Recurrence Of Medulloblastoma Research Articles

TRLS-11. PNOC005: ONCOLYTIC MEASLES VIRUS FOR THE TREATMENT OF CHILDREN AND YOUNG ADULTS WITH RECURRENT MEDULLOBLASTOMA OR ATYPICAL TERATOID RHABDOID TUMOR

Abstract BACKGROUND PNOC005 is a phase 1 clinical trial investigating the safety and tolerability of intratumoral or intrathecal administration of oncolytic measles virus (MV-NIS) in children and young adults with recurrent medulloblastoma (MB) or atypical teratoid/rhabdoid tumor (ATRT). METHODS Patients with recurrence of MB or ATRT were stratified into Stratum A (local recurrence) or B (disseminated recurrence). Stratum A patients received MV-NIS directly into the tumor bed at time of surgical resection. Stratum B patients received a single dose of MV-NIS via lumbar puncture. After safety was demonstrated in Stratum A and B, Stratum C was added with repeat dosing on Day 0 and 7 for patients with recurrent disseminated MB. Specimens for viral shedding were collected. Blood was collected on days 0, 4, 7, 14, and 28. RNA-sequencing deconvolution and time-series analysis were performed to estimate the composition and phenotypes of peripheral blood mononuclear cells (PBMCs). RESULTS Thirty-four patients (median age 8.5, range 2-31) enrolled between February 2017 and April 2021, with 23 evaluable patients with MB and 4 with ATRT. One patient experienced a dose-limiting toxicity (grade 3 alanine aminotransferase increase). There were four MV-NIS-related adverse events grade 3 or greater across all strata. Viral shedding was detected in 5 patients, all of which cleared by end-of-treatment. We found a similar gene-expression program in PMBCs that correlated across patients (n=18), which was upregulated at days 4-7 post treatment and consistent with an antiviral response. Concomitant changes in B, T, and natural-killer cell composition and activation were consistent with this interpretation. CONCLUSION This is the first trial investigating intratumoral as well as repeated intrathecal delivery of MV-NIS in children with MB and ATRT. We show that therapy is safe and well-tolerated with minimal adverse effects. Immune markers and biologic correlates preliminarily indicate anti-viral effects in tumors.

Effective re-induction regimen for children with recurrent medulloblastoma.

There is no standard treatment for the recurrence of medulloblastoma, the most common malignant childhood brain tumor, and prognosis remains dismal. In this study, we introduce a regimen that is well-tolerated and effective at inducing remission. The primary objectives of this study were to assess tolerability of the regimen and overall response rate (ORR). A retrospective chart review of patients with recurrent medulloblastoma, treated at two institutions with a re-induction regimen of intravenous irinotecan and cyclophosphamide with oral temozolomide and etoposide, was performed. Demographic, clinicopathologic, toxicity, and response data were collected and analyzed. Nine patients were identified. Median age was 5.75 years. Therapy was well-tolerated with no therapy-limiting toxicities and no toxic deaths. Successful stem cell collection was achieved in all 5 patients in whom it was attempted. ORR after 2 cycles was 78%. Three patients had a complete response, 4 patients had a partial response, 1 patient had stable disease, and 1 patient had progressive disease. Four patients are alive with no evidence of disease (NED), 2 patients are alive with disease, 2 patients have died of disease, and 1 patient died of toxicity related to additional therapy (NED at time of death). This regimen is well-tolerated and effective. Tumor response was noted in the majority of cases, allowing patients to proceed to additional treatment with no or minimal disease. Further study of this regimen in a clinical trial setting is an important next step.

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen

Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. ClinicalTrials.gov Identifier: NCT01356290.

