for disease presentation, treatment, and outcomes. A subset of the patients returned to centers and completed functional vision questionnaires (Child Vision Function Questionnaire - ages 0 – 7 and Cardiff Visual Ability Questionnaire for Children - ages > 8) and had visual acuity assessed. For participants who could not yet return for a study evaluation, medical record abstraction alone was performed. Results: Among 463 participants enrolled to date, 270 (58%) had unilateral disease. One patient with metastatic RB did not survive, resulting in overall survival of 99.6. There was one case of secondary leukemia. The eye group distribution (International Intraocular Retinoblastoma Classification) was 0.4% A, 5.6% B, 7.0% C, 36.0% D, 49.0% E and 2.0% not classified. 131 (49%) patients underwent primary enucleation and are not included in further analyses. Among the remaining 139 patients, 3% were treated with local ophthalmic therapy only, 22% with intravenous chemotherapy (IV) only, 53% with intra-arterial chemotherapy (IAC) only, 22% with IV and IAC, and 35% required secondary enucleation. Globe salvage after chemotherapy was successful in 100% A, 93% B, 82% C, 72% D, and 48% E eyes. This salvage was achieved with IV only, IAC only, or both in 22%, 58% and 20% respectively. The mean percentage of patients receiving IAC per year increased from 13% (2008 – 2013) to 21% (2014 – 2017) to 28% (2018 – 2022). In 29 patients without enucleation who reported functional vision to date, the mean scores (survey theoretical ranges) were 0.72 for < 3 years (0.57 to 0.87), 0.82 for 3 -7 years (0.56 to 0.94) and -2.72 for > 8 years (-2.53 to -0.51), all considered good functional vision. In 20 of these 29 patients, 4 eyes had normal vision (20/20-20/40) across A to D groups. Moderate vision loss (> 20/40 – 20/70) was noted in 3 D eyes and low vision (> 20/70 - < 20/200) in 1 D eye. Twelve B through E eyes met criteria for a legally blind eye (>20/200). Conclusions: In this cohort of RB patients with unilateral disease treated from 2007 - 2022, 66% required primary or secondary enucleation. Among 29 patients with globe salvage, self-reported functional vision was good, but 12 eyes in 20 of the patients were legally blind. IAC only or IV plus IAC was most used in those who avoided secondary enucleation. With ongoing cohort accrual and increased IAC use, it will remain to be determined if globe salvage with functional vision will improve.

Objective: To report diagnosis, treatment, and outcomes of vaginal yolk sac tumor (YST) cases at a single institution and review literature on vaginal YST to outline advancements in diagnosis, treatment, and survival. Design: Retrospective chart review of female patients less than 21 years of age with pathologic diagnosis of vaginal YST treated at a large children's hospital, and summary of a 100-year review of the literature on vaginal yolk sac tumor. Setting: Children's Healthcare of Atlanta, a tertiary center in Atlanta, GA. Participants: Female patients less than 21 years of age diagnosed with vaginal YST. Results: Two cases of vaginal YST at our institution are outlined. Both patients presented within the first 2 years of life with vaginal bleeding and were treated successfully with chemotherapy alone. After review of the literature, 137 cases of vaginal YST were found. The mean age at diagnosis was 11 months, and all patients presented with vaginal bleeding. Before 2000, more radical treatments were pursued, and 40% resulted in death. Since the year 2000, treatment has shifted toward chemotherapy and more conservative surgical management, with 51% of vaginal YST cases treated with chemotherapy alone with 92% of patients alive at time of publication. Conclusion: Our cases contribute to the limited literature demonstrating the efficacy of conservative management of rare cases of vaginal YST with chemotherapy alone. This case series and review of the literature provide mounting evidence that vaginal YST should be in the differential diagnosis in young girls with vaginal tumors, and conservative management of vaginal YST has excellent outcomes.

A 13-year-old healthy girl presented with dizziness and palpitations, found to have a left atrial mass. An 8-cm tumor was removed en bloc. Pathology confirmed grade 3 leiomyosarcoma with multifocal positive margins. She received adjuvant ifosfamide and doxorubicin, followed by concurrent proton radiotherapy and ifosfamide. Radiotherapy included 66 Gy (RBE) in 33 fractions to the operative bed. Prospectively graded toxicities included Grade 2 esophagitis and Grade 1 anorexia, dermatitis, and fatigue. She completed six cycles of ifosfamide. Two years post operation, she had no evidence of disease, intermittent palpitations with normal cardiac function, and no other cardiopulmonary or esophageal symptoms.

