Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials.

PURPOSE: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. MATERIALS AND METHODS: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3-21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. RESULTS: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS. CONCLUSIONS: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Surgical Management of Cervical Non-seminomatous Germ Cell Tumor Metastases.

OBJECTIVE/HYPOTHESIS: Testicular cancer is the most common malignancy of young males. Limited reports describe perioperative and long-term outcomes after surgical resection of metastatic, cervical, non-seminomatous germ cell tumors (NSGCT). The objective of this study was to investigate the effectiveness and safety of cervical lymphadenectomy in the management of metastatic NSGCT. STUDY DESIGN: Retrospective case series. METHODS: A single institution, retrospective review from 1998 to 2020 of patients with metastatic NSGCT who underwent cervical lymphadenectomy was conducted. Clinicopathological, surgical, and postoperative data were collected and analyzed. RESULTS: Sixty-eight predominantly white (91.0%) male patients with mean age 33.0 ± 11.3 years were included. Most (82.2%) presented with stage III disease at initial diagnosis. All patients had undergone primary platinum-based chemotherapy 1.0 to 22.7 months prior to selective ND. Surgery mainly involved nodal levels III (67.6%), IV (92.6%) and/or Vb (77.9%) and was frequently performed with concomitant thoracoabdominal NSGCT resections (63.2%). Cervical specimens predominantly revealed mature teratoma (83.8%) as solitary (69.1%) or component of mixed (14.7%) NSGCT. Ten (14.7%) perioperative complications occurred as vocal cord paresis (n = 6) from thoracic surgery and chyle leakage (n = 4). All resolved conservatively except two vocal cord paralyzes that required surgical repair due to tumor involvement of vagus nerve. Six instances of cervical recurrence occurred at median 12.5 (range, 5.8-38.6) months from ND, all re-demonstrating purely mature teratoma. The two-year cervical, non-cervical, and overall recurrence-free survivals were 83%, 55%, and 55%, respectively. Two-year disease-free and overall survivals were both 93%. CONCLUSIONS: Selective neck dissection is a safe, effective method for managing cervical NSGCT metastases. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1528-1534, 2021.

Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET.

PURPOSE: Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. EXPERIMENTAL DESIGN: Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34+-NSG-SGM3). RESULTS: Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (107 or 108 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8+ T-cell infiltration. CONCLUSIONS: Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.

Primary intracranial germ cell tumors in children 36-year experience of a single center.

PURPOSE: Intracranial germ cell tumors (ICGCTs) comprise approximately 0.4%-3% of all brain tumors. In this study, we aim to evaluate clinical characteristics, treatment and outcomes of patients with ICGCT. PATIENTS AND METHODS: All patients with ICGCT diagnosed in Hacettepe University's Pediatric Oncology Department between January 1980 and January 2016 were evaluated, retrospectively. RESULTS: We identified 52 patients (male/female: 2.46) diagnosed with ICGT. Median age was 140 months. The median duration of symptoms was 3 months. Patients with endocrine symptoms were diagnosed later than others (P = 0.028). The primary site was pineal region in 20 patients, nonpineal region in 32 which included six bifocal involvements. Pineal location was more common in boys than girls (P = 0.02). Histopathological diagnosis was germinoma in 28 patients, nongerminomatous malignant germ cell tumors in 14 and immature teratoma in 4. The mean age for germinoma was higher than that of nongerminomatous tumors (P = 0.032). Patients treated with surgery and radiotherapy and chemotherapy. Median follow-up time was 52.5 months. Thirty-six patients were alive for 12-228 months. Relapsed/progressive disease was observed in 11 patients. Nongerminomatous tumors more frequently showed relapse/progression than germinoma (P = 0.06). Five-year overall and event-free survival rates for the whole group were 72.6% and 57.2%, respectively. Overall and event-free survival rates for germinoma were better than malignant nongerminomatous tumors. CONCLUSION: Although the ratio of ICGCTs to central nervous system tumors in our series was similar to western countries, some clinical features such as tumor location were similar to cases from East Asian countries. Although similar protocols were used survival rates lower than developed western and eastern developed countries.

Brain atypical teratoid rhabdoid tumor in an adult with long-term survival: Case report and review of literature.

Atypical teratoid/rhabdoid tumor (AT/RT) represents a rare malignant embryonic tumor of infant and early childhood. Its prognosis remains dismal despite aggressive multimodal treatment. We report the case of a 24-year-old male who was diagnosed with left parietal AT/RT after total resection and who is still in good health and recurrence free 4 years after surgery and adjuvant chemotherapy and radiotherapy.

Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy.

Central nervous system (CNS) tumors are the most common solid tumor in pediatrics, accounting for approximately 25% of all childhood cancers, and the second most common pediatric malignancy after leukemia. CNS tumors can be associated with significant morbidity, even those classified as low grade. Mortality from CNS tumors is disproportionately high compared to other childhood malignancies, although surgery, radiation, and chemotherapy have improved outcomes in these patients over the last few decades. Current therapeutic strategies lead to a high risk of side effects, especially in young children. Pediatric brain tumor survivors have unique sequelae compared to age-matched patients who survived other malignancies. They are at greater risk of significant impairment in cognitive, neurological, endocrine, social, and emotional domains, depending on the location and type of the CNS tumor. Next-generation genomics have shed light on the broad molecular heterogeneity of pediatric brain tumors and have identified important genes and signaling pathways that serve to drive tumor proliferation. This insight has impacted the research field by providing potential therapeutic targets for these diseases. In this review, we highlight recent progress in understanding the molecular basis of common pediatric brain tumors, specifically low-grade glioma, high-grade glioma, ependymoma, embryonal tumors, and atypical teratoid/rhabdoid tumor (ATRT). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Meta-Analysis of Treatment Modalities in Metastatic Atypical Teratoid/Rhabdoid Tumors in Children.

BACKGROUND: Metastatic atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy, and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patients. METHODS: We performed a meta-analysis of 1578 articles published through September 2018, including 44 studies with a total of 123 subjects. In addition, seven patients were included through chart review of patients treated at Nationwide Children's Hospital. RESULTS: Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant effect on survival (P = 0.0355); 3-year OS for infants less than 18 months was 21%, 18 to 36 months was 26%, and greater than 36 months was 36%. Location of the primary tumor, metastatic stage, and extent of surgical resection did not have a significant impact on OS. On univariate analysis, XRT (P < 0.0001), IT (P = 0.01), and AuHCR (P < 0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% vs 9% in those who did not). On multivariable analysis, XRT (P = 0.0006), IT (P = 0.0124), and AuHCR (P < 0.0001) were independently associated with reduced risk of death. CONCLUSIONS: Although more research is warranted to make generalizable conclusions, these results suggest that treatment regimens for patients with metastatic AT/RTs should include AuHCR, XRT, and IT.

Changes in glomerular filtration rate and clinical course after sequential doses of carboplatin in children with embryonal brain tumors undergoing autologous stem cell transplantation.

BACKGROUND: Treatment for malignant embryonal brain tumors in young children usually employs cycles of standardly dosed cisplatinum followed by high-dose carboplatinum-containing conditioning with single or tandem autologous stem cell rescue (HDC-ASCR). High-dose carboplatin is potentially nephrotoxic, and additive platinum exposure may acutely impact renal function. Aiming to determine if decrease in renal function during conditioning assessed prior to each carboplatin dose was associated with acute increases in creatinine, requirement for dialysis or transplant-related mortality (TRM). This was a retrospective study of consecutive patients with medulloblastoma (n = 15) / atypical teratoid/rhabdoid tumor (AT/RT, n = 5) receiving HDC-ASCR. Fifteen patients underwent 1 HDC-ASCR (carboplatin × 3 doses/ etoposide/ thiotepa) and 5 patients underwent at least 1 of 3 planned tandem HDC-ASCR (carboplatin × 2 doses/ thiotepa). Renal function was assessed by daily creatinine and nuclear medicine glomerular filtration rate (GFR)/ creatinine clearance before each carboplatin dose. RESULTS: In this cohort of 20 patients, 3 had doses of carboplatin omitted due to decreases in GFR: 1 did not develop nephrotoxicity, 1 experienced nephrotoxicity without need for dialysis, and 1 required dialysis temporarily but recovered renal function. Two patients did not have GFR changes but developed post-ASCR renal failure requiring dialysis and TRM. CONCLUSION: Daily assessment of renal function by GFR, prior each dose of carboplatin during HDC-ASCR, will help in protecting the kidney in heavily treated population of oncology/HSCT patients. Although the study had a small number of patients which is a major limitation of the study, but it points to a serious transplant-related morbidity and mortality. So, larger scale studies are needed to clarify the best approach to carboplatin dosing to insure the optimal balance between efficacy and toxicity.

Prognostic Value of Teratoma in Primary Tumor and Postchemotherapy Retroperitoneal Lymph Node Dissection Specimens in Patients With Metastatic Germ Cell Tumor.

PURPOSE: Presence of teratoma in patients with metastatic testicular germ cell tumor (GCT) is of unknown prognostic significance. We report survival outcomes of patients with or without teratoma in primary tumor and postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) specimen and assess impact on prognosis. PATIENTS AND METHODS: Patients with metastatic nonseminomatous GCT (NSGCT) who were evaluated at Indiana University between 1990 and 2016 and had primary testicular tumor specimen from orchiectomy (ORCH) were included. All patients were treated with cisplatin-based combination chemotherapy. The cohort was divided into 2 groups according to presence or absence of teratoma in ORCH specimen. Survival data were correlated with histopathologic findings. Differences in progression-free (PFS) and overall survival (OS) were evaluated using log-rank tests and Cox proportional hazards models to adjust for known adverse prognostic factors. RESULTS: We identified 1,224 consecutive patients evaluated at Indiana University between 1990 and 2016 who met inclusion criteria. Median age was 27 years (range, 13-71 years); 689 patients had teratoma in ORCH specimen, and 535 did not. With median follow-up of 2.3 years, 5-year PFS was 61.9% (95% CI, 57.1% to 66.2%) for those with teratoma versus 63.1% (95% CI, 58.0% to 67.8%) for those without (P = .66); 5-year OS was 82.2% (95% CI, 77.9% to 85.8%) versus 81.4% (95% CI, 76.5% to 85.3%; P = .91), respectively. A total of 473 patients underwent PC-RPLND; 5-year PFS for patients with pure teratoma in PC-RPLND specimen versus necrosis only was 65.9% versus 79.1% (P = .06), and 5-year OS was 90.3% versus 93.4% (P = .21), respectively. CONCLUSION: Presence of teratoma in ORCH and PC-RPLND specimens was not a prognostic factor in this large retrospective study of patients with NSGCT.

Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333.

PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. PATIENTS AND METHODS: Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. RESULTS: Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. CONCLUSION: The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.

Long-Term Oncologic Outcomes after Primary Retroperitoneal Lymph Node Dissection: Minimizing the Need for Adjuvant Chemotherapy.

PURPOSE: We analyzed the oncologic outcomes of men undergoing primary retroperitoneal lymph node dissection and characterized the use of adjuvant chemotherapy and template dissections. MATERIALS AND METHODS: Retrospective review of the Indiana University testis cancer database identified patients who underwent primary retroperitoneal lymph node dissection between January 2007 and December 2017. Patients and providers were contacted to obtain information regarding adjuvant therapy, recurrence and survival. The primary outcome was recurrence-free survival. Kaplan-Meier curves assessed survival differences stratified by pathological stage, template of dissection and use of adjuvant chemotherapy. RESULTS: A total of 274 patients were included in the study. Most men presented with clinical stage I disease (214, 78%). A modified unilateral template was performed in 257 (94%) and bilateral template in 17 (6%). Overall 148 (54%) and 126 (46%) men had pathological stage (PS) I and PS-II disease, respectively. Thirteen patients (10%) with PS-II disease were treated with adjuvant chemotherapy. With a median followup of 55 months only 33 (12%) patients had recurrence. Of the 113 patients with PS-II disease who did not receive chemotherapy 21 (19%) had disease relapse and 81% were cured with surgery alone and never had recurrence. No difference in recurrence-free survival was noted between modified and bilateral template dissections. CONCLUSIONS: The use of adjuvant chemotherapy has been minimal during the last decade. The majority (81%) of men with PS-II disease were cured with retroperitoneal lymph node dissection alone and were able to avoid chemotherapy. Modified unilateral template dissection provided excellent oncologic control while minimizing morbidity.

Pure pediatric ovarian immature teratomas: The French experience.

