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The WHO classifications of 2017 and 2022 recommend the use of pituitary transcription factors PIT-1, T-PIT and SF-1 as well as GATA3 and ERα for histopathological diagnosis. The aim of this study is to demonstrate their diagnostic impact in a large retrospective cohort. 921 PitNETs/PAs diagnosed in our department between October 2004 and April 2018 were retrospectively reassessed according to the WHO classifications 2017 and 2022. The original classification (WHO 2004) and the clinical data were retrieved from the patient records. Hormone-immunonegative null cell adenomas represented the largest subgroup (397 of 921) in the WHO 2004 classification. Of these, 377 were reclassified as gonadotroph PitNETs/PAs, and 14 were assigned to a non-gonadotroph hormone-producing cell line. Only 6 cases remained null cell tumors. 27 of 35 plurihormonal adenomas were assigned to a specific cell line in the 2017 and 2022 WHO classifications. Of 489 adenomas formerly classified as expressing of 1 or 2 hormones, the histopathological diagnosis was confirmed in 459 cases with the use of TP. Of the remaining 30 cases, 12 cases with positive immunostaining of 2 hormones could be assigned to a single cell line, and 18 cases changed their lineage. The correct correlation with clinical data significantly improved from 75.4% (WHO 2004) to 96.2% (WHO 2017 and 2022). Corticotroph PitNETs showed the highest risk for recurrence (21.9%) and progression (55.8%). The new classification enables more accurate (sub)classification and significantly improves clinicopathological correlation. In individual cases, it is essential to consider the reclassification to predict the clinical prognosis and to schedule the follow-up accordingly.

Background Treatment options for oncological diseases have been enhanced by the advent of targeted therapies. The point mutation of the BRAF gene at codon 600 (BRAF V600E) is found in several tumor entities and can be approached with selective inhibitory antibodies. The BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases and in other cancer diseases. Therefore the BRAF V600E mutation is a highly interesting oncological target in brain tumors. Methods This study assesses the BRAF V600E mutation status in 969 intracranial neoplasms using a tissue microarray method and immunohistochemical staining with the mutation-specific VE-1 antibody, followed by sequencing of positively stained cases. Results Out of 784 primary brain tumors seven cases with a BRAF V600E mutation were detected (7/784, 1 %). Six of these cases were neuroepithelial tumors (6/667, 1 %) encompassing 2 astrocytomas WHO grade II (2/42, 5 %), 1 gliosarcoma WHO grade IV (1/75, 1 %) and 3 glioblastomas WHO grade IV (3/312, 1 %). Interestingly, all three mutant glioblastomas showed epithelioid histopathological features. Patients with V600E mutated astrocytic tumors were significantly younger (mean age 15.3 years) than wildtype cases (58.2 years). Among three rhabdoid meningiomas, one case was mutated (1/3) while all other grade I-III meningiomas (1/116, 1 %) and all fifty vestibular schwannomas analyzed were of wildtype status. The vast majority of the BRAF V600E mutations were found in cerebral metastases of malignant melanomas and carcinomas (29/135, 22 %), with false-positive staining found in four breast cancer cases and two non-small-cell lung carcinoma (NSCLC) samples. Conclusions Our data suggest routine screening for BRAF V600E mutations for glioblastomas WHO grade IV below the age of 30, especially in glioblastomas with epithelioid features and in all rhabdoid meningiomas WHO grade III. For colorectal carcinoma, thyroid cancer, malignant melanoma and gliomas BRAF V600E immunostaining is sufficient for screening purposes. We also recommend routine immunohistochemical staining followed by sequencing validation in rare CNS metastases or metastases of unknown primary. Immunohistochemical analysis using mutation-specific antibodies on tissue microarrays is a feasible, time- and cost-efficient approach to high-throughput screening for specific mutations in large tumor series but sequencing validation is necessary in unexpected cases.

Background Medical students show varying clinical practical skills when entering their final year clinical clerkship, which is the final period to acquire and improve practical skills prior to their residency. We developed a one-on-one mentoring program to allow individually tailored teaching of clinical practical skills to support final year students with varying skill sets during their neurosurgical clinical clerkship. Methods Each participating student ( n  = 23) was paired with a mentor. At the beginning students were asked about their expectations, teaching preferences and surgical interest. Regular meetings and evaluations of clinical practical skills were scheduled every 2 weeks together with fixed rotations that could be individually adjusted. The one-on-one meetings and evaluations with the mentor gave each student the chance for individually tailored teaching. After completion of the program each student evaluated their experience. Results The mentoring program was well received by participating students and acquisition or improvement of clinical practical skills was achieved by most students. A varying practical skill level and interest in the field of surgery was seen. Conclusions A neurosurgical one-on-one mentoring program is well received by final year medical students and allows for individually tailored learning of clinical practical skills.

Background The extent of resection (EOR) is known to impact recurrence free survival in vestibular schwannomas (VS). Identifying predictive factors for complete resection may direct treatment decisions in the future. In recent years there is increasing evidence for the involvement of inflammatory processes in the development and growth of VS. It is currently unclear whether inflammatory changes may also play a role in the extent of resection in VS. Methods In this retrospective study, we analyzed clinical data, tumor extension, cystic characteristics and immunohistochemical markers for inflammation (CD68, CD163, CD3, CD8) and proliferation (MIB-1) as potential factors influencing the EOR in 1007 surgically treated primary sporadic VS. With CART-determined specific cut-offs for each inflammation marker, a common inflammatory score from 0 to 2 was determined. Univariate and multivariate analyses were performed for the EOR. Results Total resection was achieved in 86.5% of cases. Incomplete resection was associated with advanced age ( p  = 0.0002), larger tumor size ( p  < 0.0001) and cystic characteristics on preoperative imaging ( p  < 0.0001). Increased expression of CD163, CD68 and CD3 ( p  < 0.0001, p  = 0.0015 and p  = 0.0024 respectively) was associated with partial tumor resection (PR). CD8 was significant when its CART-determined cut-off was considered ( p  = 0.0032). A higher inflammatory score was significantly connected to partial resection ( p  < 0.0001). In the multivariate analysis, larger size ( p  < 0.0001), older age ( p  = 0.0051), cystic characteristics ( p  = 0.0005) and higher CD68 expression ( p  = 0.0341) were independently significant factors for partial resection. Conclusions Advanced age, greater tumor extension, cystic growth and higher infiltration with macrophages are independent factors for a less radical extent of resection.