Identifying and quantifying conservation-practice adoption in U.S. cropland is key to accurately monitoring trends in soil health regionally and nationally and informing climate change mitigation efforts. We present the results of an automated system used across 645 counties in the United States Corn Belt from 2005 to 2018, mapped at field-scale and summarized for distribution at aggregated scales. Large-scale mapping by OpTIS (Operational Tillage Information System), a software tool that analyzes remotely sensed data of agricultural land, provides trends of conservation tillage (defined as >30% residue cover), cover cropping, and crop rotations, while modeling by DNDC (Denitrification–Decomposition), a process-based model of carbon and biogeochemistry in soil, provides estimates of the ecosystem outcomes associated with the changes in management practices mapped by OpTIS. Ground-truthing data acquired via OpTIS mobile, a roadside field-surveying app, were used for verification in 30 counties. OpTIS results for the Corn Belt show adoption of cover crops after planting corn and soy increased from 1% to 3% of the mapped area when comparing 2006 to 2018. Comparison of trends for conservation tillage use from 2006 to 2018 shows a slight decrease in conservation tillage adoption, from 46% to 44%. Results from DNDC show these soils sequestered soil organic carbon (SOC) at an area-weighted mean change in SOC (dSOC) rate of 161 kgC/ha/year. Comparatively, in a scenario modeled without the adoption of soil health management practices, the same soils would have lost SOC at an area-weighted rate of −65 kgC/ha/year. As many factors affect changes to SOC, including climate and initial SOC in soils, modeling counterfactual scenarios at the field scale demonstrates outcomes of current soil health management in comparison to regional management practices and best management practices, with respect to SOC sequestration. Regional trends in adoption rates of conservation agriculture and resulting soil health implications are of great use for a wide range of stakeholders. We demonstrate the capability of OpTIS remote sensing to deliver robust, large-scale, multi-sensor, ground-verified monitoring data of current and historical adoption of conservation practices, and of DNDC process-based modeling to provide assessments of the associated environmental outcomes across regions in U.S. cropland.

OBJECTIVE:To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT). METHODS:Patients <18 years with ovarian and testicular GCT (respectively OGCT and TGCT) were prospectively registered according to the guidelines of MAKEI 96. After resection of the primary tumor, patients staged ≥II received risk-stratified cisplatin-based combination chemotherapy. Patients were analyzed in respect to age (six age groups divided into 3-year intervals), histology, stage, and therapy. The primary end point was overall survival. RESULTS:Between January 1996 and March 2016, the following patients were registered: 1047 OGCT, of those, 630 had ovarian teratoma (OTER) and 417 had malignant OGCT (MOGCT); and 418 TGCT, of those, 106 had testicular teratoma (TTER) and 312 had malignant TGCT (MTGCT). Only in MTGCT, older age correlated with a higher proportion of advanced tumors. All 736 teratomas and 240/415 stage I malignant gonadal GCT underwent surgery and close observation alone. In case of watchful waiting, the progression rate of OGCT was higher than that of TGCT. However, death from disease was reported in 8/417 (1.9%) MOGCT and 8/312 (2.6%) MTGCT irrespective of adjuvant chemotherapy and repeated surgery. CONCLUSIONS:The different pathogenesis and histogenesis of gonadal GCT reflects sex- and age-specific patterns that define clinically relevant risk groups. Therefore, gender and age should be considered in further research on the biology and clinical practice of pediatric gonadal GCT.

BackgroundAdolescents 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.MethodsAn 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 <11 years), adolescents (11 to <18 years), and young adults (18 to ≤30 years). The study compared EFS and adjusted for risk group by using Cox proportional hazards analysis.ResultsFrom a total of 2024 individual records, 593 patients met the inclusion criteria: 90 were children, 109 were adolescents, and 394 were young adults. The 5‐year EFS rate was lower for adolescents (72%; 95% confidence interval [CI], 62%‐79%) than children (90%; 95% CI, 81%‐95%; P = .003) or young adults (88%; 95% CI, 84%‐91%; P = .0002). The International Germ Cell Cancer Collaborative Group risk group was associated with EFS in the adolescent age group (P = .0020). After adjustments for risk group, the difference in EFS between adolescents and children remained significant (hazard ratio, 0.30; P = .001).ConclusionsEFS for adolescent patients with metastatic GCTs was similar to that for young adults but significantly worse than for that children. This finding highlights the importance of coordinating initiatives across clinical trial organizations to improve outcomes for adolescents and young adults.LAY SUMMARY Adolescent males with metastatic germ cell tumors (GCTs) are frequently treated with regimens developed for children. In this study, a large data set of male patients with metastatic GCTs across different age groups has been built to understand the outcomes of adolescent patients in comparison with children and young adults. The results suggest that adolescent males with metastatic GCTs have worse results than children and are more similar to young adults with GCTs. Therefore, the treatment of adolescents with GCTs should resemble therapeutic approaches for young adults.

The diagnosis of ovarian cancer in adolescents and young adults is always challenging. Many issues exist, and most important of these may be access to care with an appropriate provider. A range of histologies occur in the ovaries, and their frequency changes markedly as patients progress from adolescence to young adulthood. The very curable germ cell tumors of adolescence slowly give way to aggressive carcinomas, which require a different treatment approach. Special consideration is needed for treatment of toxicity. In an ideal world, centers consisting of pediatric, medical, and gynecological oncologists may be the most appropriate to care for these complex and diverse patients.

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 alpha-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.

PURPOSETo 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.METHODSWe 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.RESULTSA 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.CONCLUSIONTumor 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.

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). 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 <11 years), SR2 (EFS >80%, age >= 11y) and poor risk (PR) (EFS <= 70%, age <= 11y). 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. 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. (C) 2018 Published by Elsevier Ltd.