A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal.

The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors.

Combination Therapy of Intravenously Injected Microglia and Radiation Therapy Prolongs Survival in a Rat Model of Spontaneous Malignant Glioma.

Purpose: The aim of this study was to investigate the efficacy of combination therapy with intravenously injected microglia (MI) and radiation therapy (RT) for malignant glioma in rats.

Methods And Materials: Transgenic rats expressing v-erbB and spontaneously developing malignant glioma were used. The rats were divided into 4 groups: control (n = 19), RT alone (n = 10), MI alone (n = 9), and combination MI and RT (MI + RT) (n = 10).

Germline MSH6 Mutation in a Patient With Two Independent Primary Glioblastomas.

We previously reported a patient who had developed 2 glioblastomas at the age of 54 and 64 years, respectively. The first glioblastoma in the right frontal lobe was treated with surgery and radiotherapy. Ten years later, the patient developed a second, left frontal glioblastoma.

CASP9 germline mutation in a family with multiple brain tumors.

We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which three brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features.

Braf Mutations Initiate the Development of Rat Gliomas Induced by Postnatal Exposure to N-Ethyl-N-Nitrosourea.

A single dose of N-ethyl-N-nitrosourea (ENU) during late prenatal or early postnatal development induces a high incidence of malignant schwannomas and gliomas in rats. Although T->A mutations in the transmembrane domain of the Neu (c-ErbB-2) gene are the driver mutations in ENU-induced malignant schwannomas, the molecular basis of ENU-induced gliomas remains enigmatic. We performed whole-genome sequencing of gliomas that developed in three BDIV and two BDIX rats exposed to a single dose of 80 mg ENU/kg body weight on postnatal day one.

The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.

The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered.

Molecular subgroups of adult medulloblastoma: a long-term single-institution study.

Background: Recent transcriptomic approaches have demonstrated that there are at least 4 distinct subgroups in medulloblastoma (MB); however, survival studies of molecular subgroups in adult MB have been inconclusive because of small sample sizes. The aim of this study is to investigate the molecular subgroups in adult MB and identify their clinical and prognostic implications in a large, single-institution cohort.

Methods: We determined gene expression profiles for 13 primary adult MBs.

Glioblastoma in the Canton of Zurich, Switzerland revisited: 2005 to 2009.

Background: A population-based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009.

Methods: Patients with glioblastoma who were diagnosed between 2005 and 2009 were identified by the Zurich and Zug Cancer Registry.

Epidemiology.

More than 250,000 new cases of primary malignant brain tumors are diagnosed annually worldwide, 77% of which are gliomas. A small proportion of gliomas are caused by the inheritance of rare high-penetrance genetic variants or high-dose radiation. Since 2009, inherited genetic variants in 10 regions near eight different genes have been consistently associated with glioma risk via genome-wide association studies.

Cancer prevention as part of precision medicine: 'plenty to be done'.

Cancer burden worldwide is projected to rise from 14 million new cases in 2012 to 24 million in 2035. Although the greatest increases will be in developing countries, where cancer services are already hard pressed, even the richest nations will struggle to meet demands of increasing patient numbers and spiralling treatment costs. No country can treat its way out of the cancer problem.

Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma.

The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly.

Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas.

Schwannomas are benign nerve sheath tumors composed of well-differentiated Schwann cells. Other than frequent NF2 (neurofibromatosis type 2) mutations (50%-60%), their molecular pathogenesis is not fully understood. LATS1 and LATS2 are downstream molecules of NF2 and are negative regulators of the yes-associated protein (YAP) oncogene in the Hippo signaling pathway.

Alterations of the RRAS and ERCC1 genes at 19q13 in gemistocytic astrocytomas.

Gemistocytic astrocytoma (World Health Organization grade II) is a rare variant of diffuse astrocytoma that is characterized by the presence of neoplastic gemistocytes and has a significantly less favorable prognosis. Other than frequent TP53 mutations (>80%), little is known about its molecular profile. Here, we show that gemistocytic astrocytomas carry a lower frequency of IDH mutations than fibrillary astrocytomas (74% vs 92%; p = 0.