Advanced MRI findings of supratentorial medulloblastoma recurrence in a young adult: a case report and literature review

Advanced MRI findings of supratentorial medulloblastoma recurrence in a young adult: a case report and literature review

XRT-07. LATE-ONSET LYMPHOPENIA DURING CRANIOSPINAL RADIATION IS ASSOCIATED WITH AN INCREASED RISK OF TUMOR RECURRENCE IN NEWLY-DIAGNOSED PEDIATRIC MEDULLOBLASTOMA

Abstract A recent publication (PMID 33556478) demonstrated an increased risk of tumor recurrence in patients with newly-diagnosed pediatric medulloblastoma who have decreased lymphocyte counts early in their course of craniospinal radiation (CSI) (weeks 1 and 2). We set out to confirm this data in an independent population of pediatric patients with newly-diagnosed medulloblastoma. We analyzed 54 patients treated from 1997-2013. All patients that received radiation in or after 2007 received protons. Per standard of care, patients with clinically high-risk disease were treated with 36-39.6 Gy CSI while patients with standard-risk disease received 23.4 Gy. Total dose to the primary site of disease ranged from 54-55.8 Gy. The mean patient age at diagnosis was 8 years. 16/54 (30%) patients developed a recurrence at an average of 30.2 months after diagnosis. Lymphocyte counts were analyzed both as a continuous variable and as CTCAE v5.0 grades (grades 0-2 lymphopenia (ALC >/=500) compared to grade 3 and 4 (ALC<500/mm3)) using Cox regression. As expected, patients with M+ disease had increased risk of tumor recurrence (p=0.001). There was no correlation between risk of tumor recurrence and early lymphopenia (weeks 0-3 radiation). However, in both weeks 4 and 5 of radiation, decreases in ALC closely correlated with an increased risk of tumor recurrence (week 4 p=0.038, week 5 p=0.042). Similarly, patients with grade 3/4 lymphopenia at weeks 4 and 5 of radiation had an increased risk of tumor recurrence (week 4 p=0.040, week 5 p=0.008) compared to those with grade 0-2 lymphopenia. In summary, both M+ disease and lymphopenia during weeks 4 and 5 of radiation correlated with an increased risk of tumor recurrence in pediatric medulloblastoma.

COT-13 OUTCOMES OF MEDULLOBLASTOMA IN KOBE CHILDREN,S HOSPITAL OVER THE RECENT 11 YEARS

Abstract Introduction Medulloblastoma is the most frequent malignant brain tumor in children, which 5-year survival rate have improved to 70-85%. In this study, we retrospectively reviewed outcomes and late complications of 31 medulloblastoma cases treated at our institute from 2010 to 2021. Cases The mean age of the cases was 6.5 years. 22 cases were total resection and 17 were judged to be in the high-risk group. With respect to histopathological diagnosis, 23 cases were classified as classic type, 2 as desmoplastic/nodular type, 2 as with extensive nodularity type, and 4 as anaplastic/large cell type. As for molecular analysis, WNT was 2, SHH was 3 , Group 3 was 3, Group 4 was 8 cases. One case was lost due to relocation. Results 21 patients have no recurrence of medulloblastoma, but two were victims of second cancers. The remaining 19 cases were all in the standard-risk group and survived with a complete reaction (CR). There were 9 cases of recurrence (including disseminated disease) and the survived case after retreatment was only one in the high-risk group which indicated CR. Discussion The 5-year survival rate for patients in standard-risk group at our institution was 92.3%, indicating improved outcomes. The poor prognosis group could be divided in group who developed recurrence or second cancers after 5 years or more and group who indicated insufficient reaction to multimodality treatment and died around 2 years after diagnosis. As late complications, there were 5 cases of higher functional impairment, who were 16.7% of whole cases and almost in the high-risk group. It is necessary to pursue further treatment for the high-risk group and to recognize that the number of survivors of medulloblastoma cases is increasing, and to support for the AYA generation.

