Isochromosome 17q Is a Negative Prognostic Factor in Poor-Risk Childhood Medulloblastoma Patients

Pan, Edward; Pellarin, Malgorzata; Holmes, Emi; Смирнов, Иван; Misra, Ankita; Eberhart, Charles G.; Burger, Peter C.; Biegel, Jaclyn A.; Feuerstein, Burt G.

doi:10.1158/1078-0432.ccr-04-0465

Cited by 80 publications

(13 citation statements)

References 31 publications

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“…Isochromosome 17q (i17q) is one of the most frequent recurring abnormalities in medulloblastoma, occurring in approximately 40-50% of cases, predominantly within the Group 4/D subtype in adults. 7 It has been reported to be a negative prognostic factor; 8,9 in childhood medulloblastoma, it has been commonly associated with mutations in TP53 and desmoplastic histology 10 , which was consistent with what we found in our case despite its occurrence in an adult. A predominant difference is that studies in the childhood form associated 17p loss with the SHH subgroup.…”

Section: Clinical Case Reportsupporting

confidence: 92%

Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib

Lou

Schomaker

Wilson

et al. 2016

Cancer Biology & Therapy

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Medulloblastoma is an aggressive primitive neuroectodermal tumor of the cerebellum that is rare in adults. Medulloblastomas fall into 4 prognostically significant molecular subgroups that are best defined by experimental gene expression profiles: the WNT pathway, sonic hedgehog (SHH) pathway, and subgroups 3 and 4 (non-SHH/WNT). Medulloblastoma of adults belong primarily to the SHH category. Vismodegib, an SHH-pathway inhibitor FDA-approved in 2012 for treatment of basal cell carcinoma, has been used successfully in the setting of chemorefractory medulloblastoma, but not as a first-line therapy. In this report, we describe a sustained response of an unresectable multifocal form of adult medulloblastoma to vismodegib. Molecular analysis in this case revealed mutations in TP53 and a cytogenetic abnormality, i17q, that is prevalent and most often associated with subgroup 4 rather than the SHH-activated form of medulloblastoma. Our findings indicate that vismodegib may also block alternate, non-canonical forms of downstream SHH pathway activation. These findings provide strong impetus for further investigation of vismodegib in clinical trials in the first-line setting for pediatric and adult forms of medulloblastoma.

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Section: Clinical Case Reportsupporting

confidence: 92%

Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib

Lou

Schomaker

Wilson

et al. 2016

Cancer Biology & Therapy

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“…Eberhart et al have shown that moderate to severe anaplasia in medulloblastoma cells is also associated with poor survival [6]. Additionally, large-scale genomic changes such as isochromosome 17q, with loss of chromosome 17p and gain of 17q, present in 30–50 % of medulloblastomas, are associated with poor prognosis [7, 8]. …”

Section: Introductionmentioning

confidence: 99%

Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience

et al. 2013

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Purpose Chemotherapy for relapsed medulloblastoma has been inadequate, and most patients succumb to disease. Methods We retrospectively reviewed nine cases of relapsed medulloblastoma treated with bevacizumab, irinotecan, ±temozolomide. Patients received one to three prior therapeutic regimens. Five patients received 10 mg/kg bevacizumab and 125–150 mg/m2 irinotecan IV every 2 weeks, with temozolomide, starting at a median dose of 150 mg/m2 orally for 5 days monthly. Two patients received bevacizumab and irinotecan, but not temozolomide, due to provider preference. Two of nine patients received 15 mg/kg bevacizumab IV, 90 mg/m2 irinotecan orally for five consecutive days, 100 mg/m2/day temozolomide IV for 5 days, and 1.5 mg/m2 vincristine IV, each administered every 21 days. Results Median time to progression was 11 months. Median overall survival was 13 months. Objective tumor response at 3 months was 67 %, including six patients with partial response (PR) and three patients with stable disease (SD). At 6 months, objective response was 55 %, with two patients with PR and three with complete response. Additionally, one patient had SD and three had PD. Two patients remain alive and progression free at 15 and 55 months; another is alive with disease at 20 months. Toxicities included two patients with grade III neutropenia, two with grade III thrombocytopenia, one with grade III elevation of liver function tests, and one patient with grade III diarrhea. Conclusions The combination of bevacizumab and irinotecan, with or without temozolomide, produces objective responses with minimal toxicity in children with recurrent medulloblastoma. Prospective clinical trials are needed to evaluate the efficacy of this strategy.

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“…Presence of isochromosome 17q serves as a negative prognosis indicator [12]. The mechanism by which this abnormality plays a role in tumorigenesis has not been clearly elucidated.…”

Section: Biologymentioning

confidence: 99%

“…Chromosome arm17p contains several tumor supressor genes, and thus it is postulated that deletion of this gene region may be the culprit. One of these genes is the tumor suppressor p53 [9, 12–14]. …”

Section: Biologymentioning

confidence: 99%

Medulloblastoma—Biology and Microenvironment:A Review

Byrd

Grossman

Ahmed

2012

Pediatric Hematology and Oncology

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Isochromosome 17q Is a Negative Prognostic Factor in Poor-Risk Childhood Medulloblastoma Patients

Cited by 80 publications

References 31 publications

Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib

Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib

Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience

Medulloblastoma—Biology and Microenvironment:A Review

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