OBJECTIVE: To describe characteristics and outcome of pediatric ovarian immature teratomas (IT) to better define the place of chemotherapy. METHODS: Children with ovarian IT enrolled in TGM95 and TGM2013 studies were analyzed. Norris grading and International Federation of Gynecology and Obstetrics staging system were used. RESULTS: Thirty-six cases were identified with a median age of 11 years (range = 1-18): 35 of 36 stage I (17 stage IA, 13 stage IC, and 5 stage IX), including seven patients with gliomatosis peritonei (GP), and 1 stage IIIB (IT peritoneal implants). Centrally reviewed Norris grading was performed in 31 cases: 14 grade I and 17 grade II/III tumors. All patients underwent upfront surgery: 19 unilateral oophorectomy, 14 unilateral adnexectomy, 2 unilateral cystectomy, and 1 bilateral cystectomy. No extensive GP surgery was performed. Six patients received adjuvant vinblastin, bleomycin, and cisplatinum because of tumor rupture (n = 5, including two patients with GP) or stage III (n = 1). After a median follow-up of 39.5 months (range = 6-238), two events occurred 10 and 11 months after diagnosis: one bilateralization (initial stage IX, grade I) and one IT peritoneal relapse (initial stage IA, grade II), respectively. Both were successfully rescued by platinum-based chemotherapy and delayed surgery. No stage IC patients treated without adjuvant chemotherapy relapsed (four grade I and three grade III). None of the seven patients with GP progressed. Five-year event-free survival and overall survival were 94% (95% CI = 81-98%) and 100%. CONCLUSIONS: The current series confirms the excellent prognosis of pediatric ovarian IT, arguing for conservative surgical approach in GP and against systematic adjuvant chemotherapy, even in ruptured tumors.

Percutaneous Intratumor Laser Ablation for Fetal Sacrococcygeal Teratoma.

OBJECTIVE: To evaluate the efficiency of percutaneous intratumor laser ablation for fetal solid sacrococcygeal teratoma (SCT). SUBJECTS AND METHODS: We carried out percutaneous ultrasound-guided intratumor laser ablation through a 17-gauge needle using an output of 40 W in 7 fetuses with large solid SCT and reviewed the literature for minimally invasive therapy for this condition. RESULTS: Laser ablation was carried out at a median gestational age of 20 (range 19-23) weeks, and in all cases there was elimination of obvious vascularization within the tumor and improvement in cardiac function. Three (43%) babies survived and had surgical excision of the tumor within 2 days of birth, 3 liveborn babies died within 5 days of birth and before surgery, and 1 fetus died within 2 weeks after the procedure. In previous series of various percutaneous interventions for predominantly solid SCT the survival rate was 33% (2/6) (95% CI 9.7-70%) for endoscopic laser to superficial vessels, 57% (4/7) (95% CI 25-84%) for intratumor laser, 67% (8/12) (95% CI 39-86%) for intratumor radiofrequency ablation, and 20% (1/5) (95% CI 3.6-62%) for intratumor injection of alcohol. CONCLUSIONS: In solid SCT, the reported survival from intratumor laser or radiofrequency ablation is about 50%, but survival does not mean success, and it remains uncertain whether such interventions are beneficial or not because the number of fetuses is small and there were no controls that were managed expectantly.

Spinal cord atypical teratoid/rhabdoid tumors in children: Clinical, genetic, and outcome characteristics in a representative European cohort.

BACKGROUND: Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT. METHODS: Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3). RESULTS: Median observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation. CONCLUSIONS: Long-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.

Overall Survival of Primary Intracranial Atypical Teratoid Rhabdoid Tumor Following Multimodal Treatment: A Pooled Analysis of Individual Patient Data.

No standard treatment protocol to guide the management of the primary central nervous system atypical teratoid rhabdoid tumors (ATRTs). To evaluate the efficacy of GTR (gross total resection), RT (radiotherapy), CCMT (conventional chemotherapy), or intensified chemotherapy (ICMT) and verify the optimal treatment strategy. A total of 501 cases (18 cases from our center and 483 cases from published literature) were eligible for analysis. Clinical characteristics were reviewed, and overall survival (OS) of each combined treatment modality was compared. These prior publication data were processed according to PRISMA guidelines. This study included 265 (52.9%) males and 216 (43.1%) females. The median age of the cohort was 2.2 years with 295 (58.9%) cases younger than 3 years. GTR was achieved in 217 (43.3%) patients. Initial adjuvant CCMT, CCMT plus intrathecal chemotherapy (ITCMT), CCMT plus high-dose chemotherapy (HDCMT), and CCMT plus ITCMT and HDCMT were administered in 228 (45.5%), 78 (15.6%), 55 (11.0%), and 24 (4.8%) patients, respectively. Radiotherapy (RT) was prescribed in 266 (53.1%) patients. Fewer patients younger than 3 years old received RT (21.9% vs 33.0%, p < 0.001, chi-square test). The OS of the entire cohort at 1, 3, and 5 years were 56.6, 35.9, and 30.8%, respectively. After adjusting for age and sex, GTR (HR 0.630; p < 0.001), RT (HR = 0.295; p < 0.001), CCMT (HR = 0.382; p < 0.001), and ICMT (HR = 0.209; p < 0.001) were independent prognostic factors. The 3-year OS of surgery alone, surgery plus CCMT, surgery plus RT, surgery plus ICMT, surgery plus CCMT and RT, and surgery plus ICMT and RT were 8.9, 13.4, 23.7, 37.4, 48.3, and 68.5%, respectively. When taking into consideration the extent of tumor resection (n = 462), GTR followed by RT, CCMT, intrathecal chemotherapy, and high-dose chemotherapy provided the best OS (5-year OS 88.2%). In younger children, adjuvant ICMT had a greater 3-year OS than adjuvant RT alone (34.0% vs 0%, p = .001). This study identified independent favorable predictors for OS of ATRTs and distinguished significantly different OS following various treatment modalities. If tolerable, intensive treatment with GTR followed by adjuvant RT and ICMT is recommended. Intensified CCMT could be an alternative to avoid radiological radiotoxicity for younger children CRD42018098841.