The detection of IDH mutations in patients with diffusely infiltrating malignant astrocytomas resulted in substantial modifications in the concept of WHO classification of these tumors. An important underlying observation was that patients with anaplastic astrocytomas (AA) without IDH mutation had a clinical course similar to that of patients with glioblastomas (GBM). The underlying observations of the German Glioma Network and NOA-04, however, were based on mixed patient cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually had radiotherapy or chemotherapy only. This intrinsic shortcoming of the study raised the question of whether patients with AA, IDH wildtype, WHO grade III, might have better prognosis if treated with combined radiochemotherapy than patients with GBM receiving the same combination therapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of an IDH mutation are still important if neither vascular proliferation nor necrosis are detectable. All patients in the cohort investigated here with the diagnosis of AA or GBM were subjected to a combined radiochemotherapy according to the Stupp protocol independently of the histopathological diagnosis. Thus, the analysis of these patients allows to clarify whether patients with AA, IDH wildtype, WHO grade III have a prognosis similar to that of GBM, IDH wildtype, WHO grade IV, even under equivalent therapeutic conditions. We determined the IDH1 and IDH2 status by sequencing, the MGMT status by pyrosequencing after bisulfite treatment and the EGFR status of the patients by FISH. In fact, the patients with the histopathological diagnosis of an AA IDH wild-type under similar aggressive therapy showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a GBM (mOS 13 months). Instead, patients with an AA and an IDH mutation receiving the same therapy had a mOS of 54 months. Thus, it can be concluded that in the absence of an IDH mutation, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ actually lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and an IDH mutation are examined, there is still a difference between patients with necrosis and/or vascular proliferation and those whose tumors do not show such characteristics. Accordingly, in patients with malignant astrocytomas with IDH mutation it can be concluded that a histological differentiation between AA IDH mutated and GBM IDH mutated remains beneficial from a prognostic perspective.

Despite many years of research efforts and clinical trials the prognosis of patients diagnosed with glioblastoma remains very poor. The oligodendrocyte transcription factor 2 (Olig2) was identified as a marker for glioma stem cells, which are believed to be responsible for glioma recurrence and therapy resistance. In this retrospective analysis we assessed the prognostic value of oligodendroglial and glioma stem cell markers in 113 IDH-wildtype glioblastomas. Immunohistochemical staining for Olig2, NogoA, AQP4 and Nestin was performed in combination with sequencing of IDH1 and IDH2 as well as promotor methylation analysis of the MGMT gene. Even though differences in overall survival according to Olig2 expression were observed, univariate and multivariate survival analysis did not reveal a firm significant prognostic impact of Olig2, NogoA, AQP4 or Nestin expression. Additionally, no differences in the expression of these markers depending on clinical status, age or gender were found. The established independent prognostic factors age<65, Karnofsky Performance Status> = 70 and methylated MGMT gene promoter were significant in the multivariate analysis. In conclusion expression of oligodendroglial and glioma stem cell markers do not have an independent prognostic effect in IDH-wildtype glioblastoma.

Alterations of the v-raf murine sarcoma viral oncogene homolog B (BRAF) have been extensively studied in several tumor entities and are known to drive cell growth in several tumor entities. Effective targeted therapies with mutation-specific small molecule inhibitors have been developed and established for metastasized malignant melanoma. The BRAF V600E mutation and KIAA1549-BRAF fusion are alterations found in several brain tumors and show a distinct prognostic impact in some entities. Besides the diagnostic significance for the classification of central nervous system tumors, these alterations present possible therapy targets that may be exploitable for oncological treatments, as it has been established for malignant melanomas. In this review the different central nervous system tumors harboring BRAF alterations are presented and the diagnostic significance, prognostic role, and therapeutic potential are discussed.

Background Starting the first job as a young physician is a demanding challenge. Certain skills are important to master this transformation that go beyond the theoretical knowledge and practical skills taught in medical school. Competencies such as communication, leadership and career management skills are important to develop as a young physician but are usually not sufficiently taught in medical school in a structured and comprehensive way. Methods We performed an online survey among final year medical students regarding how they perceive their current competency level in communication, leadership and career management skills. We also assessed how they rate the importance to acquire these competencies and the current emphasis during their medical school education regarding these topics. Results Of 450 final year medical students 80 took part in the voluntary survey and 75 complete datasets were returned (16.7%). The majority of respondents rated different communication skills, leadership skills and career management skills as important or very important for their later clinical work. However, most students felt to be poorly or very poorly prepared by the current medical school curriculum, especially for certain leadership and career management skills. Overall, 90.7% of participants expressed interest in an additional educational course that covers subjects of communication, leadership and career management skills during the later stage of medical school, preferably as a hybrid in-person session that also offers synchronous online participation. Conclusions The results of the survey express the need to address communication, leadership and career management skills in the medical curriculum to be better prepare students for the demands of residency and their further course as physicians. An educational format during the final year of medical school may be suitable to address mentioned topics in the framework of clinical practical exposure.