The role of neoadjuvant chemotherapy in the management of metastatic central nervous system germinoma: A meta-analysis.

BACKGROUND: The role of neoadjuvant chemotherapy in treating patients with metastatic central nervous system (CNS) germinoma is controversial. METHODS: We compared the relapse-free survival (RFS) of different treatment modalities by performing a meta-analysis using published data. We summarized all data using standard descriptive statistics. We used the Kaplan-Meier method to estimate RFS and their corresponding 95% confidence intervals (CIs). We used the log-rank test for the comparison of survival functions. RESULTS: We identified 97 patients with a median age at presentation of 15 years (range: 7-38). Sites of metastasis were cerebrospinal fluid (CSF) disease only (n = 12), brain parenchyma (n = 18), spinal cord (n = 9), ventricular and CSF (n = 10), ventricular only (n = 31), and other (n = 17). The 3-year RFS among patients who received any form of radiotherapy was 89% (95% CI: 83-96) compared with 0% for patients who received a chemotherapy-only regimen (p = .001). Five-year RFS among patients who received craniospinal irradiation (CSI) was 92% (95% CI: 84-100) compared with 76.4% (95% CI: 63-90) in the non-CSI group (with or without neoadjuvant chemotherapy) (p = .014). Five-year RFS of patients who received CSI less than 24 Gy with neoadjuvant chemotherapy was 100% compared with 92% (95% CI: 83-100) CSI dose greater than or equal to 24 Gy alone (p = .3). CONCLUSIONS: Our analysis does not support avoiding spinal irradiation among patients with radiographic metastatic CNS germinoma. Future studies are needed to confirm whether neoadjuvant chemotherapy will allow a reduction of irradiation dose without compromising survival.

A Novel Case of Concurrent T-cell and Early T-cell Precursor Lymphoblastic Lymphoma in an Adolescent Female.

In the context of an evolving understanding of early T-cell precursor (ETP) lymphoma and leukemia, we present a case of concurrent T-cell lymphoblastic lymphoma and ETP lymphoma in an adolescent female. To our knowledge, this represents the first reported case of both lymphoblastic lymphoma and ETP lymphoma as distinct and conjoined components of the same neoplasm. As an exception to current literature, our patient had a strictly lymphomatous ETP component with no leukemic manifestation. Her ETP component remained viable following induction, supporting ETP resistance to chemotherapy. The patient remains in remission 4 years postallogeneic matched sibling donor bone marrow transplant.

Prognostic factors for patients with relapsed central nervous system nongerminomatous germ cell tumors.

We aimed toidentify prognostic factors that may help better understand the behavior of relapsed central nervous system nongerminomatous germ cell tumors. We identified nine studies, including 101 patients; 33 patients (33%) were alive 12 months post-initial relapse. Sixty percent of patients with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level ≤25 ng/mL at initial diagnosis were survivors compared with 28% among patients with serum/CSF AFP level >25 ng/mL (P = 0.01). Seventy-one percent of patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy at relapse were survivors compared with 7% among patients who had less than CR/CCR (P < 0.0001). Forty-eight percent of patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) following relapse were survivors compared with 12% among patients who did not receive HDCx/AuHCR (P = 0.0001). Local relapse site, gross total surgical resection, and radiotherapy at relapse were not associated with improved outcomes.

Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Evaluation of the Pediatric Neuro-Oncology Resources Available in Chile.