Olig2 labeling index is correlated with histological and molecular classifications in low-grade diffuse gliomas.

Diagnosis of low-grade diffuse gliomas based on morphology is highly subjective and, therefore, is often difficult, with significant intra- and interobserver variability. Here, we investigated WHO grade II diffuse astrocytomas, oligoastrocytomas and oligodendrogliomas for immunohistochemical expression of Olig2, measuring its labeling index (LI), and evaluated the significance of Olig2 LI in the histological and molecular classifications. The means of Olig2 LI in glioma cells were 43.

TP53, MSH4, and LATS1 germline mutations in a family with clustering of nervous system tumors.

Exome DNA sequencing of blood samples from a Li-Fraumeni family with a TP53 germline mutation (codon 236 deletion) and multiple nervous system tumors revealed additional germline mutations. Missense mutations in the MSH4 DNA repair gene (c.2480T>A; p.

International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading.

Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties.

MiR-22 is frequently downregulated in medulloblastomas and inhibits cell proliferation via the novel target PAPST1.

Medulloblastoma is the most frequent malignant central nervous system tumor in children. MicroRNAs (miRs) are small, non-coding RNAs that target protein-coding and non-coding RNAs, and play roles in a variety of cellular processes through regulation of multiple targets. In the present study, we analyzed miR-22 expression and its effect in cell proliferation and apoptosis in medulloblastomas.

TERT promoter mutations in primary and secondary glioblastomas.

Telomerase reverse transcriptase (TERT) is up-regulated in a variety of human neoplasms. Mutations in the core promoter region of the TERT gene, which increases promoter activity, have been reported in melanomas and a variety of human neoplasms, including gliomas. In the present study, we screened for TERT promoter mutations by direct DNA sequencing in a population-based collection of 358 glioblastomas.

Characterization of microglia/macrophages in gliomas developed in S-100β-v-erbB transgenic rats.

Glioma-infiltrating microglia/macrophages are referred to as tumor-associated macrophages (TAMs). Transgenic (TG) rats expressing v-erbB, which is a viral form of the epidermal growth factor receptor, under transcriptional regulation by the S100-β promoter, develop brain tumors. This study was designed to clarify the pathological characteristics of TAMs in these experimental tumors.

PDGFRA gain in low-grade diffuse gliomas.

Glioblastomas with a proneural expression signature are characterized by frequent IDH1 mutations (i.e. genetic hallmarks of secondary glioblastomas) and PDGFRA (platelet-derived growth factor receptor-α) amplification.

The definition of primary and secondary glioblastoma.

Glioblastoma is the most frequent and malignant brain tumor. The vast majority of glioblastomas (~90%) develop rapidly de novo in elderly patients, without clinical or histologic evidence of a less malignant precursor lesion (primary glioblastomas). Secondary glioblastomas progress from low-grade diffuse astrocytoma or anaplastic astrocytoma.

DMBT1 homozygous deletion in diffuse astrocytomas is associated with unfavorable clinical outcome.

Primary glioblastomas develop with a short clinical history, without evidence for less malignant precursor lesions, while secondary glioblastomas slowly develop via progression from diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The time until progression and the clinical outcome of diffuse astrocytomas vary significantly. We have shown that IDH1 mutations reliably distinguish between primary glioblastomas (without IDH1 mutations) and secondary glioblastomas (with IDH1 mutations).

MET gain in diffuse astrocytomas is associated with poorer outcome.

Glioblastoma may develop rapidly without evidence for precursor lesions (primary glioblastomas), or progress from diffuse or anaplastic astrocytomas (secondary glioblastomas). Despite having distinct genetic profiles, these glioblastoma subtypes have similar histological features. We hypothesized that the highly malignant phenotype of glioblastoma may be attributable to genetic alterations that are common to both glioblastoma subtypes.