COT-14 OUTCOMES OF MEDULLOBLASTOMA IN KOBE CHILDREN,S HOSPITAL OVER THE RECENT 11 YEARS

Abstract Introduction Medulloblastoma is the most frequent malignant brain tumor in children, which 5-year survival rate have improved to 70-85%. In this study, we retrospectively reviewed outcomes and late complications of 31 medulloblastoma cases treated at our institute from 2010 to 2021. Cases The mean age of the cases was 6.5 years. 22 cases were total resection and 17 were judged to be in the high-risk group. With respect to histopathological diagnosis, 23 cases were classified as Classic type, 2 as Desmoplastic/nodular type, 2 as With extensive nodularity type, and 4 as Anaplastic/Large cell type. As for molecular analysis, WNT was 2, SHH was 3 , Group 3 was 3, Group 4 was 8 cases. One case was lost due to relocation. Results 21 patients have no recurrence of medulloblastoma, but two were victims of second cancers. The remaining 19 cases were all in the standard-risk group and survived with a complete reaction (CR). There were 9 cases of recurrence (including disseminated disease) and the survived case after retreatment was only one in the high-risk group which indicated CR. Discussion The 5-year survival rate for patients in standard-risk group at our institution was 92.3%, indicating improved outcomes. The poor prognosis group could be divided in group who developed recurrence or second cancers after 5 years or more and group who indicated insufficient reaction to multimodality treatment and died around 2 years after diagnosis. As late complications, there were 5 cases of higher functional impairment, who were 16.7% of whole cases and almost in the high-risk group. It is necessary to pursue further treatment for the high-risk group and to recognize that the number of survivors of medulloblastoma cases is increasing, and to support for the AYA generation.

INNV-16. SPINAL POST-TREATMENT SURVEILLANCE IN MEDULLOBLASTOMA – A SYSTEMATIC REVIEW OF THE LITERATURE AND CLINICAL TRIALS

Abstract BACKGROUND Monitoring for dissemination in medulloblastoma involves spinal MRIs (sMRIs) and lumbar punctures (LPs). The frequency and duration of these studies vary depending on risk of dissemination; general practice varies between and within institutions. Our goal is to review the current practice in post-treatment monitoring via examination of published data, clinical trial standards, and expert practice. METHODS We reviewed the available literature and accessible clinical trial protocols. Using PRISMA guidelines, we conducted searches of Ovid MEDLINE, Embase, and PubMed to identify studies which detailed relapse rates and patterns, and recommended practice for patients with medulloblastoma aged 3-21 years. Eligible studies from 1990 to present were included. RESULTS Thirteen multi-institutional clinical trials from North America and Europe were analyzed for frequency of post-therapy surveillance with LPs/sMRIs. Several studies (n=8) recommend LPs/sMRIs every 3-6 months in standard risk and every 3 months in high risk disease for two years when initially completing therapy, and then often diverge in frequency after 2 years. Some studies (n=5) did not include post-treatment recommendations. Cumulative data on relapse from available clinical trial reports and single institution studies (n=673 relapses) demonstrated local failure rate of 18.4%, distant failure of 49.1%, and combined distant and local failure of 32.5%. Spine-only relapses were reported to occur in approximately 13-20%, with one small study reporting spine-only relapse rate of 37.5%. DISCUSSION Patterns of recurrence in medulloblastoma have shifted over time as therapeutic approaches have evolved, including more spinal-only recurrences. Standardized guidance regarding surveillance could have significant impact on clinical detection and streamline management to minimize unnecessary examinations. Early detection of recurrent disease could optimize treatment options for providers and families, whether focusing on curative approaches or quality of life.

Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a "MEMMAT-like" Metronomic Antiangiogenic Approach.

Simple SummaryAbout 30% of patients with medulloblastoma experience recurrence, which is usually incurable despite intensive chemotherapy. The aim of our retrospective study was to evaluate a novel combinatorial metronomic antiangiogenic approach (“MEMMAT-like”) for recurrent medulloblastoma consisting of five oral drugs, an intravenous antibody against vascular endothelial growth factor, and intrathecal therapy. The study, conducted between 2006 and 2016, included 29 consecutive patients with first or multiple recurrences treated according to this “MEMMAT-like” strategy and confirmed a significantly longer median overall survival than in previously reported studies. As of 07/2022, 9/29 patients are alive 86 to 164 months after recurrence. Treatment was primarily out-patient and well-tolerated. Toxicities did occur but were manageable. The novel combination significantly improved overall and progression-free survival for patients with recurrent medulloblastoma. A formal study (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) has been completed and is currently being evaluated.Medulloblastoma (MB) recurrence is usually incurable despite intensive therapy including high-dose chemotherapy. An evolving alternative approach to conventional chemotherapy aims at interfering with tumor angiogenesis at different levels. We report on a novel combinatorial metronomic antiangiogenic approach. The study is a retrospective observational study of 29 consecutive patients with first or multiple recurrences prospectively treated according to the MEMMAT strategy (“MEMMAT-like”) before the formal protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) started. The study period was 11/2006 to 06/2016. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by IV bevacizumab and intraventricular therapy consisting of alternating etoposide and liposomal cytarabine. Median overall survival (OS) after recurrence for the whole group was 29.5 months, OS was 48.3 ± 9.3% at three years and 34.5 ± 8.8% at five years, and progression-free survival was 42.0 ± 9.5% at three years and 29.4 ± 9% at five years. As of 07/2022, 9/29 patients are alive 86 to 164 months after the recurrence that prompted the “MEMMAT-like” therapy. Treatment was primarily out-patient and generally well-tolerated. Toxicities did occur but were manageable. In conclusion, antiangiogenic therapy according to the MEMMAT strategy increased median OS of patients with recurrent MB and may lead to long-term survival. Adherence to the protocol, including intraventricular therapy, appears important.

Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma.

SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.

MEDB-58. Risk factors and risk prediction models for medulloblastoma recurrence

BACKGROUND: There is a clear need for systematic appraisal of models/factors predicting medulloblastoma recurrence because clinical decisions about adjuvant treatment are taken on the basis of such variables. METHODS： A total of 273 patients diagnosed with medulloblastoma were retrospectively analyzed. The pre-rediotherapy neutrophile-lymphocyte ratio (NLR) was calculated, and other clinical characteristics were collected such as genetic type , whether with dissemination, degree with excision. The Kaplan-Meier method was used for survival analysis. Cox regression models was used to identify independent prognostic factors. R software was used to develop a nomogram with all the independent prognostic factors included. The prognostic predictive ability of the nomogram was evaluated by Concordance-index (C-index), area under the curve (AUC), and calibration curve. RESULTS: The median median progression-free survival time was 63.8 months in overall cohort. Univariate and multivariate cox hazards regression analysis identified independent prognostic factors associated with the PFS of patients with medulloblastoma to include age, residual tumor volume ＞1.5cm3 after excision, NLR ＞4.5, whether with dissemination before RT, and whether the genetic type is group 3,which were integrated to establish a nomogram. The C-indexes of nomogram were 0.696 and 0.676 in the training and validation cohort, respectively. The AUC of predicting 3-years PFS showed satisfactory accuracy as well (Training cohort: AUC=0.696; Validation cohort: AUC=0.676). The calibration curve showed agreement between the ideal and predicted values. Kaplan-Meier curves based on the PFS showed significant differences between nomogram predictive low-, and high groups (P < 0.001). CONCLUSIONS: We found that pre-treatment NLR was an independent prognostic factor for recurrence or metastasis of medulloblastoma after treatment. In combination with NRL and clinical factors, nomogram has a good prediction of PFS in patients with medulloblastoma after radiotherapy. It has the potential to facilitate more precise risk stratification to guide personalized treatment of medulloblastoma.

MEDB-25. Do extracellular vesicles transfer a multidrug resistant phenotype via ABC transporters in medulloblastoma?

INTRODUCTION: Medulloblastoma is the most common malignant paediatric brain tumour accounting for 20% of all childhood tumours; approximately one-third of patients present with metastatic disease at diagnosis and the outcome for these patients remains very poor. The high frequency of recurrence and metastatic relapse in medulloblastoma supports the idea of intrinsic drug resistance within cells. This work looks at the ATP-binding cassette (ABC) transporters, known to be upregulated in several cancers, and we hypothesise that extracellular vesicles may transfer ABC transporters to surrounding cells, promoting multidrug resistance within tumours. METHODS: The Cavalli dataset, made up of 763 patient samples, was used to assess the gene expression of a number of ABC transporters across medulloblastoma subgroups. ABC transporter gene and protein expression was then further assessed in medulloblastoma cell lines, including drug-tolerant lines, using qPCR and western blot. Cell viability analysis was used to assess changes in drug response. Matched cell and EV protein samples were used for proteomic analysis. RESULTS: Patient gene expression data showed that high expression of two ABC transporters correlated with reduced patient survival in high-risk subgroups. qPCR analysis of medulloblastoma cell lines showed differential subgroup expression patterns. Additionally, qPCR analysis of drug-tolerant cell lines showed significant increases in the expression of specific drug transporters across the subgroups. RNA-seq confirmed the presence of ABC transporter mRNA in exosomes isolated from high-risk medulloblastoma cell lines. Functional studies of EV transference of ABC transporters are ongoing. CONCLUSIONS: Data to date supports the hypothesis that multidrug transporter carrying extracellular vesicles may transfer their multidrug resistant phenotype to surrounding cells in medulloblastoma, promoting drug resistance. Future work will test this hypothesis by knocking down candidate ABC transporters and assessing the effect on transference of drug resistance by extracellular vesicles.

MEDB-21. SOX2+ cells: the perpetrators of medulloblastoma relapse

Pediatric brain tumors are the number one cause of cancer-related death in children, with medulloblastoma being the most common type. While survival in patients with medulloblastoma has dramatically improved since chemotherapy was added to standard of care protocols, still 30% of tumors will recur. As recurrent disease in medulloblastoma patients in considered uniformly lethal, it is key to identify the cells allowing tumor relapse, and their targetable regulators. By analyzing single cell transcriptomic data, we uncovered a population of SOX2 labeled astrocyte like cells resistant to SMO inhibitors in clinical trials. Using SOX2-enriched medulloblastoma cultures, we observed that SOX2+ cells rely on non-canonical GLI signaling to propagate medulloblastoma. Therefore, in vivo inhibition of SHH signaling using functionally different GLI inhibitors depleted the SOX2+ cell pool, what led to less aggressive tumors that lacked the ability to further engraft. Stressing the translational relevance of our findings, a clinically relevant GLI inhibitor not only exhausted SOX2+ cells driving tumor relapse, but increased overall survival in mice harboring medulloblastoma. Our results emphasize the importance of using targeted therapies that deplete SOX2+ cells to prevent medulloblastoma recurrence.

Analysis of risk factors of medulloblastoma recurrence based on the molecular subgroups

Analysis of risk factors of medulloblastoma recurrence based on the molecular subgroups

Medulloblastoma recurrence and metastatic spread are independent of colony-stimulating factor 1 receptor signaling and macrophage survival

Tumor infiltration by immunosuppressive myeloid cells or tumor-associated macrophages (TAMs) contributes to tumor progression and metastasis. In contrast to their adult counterparts, higher TAM signatures do not correlate with aggressive tumor behavior in pediatric brain tumors. While prominent TAM infiltrates exist before and after radiation, the degree to which irradiated macrophages and microglia support progression or leptomeningeal metastasis remains unclear. Patients with medulloblastoma often present with distant metastases and tumor recurrence is largely incurable, making them prime candidates for the study of novel approaches to prevent neuroaxis dissemination and recurrence. Macrophage depletion was achieved using CSF-1 receptor inhibitors (CSF-1Ri), BLZ945 and AFS98, with or without whole brain radiation in a variety of medulloblastoma models, including patient-derived xenografts bearing Group 3 medulloblastoma and a transgenic Sonic Hedgehog (Ptch1+/-, Trp53-/-) medulloblastoma model. Effective reduction of microglia, TAM, and spinal cord macrophage with CSF-1Ri resulted in negligible effects on the rate of local and spinal recurrences or survival following radiation. Results were comparable between medulloblastoma subgroups. While notably few tumor-infiltrating lymphocytes (TILs) were detected, average numbers of CD3+ TILs and FoxP3+ Tregs did not differ between groups following treatment and tumor aggressiveness by Ki67 proliferation index was unaltered. In the absence of other microenvironmental influences, medulloblastoma-educated macrophages do not operate as tumor-supportive cells or promote leptomeningeal recurrence in these models. Our data add to a growing body of literature describing a distinct immunophenotype amid the medulloblastoma microenvironment and highlight the importance of appropriate pediatric modeling prior to clinical translation.

Circulating Lymphocyte Counts Early During Radiation Therapy Are Associated With Recurrence in Pediatric Medulloblastoma.

Decreased peripheral lymphocyte counts are associated with survival after radiation therapy (RT) in several solid tumors, although they appear late during or after the radiation course and often correlate with other clinical factors. Here we investigate if absolute lymphocyte counts (ALCs) are independently associated with recurrence in pediatric medulloblastoma early during RT. We assessed 202 patients with medulloblastoma treated between 2000 and 2016 and analyzed ALC throughout therapy, focusing on both early markers (ALC during week 1 - ALCwk1; grade 3+ Lymphopenia during week 2 - Lymphopeniawk2) and late markers (ALC nadir). Uni- and multivariable regressions were used to assess association of clinical and treatment variables with ALC and of ALC with recurrence. Thirty-six recurrences were observed, with a median time to recurrence of 1.6 years (range, 0.2-10.3) and 7.1 years median follow-up. ALC during RT was associated with induction chemotherapy (P < .001), concurrent carboplatin (P = .009), age (P = .01), and high-risk status (P = .05). On univariable analysis, high-risk disease (hazard ratio = 2.0 [1.06-3.9]; P= .03) and M stage≥1 (hazard ratio = 2.2 [1.1-4.4]) were associated with recurrence risk, as was lower ALC early during RT (ALCwk1, hazard ratio = 0.28 [0.12-0.65]; P = .003; Lymphopeniawk2, hazard ratio = 2.27 [1.1-4.6]; P = .02). Neither baseline ALC nor nadir correlated with outcome. These associations persisted when excluding carboplatin and pre-RT chemotherapy patients, and in the multivariable analysis accounting for confounders lymphocyte counts remained significant (ALCwk1, hazard-ratio = 0.23 [0.09-0.57]; P = .002; Lymphopeniawk2, hazard-ratio = 2.3 [1.1-4.8]; P = .03). ALC during weeks 1 and 2 of RT was associated with recurrence, and low ALC is an independent prognostic factor in medulloblastoma. Strategies to mitigate the risk of radiation-induced lymphopenia should be considered.

Survival of children with recurrent medulloblastoma undergoing sequential therapy: an analysis of 101 cases

OBJECTIVE To study the clinical features of children with recurrent medulloblastoma (MB) and treatment regimens. METHODS A retrospective analysis was performed on 101 children with recurrent MB who were admitted to the hospital from August 1, 2011 to July 31, 2017. The children were followed up to July 31, 2020. The Kaplan-Meier method was used for survival analysis. The Cox regression model was used for multivariate regression analysis. RESULTS Of the 101 children, 95 underwent remission induction therapy, among whom 51 had response, resulting in a response rate of 54%. The median overall survival (OS) time after recurrence was 13 months, and the 1-, 3-, and 5-year OS rates were 50.5%±5.0%, 19.8%±4.0%, and 10%±3.3% respectively. There was no significant difference in the 5-year OS rate between the children with different ages ( 0.05). There were significant differences in the 5-year OS rate between the children with or without reoperation after recurrence and between the children with different recurrence sites (P < 0.05). The children with reoperation after recurrence had a significantly longer survival time than those without reoperation (P=0.007), and the risk of death in children undergoing reoperation after recurrence was 0.389 times (95% confidence interval:0.196-0.774) that in children who did not undergo such reoperation. CONCLUSIONS As for the recurrence of MB, although remission induction therapy again can achieve remission, such children still have a short survival time. Only reoperation can significantly prolong survival time, and therefore, early reoperation can be considered to improve the outcome of children with recurrent MB.

LINC-41. TREATMENT OF RECURRENT MEDULLOBLASTOMA IN CHILDREN IN LOW INCOME SETTINGS

INTRODUCTIONChildren with recurrent medulloblastoma after initial therapy have very poor prognosis due to limited second line treatment options and significant treatment-related morbidity.METHODSA retrospective chart review of 18 children with recurrent or progressive medulloblastoma, treated initially with risk-adapted therapy in Western Ukrainian Specialized Pediatric Medical Centre from 2012 to 2019, was performed.RESULTSAll patients received first line multimodal treatment: surgery, distant beam radiotherapy and chemotherapy. Recurrent disease in 11 patients presented with metastatic dissemination and in 7 patients as local relapse. The median time to recurrence was 10 months. The median follow-up after diagnosis of recurrent disease diagnosed was 2 years and 2 months. Second line therapy included re-surgery (5 cases), radiation therapy (10 cases) and various cytostatic agents as monotherapy or combination - carboplatin, cisplatin, cyclophosphamide, etoposide, methotrexate, temozolomide, lomustine. Patients treated with radiotherapy for salvage had prolonged local control compared to those that received chemotherapy only. On follow-up 8 children are currently alive.CONCLUSIONRecurrent and progressive medulloblastoma had a poor prognosis with a 2-year overall survival (OS) of 28% on different salvage therapy. The variety in the treatment of all patients experiencing recurrence was observed due to low income country settings. The factors that influenced higher survival after recurrence of medulloblastoma were longer time to relapse, and local pattern of relapse/progression.