PURPOSE: Pediatric neuro-oncology resources are mostly unknown in Chile. We report the human and material resources available in Chilean hospitals providing pediatric neuro-oncology services. METHODS: A cross-sectional survey was distributed to 17 hospitals providing pediatric neuro-oncology services (Programa Infantil Nacional de Drogas Antineoplásicas [PINDA] hospitals, 11; private, 6). RESULTS: Response rate was 71% (PINDA, 8; private, 4). Pediatric neuro-oncology services were mainly provided within general hospitals (67%). Registries for pediatric CNS tumors and chemotherapy-related toxicities were available in 100% and 67% of hospitals, respectively. CNS tumors were treated by pediatric oncologists in 92% of hospitals; none were formally trained in neuro-oncology. The most used treatment protocols were the national PINDA protocols. All WHO essential medicines for childhood cancer were available in more than 80% of the hospitals except for gemcitabine, oxaliplatin, paclitaxel, and procarbazine. The median number of pediatric neurosurgeons per hospital was two (range, 2-6). General neuroradiologists were available in 83% of the centers. Pathology specimens were sent to neuropathologists (58%), adult pathologists (25%), and pediatric pathologists (17%). Intensity-modulated radiotherapy, conformal radiotherapy, and cobalt radiotherapy were used by 67%, 58%, and 42% of hospitals, respectively. Only one private hospital performed autologous hematopoietic cell transplant for children with CNS tumors. CONCLUSION: A wide range of up-to-date treatment modalities are available for children with CNS tumors. Our survey highlights future directions to improve the pediatric neuro-oncology services available in Chile such as the expansion of multidisciplinary clinics, palliative care services, long-term cancer survivorship programs, dedicated clinical research support teams, establishing standardized mechanism for sending pathologic specimen for second opinion to international specialized centers, and establishing specialized neuro-oncology training program.

A Possible Case of Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a Newborn With Positive Placental In Situ Hybridization of SARS-CoV-2 RNA.

Little is known about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the coronavirus disease 2019 (COVID-19) on pregnant mothers and their infants. Moreover, there is no definitive evidence that SARS CoV- 2 can be vertically transmitted from an infected mother to the unborn fetus.

Pineoblastoma in children less than six years of age: The Head Start I, II, and III experience.

BACKGROUND: We report the outcomes of patients with pineoblastoma and trilateral retinoblastoma syndrome enrolled on the Head Start (HS) I-III trials. METHODS: Twenty-three children were enrolled prospectively between 1991 and 2009. Treatment included maximal surgical resection followed by five cycles of intensive chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction. RESULTS: Median age was 3.12 years (range, 0.44-5.72). Three patients withdrew from the study treatment and two patients experienced chemotherapy-related death. Eight patients experienced progressive disease (PD) during induction chemotherapy and did not proceed to HDCx/AuHCR. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range, 18-36 Gy) with boost(s) (median dose 27 Gy; range, 18-36 Gy); three received CSI as adjuvant therapy (two post-HDCx/AuHCR) and four upon progression/recurrence. The five-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95% confidence intervals [CI]: 2.6%-36.0%) and 13% (95% CI: 4.5%-37.5%), respectively. Only three patients survived beyond five years. Favorable OS prognostic factors were CSI (hazard ratio [HR] = 0.30 [0.11-0.86], P = 0.025) and HDCx/AuHCR (HR = 0.40 [0.16-0.99], P = 0.047). CONCLUSIONS: Within the HS I-III trials, CSI and HDCx/AuHCR were statistically associated with improved survival. The high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles prior to consolidation and the potential intensification of consolidation with multiple cycles of marrow-ablative chemotherapy and irradiation.

The Risk of Developing Secondary Central Nervous System Tumors After Diagnostic Irradiation From Computed Tomography in Pediatrics: A Literature Review.

BACKGROUND: Advanced diagnostic imaging has provided tremendous benefits; however, increased use of ionizing radiation modalities such as cranial computed tomography (CT) may be associated with an increased risk of developing central nervous system tumors. METHODS: A literature review identified studies published for more than the last 50 years from 1968 to 2018 that explored the association between head CT scans and developing central nervous system tumors in pediatrics. We reviewed seven studies that described and analyzed the risk of brain tumors. RESULTS: A positive correlation between exposure to CT scans and developing central nervous system tumors was evident in all cohorts. The strength of the association varied across the studies. Exclusion of patients with predisposing factors to central nervous system tumors was examined in four studies with a decreased risk to develop central nervous system tumors noted in three studies. Two studies reported nonsignificant reduction in the excess relative risk per milliGray of brain dose after adjusting for predisposing factors, whereas the reduction was significant in one study. The frequency of CT exposure was proportional to the risk of developing tumors in two studies although not significantly maintained in two other studies. Gender had no significant effect on the central nervous system tumor risk. The calendar year at the time of imaging showed decreasing risk in those exposed to CT in more recent years compared with prior decades. CONCLUSIONS: Prospective epidemiologic studies are needed to examine the precise carcinogenic effect of exposure to ionizing radiation and help tailor further preventive measures.

