Isocitrate Dehydrogenase-1 (IDH1) is a driver gene in several cancers including brain tumors such as low-grade and high-grade gliomas. Mutations of SMARCB1 were described in atypical teratoid rhabdoid tumors and to date have not been associated with the pathogenesis of medulloblastoma. We report concurrent IDH1 and SMARCB1 mutations in a medulloblastoma patient. We searched the catalogue of somatic mutations in cancer (COSMIC) database and other mutation databases and -to our knowledge- this is the first reported case of medulloblastoma harboring both mutations together. Our patient is a thirteen-year-old male presenting with headache and vomiting at diagnosis. MRI revealed left cerebellar expansive lesion with no evidence of metastasis. A histopathological diagnosis of desmoplastic/nodular medulloblastoma was made after complete resection of the tumor. Immunophenotypic characterization and methylation profiling suggested a medulloblastoma with SHH activation. Next generation sequencing of a panel of 400 genes revealed heterozygous somatic IDH1(p.R132C), SMARCB1(p.R201Q), and CDH11(p.L625T) mutations. The patient was treated according to the HIT-SIOP PNET 4 protocol. He is in complete remission more than two years after diagnosis. In conclusion, increasing use of high throughput sequencing will certainly increase the frequency with which rare mutations or mutation combinations are identified. The exact frequency of this mutation combination and whether it has any particular therapeutic implications or prognostic relevance requires further investigation.
Abstract PURPOSE To evaluate prognostic factors and impact of participation in a randomized trial in non-metastatic medulloblastoma. METHODS AND PATIENTS 382 patients with non-metastatic medulloblastoma aged 4–21 years with primary neurosurgical resections between 2001 and 2011 were enrolled into the HIT 2000 trial and centrally reviewed. Between 2001 and 2006, 176 of these patients participated in the randomized trial HIT-SIOP PNET 4. Three different radiotherapy protocols were applied. Molecular subgroup was available for 157 patients. RESULTS Median follow-up was 6.35 [0.09–13.86] years. The 5-year progression-free (PFS) and overall survival (OS) rates were 80.3 % ± 2.1 % and 86.5 % ± 1.8 %, respectively. On univariate analysis, there was no difference in PFS and OS according to radiotherapy protocols or in patients who participated in the HIT-SIOP PNET 4 trial or not, while histology, molecular subgroup and postoperative residual tumor influenced PFS significantly. Time interval between surgery and irradiation (≤48 days vs. ≥49 days) failed the significance level (p=0.052). On multivariate analyses, molecular subgroup (WNT activated vs. Group3 HR 5.49; p=0.014) and time interval between surgery and irradiation (HR 2.2; p=0.018) were confirmed as independent risk factors. CONCLUSION Using a centralized review system, multiprofessional and multiinstitutional collaboration as established for pediatric brain tumor patients in Germany, and risk-stratified therapy, outcome for non-metastatic medulloblastoma treated within HIT-SIOP PNET4 could be maintained outside the randomized trial. Prolonged time to radiotherapy negatively influenced survival.
Abstract BACKGROUND Front line radiotherapy for diffuse intrinsic pontine glioma (DIPG) remains the only standard of care. Is this still appropriate? PATIENTS AND METHODS We examined survival outcomes across six treatment modalities including I) no treatment (n=19), II) radiotherapy alone (n=38), III) radio-chemotherapy (n=101), IV) radiotherapy and relapse chemotherapy (n=35), V) radio-chemotherapy and relapse chemotherapy (n=163), and VI) radio-chemotherapy and relapse chemotherapy, plus reirradiation (n=54). Data were collected retrospectively using the Society of Pediatric Oncology and Hematology (GPOH) and the SIOPE DIPG Registry. 410 patients were included with radiologically centrally reviewed DIPG, mostly unbiopsied. Of note, the untreated patients and radiotherapy only cohorts chose limited treatment voluntarily. RESULTS Median overall survival (MOS) of the whole cohort was 11 months and progression free survival (PFS) 7 months. PFS was not significantly different between the treatment groups. OS and post-progression survival (PPS) were significantly different between cohorts. For the respective treatment groups, median OS was 3 months (I), 7 months (II), 8 months (III), 13 months (IV), 13 months (V), and 15 months (VI). For only front line vs at least one second line therapy, MOS was 8 months vs 14 months and PPS 2 months vs 5 months. CONCLUSIONS Although subject to biases to some extent, it seems that additional therapies beyond radiation therapy are of benefit to extending survival in DIPG patients. This is at least partially caused by the introduction of reirradiation regimens. To what extent other therapies contribute to survival and quality of life is subject to further investigation.
Posterior fossa atypical teratoid rhabdoid tumor (ATRT) is a rare childhood tumor usually associated with a dismal prognosis. Although upfront surgical gross total resection (GTR) has classically been the first line of treatment, new multimodal treatments, including two-stage surgery, are showing promising results in terms of overall survival (OS) and complication rate. We present a case of a 9-month-old child treated with two-staged surgery and chemotherapy. When deemed risky, multimodal treatments, including staged surgeries, can be a safe alternative to reduce surgical mortality and morbidity. At 23 months old, the patient had normal global development and no major impact on quality of life. We, therefore, discuss the most recent advancements from a treatment perspective, including molecular targeting.
Abstract Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes MSH2 , MSH6 , MLH1 , and PMS2 . The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients’ families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including MSH2 hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics.
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