MBCL-26. FACTORS ASSOCIATED WITH LONGER SURVIVAL AFTER FIRST RECURRENCE IN MEDULLOBLASTOMA BY MOLECULAR SUBGROUP AFTER RISK-BASED INITIAL THERAPY

OBJECTIVETo evaluate differences in time to recurrence among molecular subgroups of medulloblastoma treated on a single protocol and to identify factors associated with survival after first recurrence.METHODSTime to recurrence following SJMB03 treatment was compared across methylation subgroups among relapsed patients. Therapies received subsequent to relapse were noted. Kaplan-Meier methods and log-rank tests were used for statistical analyses.RESULTS74 of 330 medulloblastoma patients developed recurrence after initial therapy. (38 Standard-Risk; 36 High-Risk). The 2- and 5-year survival after first recurrence was 30.4% and 14.6% respectively. DNA methylation-based subgroups from initial diagnosis were SHH (n=14), Group 3 (n=24), Group 4 (n=26), and unclassified (n=8). None of the pts with WNT MB had recurrent disease. Median time to first recurrence was 1.23, 0.91, and 3.09 years in SHH, Group3, and Group 4 respectively. Group 4 patients had longer post-recurrence survival than others (p-value=0.0169). Clinical risk at diagnosis (p-value=0.337), anaplasia (p-value=0.4032), TP53 (p-value=0.1969), MYC (p-value=0.8967), and MYCN (p value = 0.9404) abnormalities were not associated with post progression survival. Patients who received any therapeutic modality (chemotherapy, re-radiation and second surgery) had longer survival and those who had all three (n=10) had the best outcome (p-value<0.0001).CONCLUSIONOutcome after recurrence in medulloblastoma is dismal, however, association with subgroups is still present. Group 4 patients had a longer time to recurrence and post progression survival. No other prognostic factor at initial diagnosis was associated with outcome after recurrence. Patients who received all 3 types of conventional therapy had better survival.

MBRS-39. MAP4K4 CONTROLS PRO-INVASIVE SIGNALING IN MEDULLOBLASTOMA CELLS

The molecular mechanisms contributing to distant dissemination and local recurrence of medulloblastoma, the most common malignant brain tumor in childhood, are poorly understood and no targeted anti-invasion therapies exist till date. We explored regulators and effectors of MAP4K4, a pro-invasive kinase overexpressed in MB and associated with metastatic progression in different solid malignancies. MAP4K4 is upregulated both at mRNA and protein levels in primary pediatric brain tumors compared to normal cerebellum. MAP4K4 is required for growth factor- and irradiation-induced migration and invasion of medulloblastoma cells. It furthermore promotes turnover and activation of the receptor tyrosine kinase c-Met and of the ß1 integrin adhesion receptor 1. To characterize these clinically relevant consequences and to identify druggable targets of MAP4K4 function, we profiled the interactome of MAP4K4 in starved and growth factor stimulated medulloblastoma cells. To systematically address MAP4K4 impact on receptor expression and turnover, we determined the MAP4K4-dependent surface proteome in medulloblastoma cells. We found that MAP4K4 is part of the striatin-interacting phosphatase and kinase (STRIPAK) complex and that STRIPAK component striatin 4 is controlling cell motility and invasiveness in medulloblastoma cells. Invasiveness of medulloblastoma cells is abrogated by a truncation mutant of MAP4K4 lacking the striatin 4 interaction domain. We furthermore found that MAP4K4 mediates growth factor-induced surface expression of solute carriers and immunomodulatory proteins involved in chemoresistance and immune evasion. Thus, our study identified MAP4K4 as a missing link between pro-tumorigenic growth factor signaling and tumor cell functions relevant for disease progression. It may help identifying druggable vulnerabilities in medulloblastoma cells to restrict tumor growth and dissemination. 1. Tripolitsioti, D. et al., Oncotarget9, 23220–23236 (2018).