Critical review of the management of primary central nervous nongerminomatous germ cell tumors.

Multimodal strategies have significantly improved the outcomes for patients with central nervous system nongerminomatous germ cell tumors. Two large cooperative group studies have recently reported much improved outcomes compared with historical series. However, a substantial proportion of patients still attain inadequate responses to initial chemotherapy prior to irradiation, with adverse impact upon survival; optimal induction chemotherapy regimens and radiotherapy strategies are as yet unidentified. Outcomes for patients with relapsed disease remain poor. There is an obvious need to incorporate molecular studies within prospective clinical trials that will likely lead to the incorporation of targeted, more effective future treatment strategies.

Germinoma Involving the Retina: An Unusual Presentation of Recurrent Intracranial Mixed Germ Cell Tumor.

BACKGROUND: We report a patient with primary central nervous system mixed malignant germ cell tumor (GCT) who presented with recurrent malignant germinomatous infiltration of the retina. CASE DESCRIPTION: A 10-year-old girl initially presented with a large suprasellar mixed malignant GCT with a near-complete response after initial induction of chemotherapy and irradiation. Three and a half years after initial therapy, she presented with progressively worsening vision in her left eye. Magnetic resonance imaging showed infiltrative changes within the left optic nerve but no discrete mass. Serum and cerebrospinal fluid tumor markers were not elevated and cerebrospinal fluid cytology was negative. Left optic nerve biopsy confirmed the presence of mature teratoma and pure germinoma components. She was treated with gross-total resection of the left eye and optic nerve and chemotherapy. Histopathologic evaluation of the optic nerve showed only mature teratoma elements, but with pure germinoma cells infiltrating the inner layers of the retina. CONCLUSIONS: Loco-regional extension of suprasellar GCT to the optic nerve is not uncommon; however, to the best of our knowledge, infiltration of the tumor into the retina is not reported in the literature. Early detection of optic pathway involvement and proper delineation of the irradiation field may prevent GCT infiltration of the retina with subsequent vision loss.

The Latin American Brain Tumor Board teleconference: results of a web-based survey to evaluate participant experience utilizing this resource.

PURPOSE: The Latin American Brain Tumor Board (LATB) is a weekly teleconference connecting pediatric neuro-oncologists from referral centers in high-income countries with pediatric subspecialists from 20 Latin American countries since 2013. This survey explored the participants' experience utilizing this resource. METHODS: A cross-sectional electronic questionnaire was distributed to 159 participants through email and Cure4Kids. RESULTS: Ninety-five respondents (60%) from all the participating countries completed the survey. Sixty-one reported frequent-attendance (≥ 1 per month), 23 reported infrequent-attendance (< 1 per month), and 11 never participated. The most frequently reported attendance-barriers were the subspecialist's workload (64%), the timing of the teleconference (38%), and Internet connectivity problems (29%). Subspecialist's workload was more frequently reported as a barrier compared with other barriers, in both the frequent- and infrequent-attendance groups (p < 0.05), with the exception of the timing of the meeting in the infrequent-attendance group. More than 80% of attendees found the frequency and duration of the teleconference were sufficient. Utilizing Spanish as the primary language was reported to enhance the recommendations by 93% of the attendees. Moreover, 84% reported that the recommendations (almost) always fit the local circumstances. Furthermore, 99% of attendees found the teleconference provided a continuing medical education opportunity. Finally, 96% of attendees (almost) always found that the provided recommendations helped to improve the outcomes/quality of life of the patients. CONCLUSIONS: The LATB teleconference provided a valuable tool for the management of pediatric brain tumors in Latin America as it provided a feasible and easy to access continued medical education opportunity for the participants.

Re-induction chemotherapy regimens in patients with recurrent central nervous system mixed malignant germ cell tumors.

BACKGROUND: The lack of a standard treatment approach has contributed to poor outcomes of patients with recurrent central nervous system (CNS) mixed malignant germ cell tumors (MMGCT). There are no data in the literature supporting optimal re-induction chemotherapy regimens that should be used for patients with recurrent CNS MMGCT. METHODS: We conducted a literature review to explore the response rate of patients with recurrent CNS MMGCT to different re-induction chemotherapy regimens by searching PubMed from 1985 through November 2017. Tumors were classified according to Japanese, European, and North American prognostic group classifications determined at initial presentation. RESULTS: Forty-two responses to various re-induction chemotherapy regimens reported in 38 patients were included. Two patients were inevaluable and their responses to re-induction chemotherapy were excluded. Thirty-five responses to various re-induction chemotherapy regimens were evaluable in 33 patients following a first relapse. Six (17%) responses were reported as complete or continuous complete responses, seven (20%) partial responses, two (6%) were stable disease, two (6%) were mixed responses, and 18 (51%) were progressive disease. Five of ten patients treated without platinum-based chemotherapy experienced tumor progression. There was a trend towards a higher rate of tumor progression among histological poor prognostic group patients, and among patients relapsing within 24 months of initial diagnosis; however, it was not statistically significant. CONCLUSIONS: The histological prognostic group and time to relapse may affect the response to re-induction chemotherapy. However, further studies with larger sample size are needed to examine these associations and determine the optimal re-induction chemotherapy regimens for patients with recurrent MMGCT.

Brentuximab-vedotin maintenance following chemotherapy without irradiation for primary intracranial embryonal carcinoma in down syndrome.

BACKGROUND: Germ cell tumors (GCT) are the most common central nervous system (CNS) tumors in individuals with Down syndrome. Patients with Down syndrome treated with CNS irradiation are at increased risk of developing cerebrovascular complications such as moyamoya disease. Embryonal carcinoma components are recognized to be more resistant to conventional chemotherapy and radiotherapy and confer a very poor prognosis. CD30 is a member of the tumor necrosis factor-receptor superfamily. CD30+ has a limited expression in normal cells but is the defining marker for embryonal carcinoma. Brentuximab-vedotin is a novel antibody-drug conjugate consisting of the chimeric anti-CD30 antibody conjugated to an anti-tubulin synthetic analog monomethyl auristatin E. METHODS: A retrospective review of the patient's records was conducted in September 2017. RESULTS: We report upon our management of a teenage girl with Down syndrome and a suprasellar pure embryonal carcinoma utilizing an intensive chemotherapy regimen followed by brentuximab-vedotin without irradiation. The patient received two cycles of carboplatin and etoposide interspersed with one cycle of cyclophosphamide and etoposide for induction followed by three cycles of marrow-ablative thiotepa and carboplatin rescued by autologous hematopoietic stem cell. Finally, She received six cycles of intravenous brentuximab-vedotin. The patient continues without evidence of recurrent tumor by MRI and tumor marker surveillance 24 months since diagnosis, with no adverse sequelae of her treatment. CONCLUSIONS: Brentuximab-vedotin may provide a selective and safe alternative (or adjunct) to radiotherapy in the management of patients with CD30-positive CNS embryonal carcinoma, especially for those patients at high risk of developing irradiation-related complications.

Synchronous Central Nervous System Atypical Teratoid/Rhabdoid Tumor and Malignant Rhabdoid Tumor of the Kidney: Case Report of a Long-Term Survivor and Review of the Literature.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) with synchronous or metachronous extra-CNS disease is a rare childhood malignancy with a dismal prognosis. CASE DESCRIPTION: We report a 7-week-old female with metastatic AT/RT and synchronous malignant rhabdoid tumor of the kidney who received an intensive multimodal approach combining surgical resection, intrathecal chemotherapy, and high-dose chemotherapy with autologous peripheral blood stem cell transplant (PBSCT). She is currently 24 months old without any evidence of disease. In addition, we completed an extensive literature review of cases with CNS AT/RT and synchronous or metachronous extra-CNS primary tumors. To date, 31 pediatric cases have been reported, and the median overall-survival was 6 months after diagnosis. The only 3 survivors received autologous PBSCT, and 2 of these patients had complete resection of their CNS tumor. CONCLUSIONS: The rarity of CNS AT/RT with extra-CNS primary disease and the lack of standard treatment contribute to its reported dismal prognosis. We report a case of a long-term survivor with metastatic AT/RT and synchronous extra-CNS primary tumor. Maximal surgical resection, intrathecal chemotherapy, and consolidative autologous PBSCT may improve prognosis and avoid radiation.