Atypical Teratoid Rhabdoid Tumor of the Cauda Equina in a Child: Report of a Very Unusual Case.

Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive malignant primitive neoplasms that commonly occur in children younger than 2 years of age. The prognosis is generally dismal with a median survival time of <1 year. The majority of AT/RT occur in the posterior fossa and less frequently the supratentorium. Primary pediatric spinal AT/RT are exceedingly rare and only 15 cases have been reported to date. Here we report a very unusual case of primary spinal AT/RT extensively involving the spinal cord from T11 down to the cauda equina. In this patient, the tumor was highly aggressive and resulted in extensive dissemination into the nerve roots and paraspinal soft tissue rapidly resulting in the patient's death 1 month after diagnosis. to the best of our knowledge, this degree of involvement of the spine by a primary AT/RT has not been described before.

"Teratoid" Wilms Tumor: The Extreme End of Heterologous Element Differentiation, Not a Separate Entity.

Wilms tumor (WT) may show a diverse range of heterologous elements (HEs). Cases with predominant/prominent HEs have been reported as "teratoid" WT, albeit on the basis of poorly defined criteria. It has been suggested that "teratoid" WTs are rare, and associated with a poor response to chemotherapy, but a good outcome. However, these claims have not been tested previously in any large cohort of cases. Here, we performed a systematic study to determine the incidence, diversity, and clinicopathologic association of HEs in 691 WTs, all of which were treated according to the same protocol, which included preoperative chemotherapy, and all with central pathology review. We found that 4% (28/691) of WTs showed ≥3 HEs ("teratoid" WT in our study), which was comparable to the numbers of completely necrotic, epithelial, focal anaplastic, and blastemal WTs. "Teratoid" WTs were strongly associated with younger age at presentation (21 vs. 39 mo, P=0.0001), bilateral disease (28.6% vs. 7.2%, P=0.001), stromal-type WT (57.1% vs. 11.0%, P<0.00001), and intralobar nephrogenic rests (35.7% vs. 11.9%, P=0.0001), when compared with non-"teratoid" WT. We also found that stromal-type WT, regardless of HE differentiation, was itself associated with younger age, bilateral disease, and intralobar nephrogenic rest. Furthermore, >80% of cases with ≥3 HEs, and also of cases with 2 HEs and 1 HE, showed ≥50% stroma in their viable components. We conclude that a tendency toward stromal differentiation is a strong and unifying factor in HE formation. "Teratoid" WT represents the more extreme end of HE differentiation, rather than a separate entity, and therefore the term should not be used in the final diagnosis. The prognosis of WTs depends only on their overall histologic type and stage, and it is not additionally influenced by the presence of "teratoid" features.

Trimodality therapy for atypical teratoid/rhabdoid tumor is associated with improved overall survival: A surveillance, epidemiology, and end results analysis.

BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive central nervous system tumors. The use of radiation therapy (RT) remains controversial, especially for patients younger than three years of age. The purpose of the current investigation is to robustly analyze the impact of RT among pediatric AT/RT patients using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: SEER 18 Custom Data registries were queried for AT/RT (ICD-0-3 9508/3). A total of 190 pediatric AT/RT patients were identified, of whom 102 underwent surgery + chemotherapy and 88 underwent trimodality therapy. Univariate and multivariable analyses using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting was performed to account for indication bias. The landmark method was used to account for immortal time bias. RESULTS: The majority of patients were <3 years old (75.8%). Patients <3 were more likely to be treated without RT as compared with older patients (62% vs 38%). Doubly robust MVA identified distant disease as a negative prognostic factor (HR 2.1, P = 0.003), whereas trimodality therapy was strongly protective (HR 0.39, P < 0.001). Infants (<1), toddlers (1-2), and older children (3+) all benefited from trimodality therapy, with largest benefit for infants (HR 0.34, P = 0.02) and toddlers (HR 0.31, P < 0.001). CONCLUSION: The current study provides further evidence that trimodality therapy improves clinical outcomes among patients with AT/RT. This finding was most pronounced for younger patients; therefore, further studies are needed to confirm this finding in this vulnerable population.

Results from the UK Children's Cancer and Leukaemia Group study of extracranial germ cell tumours in children and adolescents (GCIII).

BACKGROUND: For extracranial malignant germ cell tumours (MGCTs) in the UK, the GCII study used carboplatin-based chemotherapy (JEb) and demonstrated equivalent survival to cisplatin-containing protocols. GCIII, a single-arm observational study, used new risk stratification, replaced consolidation chemotherapy with a standard number of cycles and introduced surveillance for all stage I MGCTs. Pure teratomas were registered to understand their natural history. METHODS: Patients with MGCTs were stratified to three risk groups - low risk (LR), intermediate risk (IR) and high risk (HR), using stage and prognostic factors. Patients with alpha fetoprotein (AFP) >10,000 kU/L, stage IV disease (except testis <5 years and all germinomas) or stage II-IV mediastinal tumour were classified HR. Stage I tumours (LR) received chemotherapy only if disease progressed. IR and HR patients received 4 and 6 JEB cycles, respectively. Carboplatin dose was calculated using glomerular filtration rate to give an area under the curve of 7.9 ml/m2.min. RESULTS: Eighty-six patients with MGCTs were enrolled from 2005 to 2009: 59% female, median age, 5.7 years. Twenty-five patients were LR, 21 IR and 38 HR. Seven LR patients had disease progression; all were successfully treated with chemotherapy. Overall survival (OS) for the whole group was 97%; 5-year event-free survival for JEb-treated patients was 92%, and OS, 95%. JEb was well tolerated with no observed significant hearing or renal side-effects. There was no discernible difference in carboplatin dose whether calculated by body surface area or creatinine clearance. Forty-seven patients with teratoma were managed with surgery and one had malignant transformation. CONCLUSION: Carboplatin-based chemotherapy as part of a risk-stratified approach leads to excellent survival in paediatric MGCTs, minimising potential burden of long-term effects.

Impact of Teratoma on the Cumulative Incidence of Disease-Related Death in Patients With Advanced Germ Cell Tumors.

PURPOSE: In men with metastatic germ cell tumors (GCTs), risk-directed treatment is determined, in part, by a distinction between seminoma and nonseminomatous GCT (NSGCT). The importance of NSGCT cell type is uncertain. We evaluated the long-term impact of teratoma on survival in patients with NSGCT. METHODS: Prechemotherapy, primary tumors from patients who received platinum-based chemotherapy were studied, and the histology was confirmed by a genitourinary pathologist. The cumulative incidence of disease-related death (CIDD) was the primary end point, and a competing-risk analysis was performed. RESULTS: Tumors were available from 232 patients, including 193 with NSGCT. An element of teratoma was present in 82 NSGCT primary tumors (42%). With a median follow-up of 17 years (range, 0.3 to 35 years), 58 patients with NSGCT died, 47 as a result of GCT and 11 as a result of other causes. Most GCT deaths occurred within the first 5 years and were associated with pretreatment risk status (P < .001). Death as a result of other causes rose steadily after 15 years and was not associated with risk status (P = .66). A higher CIDD was observed in patients who had NSGCT with teratoma than those with NSGCT without teratoma and seminoma (5-year CIDD rate, 27.4%, 17.4%, and 10.3%, respectively; P = .03). A higher CIDD was observed in patients who had NSGCT with mature teratoma compared with those with either NSGCT with immature teratoma or NSGCT without teratoma (5-year CIDD rate, 38.1%, 19.9%, and 17.4%, respectively; P = .01). CONCLUSION: The presence of teratoma, particularly mature teratoma, in an NSGCT primary tumor is associated with a higher CIDD, consistent with the hypothesis that differentiation is associated with adverse outcomes. Death as a result of non-GCT causes is not associated with risk status and must be separated from GCT death when evaluating long-term survival.