Clinical outcomes and patient-matched molecular composition of relapsed medulloblastoma

© 2021 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.info:eu-repo/semantics/publishedVersio

PENTACET data:23 million contextual code comments and 250,000 SATD comments

Abstract Most Self-Admitted Technical Debt (SATD) research utilizes explicit SATD features such as ‘TODO’ and ‘FIXME’ for SATD detection. A closer look reveals several SATD research uses simple SATD (‘Easy to Find’) code comments without contextual data (preceding and succeeding source code context). This work addresses this gap through PENTACET (or 5C dataset) data. PENTACET is a large Curated Contextual Code Comments per Contributor and the most extensive SATD data. We mine 9,096 Open Source Software Java projects totaling over 400 million LOC. The outcome is a dataset with 23 million code comments, preceding and succeeding source code context for each comment, and more than 250,000 SATD comments, including both ‘Easy to Find’ and ‘Hard to Find’ SATD. We believe PENTACET data will further SATD research using Artificial Intelligence techniques

Data balancing improves self-admitted technical debt detection

Abstract A high imbalance exists between technical debt and non-technical debt source code comments. Such imbalance affects Self-Admitted Technical Debt (SATD) detection performance, and existing literature lacks empirical evidence on the choice of balancing technique. In this work, we evaluate the impact of multiple balancing techniques, including Data level, Classifier level, and Hybrid, for SATD detection in Within-Project and Cross-Project setup. Our results show that the Data level balancing technique SMOTE or Classifier level Ensemble approaches Random Forest or XGBoost are reasonable choices depending on whether the goal is to maximize Precision, Recall, F1, or AUC-ROC. We compared our best-performing model with the previous SATD detection benchmark (cost-sensitive Convolution Neural Network). Interestingly the top-performing XGBoost with SMOTE sampling improved the Within-project F1 score by 10% but fell short in Cross-Project set up by 9%. This supports the higher generalization capability of deep learning in Cross-Project SATD detection, yet while working within individual projects, classical machine learning algorithms can deliver better performance. We also evaluate and quantify the impact of duplicate source code comments in SATD detection performance. Finally, we employ SHAP and discuss the interpreted SATD features. We have included the replication package1 and shared a web-based SATD prediction tool2 with the balancing techniques in this study

Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma

PURPOSE: To determine the role of amifostine as a protectant against cisplatin-induced ototoxicity in patients with average risk (AR) medulloblastoma treated with craniospinal radiotherapy and 4 cycles of cisplatin-based dose-intense chemotherapy and stem cell rescue. PATIENTS AND METHODS: The primary objective was to determine whether, in patients with AR medulloblastoma (n=62), amifostine would decrease the need for hearing aids (defined as ≥ grade 3 ototoxicity in one ear) compared to a control group (n=35), one year from initiating treatment. (Figure 1) Ninety-seven patients received CSI (23.4 Gy) followed by 55.8 Gy to the primary tumor bed, using 3-D conformal technique and 4 cycles of high-dose cyclophosphamide (4000 mg/m(2) per cycle), cisplatin (75 mg/m(2) per cycle), and vincristine (two 1.5 mg/m(2) doses per cycle) and stem cell rescue. When used, amifostine (600 mg/m(2) per dose) was given as a bolus immediately prior to and 3 hours into the cisplatin infusion. RESULTS: The median age of the 97 patients was 8.7 years (range, 3.2–20.2 years). The study and control groups were similar in age and sex distribution. Amifostine was well-tolerated. One year after treatment initiation, 13 (37.1%) of the control-group versus 9 (14.5%; p=0.005 Chi-Square one-sided test) of the amifostine-treated patients had ≥ grade 3 ototoxicity, requiring hearing aid in at least one ear. CONCLUSION: Amifostine administered prior to and during the cisplatin infusion can significantly reduce the risk of severe ototoxicity in patients with AR medulloblastoma receiving dose-intense chemotherapy

Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog–Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032

PURPOSE: Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB). PATIENTS AND METHODS: Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available. RESULTS: A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH–MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses. CONCLUSION: Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH–MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit