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Backround Median overall survival (OS) after diagnosis of glioblastoma (GBM) remains 15 months amongst patients receiving aggressive surgical resection, chemotherapy and irradiation. Treatment of patients with a poor preoperative Karnofsky Performance Status Scale (KPSS) is still controversial. Therefore, we retrospectively assessed the outcome after surgical treatment in patients with a KPSS of ≤60%. Methods We retrospectively included patients with a de-novo glioblastoma WHO °IV and preoperative KPSS ≤60%, who underwent surgery at two neurosurgical centres between September 2006 and March 2016. We recorded pre- and postoperative tumour volume, pre- and postoperative KPSS, OS, age and MGMT promoter status. Results One hundred twenty-three patients (58 females/65 males, mean age 67.4 ± 13.4 years) met the inclusion criteria. Seventy-five of the 123 patients (61%) underwent surgical resection. 48/123 patients (39%) received a biopsy. The median preoperative and postoperative tumour volume of all patients was 33.0 ± 31.3 cm 3 (IR 15.0–56.5cm 3 ) and 3.1 ± 23.8 cm 3 (IR 0.2–15.0 cm 3 ), respectively. The median KPSS was 60% (range 20–60%) preoperatively and 50% (range 0–80%) postoperatively. Patients who received a biopsy showed a median OS for patients who received a biopsy only was 3.0 months (95% CI 2.0–4.0 months), compared to patients who had a resection and had a median OS of 8 months (95% CI 3.1–12.9 months). Age ( p  < 0.001, HR: 1.045 [95% CI 1.022–1.068]), postoperative tumour volume ( p  = 0.02, HR: 1.016 [95% CI 1.002–1.029]) and MGMT promotor status ( p  = 0.016, HR: 0.473 [95% CI 0.257–0.871]) were statistically significant in multivariate analysis. In subgroup analyses only age was shown as a significant prognostic factor in multivariate analyses for patients receiving surgery ( p  < 0.001, HR: 1.046 [95% CI 1.022–1.072]). In the biopsy group no significant prognostic factors were shown in multivariate analysis. Conclusion GBM patients with a preoperative KPSS of ≤60% might profit from surgical reduction of tumour burden.

IntroductionTo assess the predictive value of magnetic resonance imaging (MRI) gadolinium enhancement as a prognostic factor in the 2016 World Health Organization Classification of Tumors of the Central Nervous System integrated glioma groups.MethodsFour-hundred fifty patients with histopathologically confirmed glioma were retrospectively assessed between 07/1997 and 06/2014 using gadolinium enhancement, survival, and relevant prognostic molecular data [isocitrate dehydrogenase (IDH); alpha-thalassemia/mental retardation syndrome X-linked (ATRX); chromosome 1p/19q loss of heterozygosity; and O6-methylguanine DNA methyltransferase (MGMT)]. The Kaplan–Meier method was used to assess univariate survival data. A multivariate Cox proportional hazards model was performed on significant results from the univariate analysis.ResultsThere were significant differences in survival between patient age (p < 0.0001), WHO glioma grades (p < 0.0001), and integrated molecular profiles (p < 0.0001). Patients with IDH1/2 mutation, loss of ATRX expression, and methylated MGMT promoter showed significantly better survival than those with the IDHwild-type (p < 0.0001), retained ATRX expression (p < 0.0001), and unmethylated MGMT promoter (p = 0.019). Survival was significantly better in patients without gadolinium enhancement (p = 0.009) who were in the IDHwild-type glioma and glioma with retained ATRX expression groups (p = 0.018 and 0.030, respectively).ConclusionsIn univariate analysis, the presence of gadolinium enhancement on preoperative MRI scans is an unfavorable factor for survival. Regarding the molecular subgroups, gadolinium enhancement is an unfavorable prognostic factor in gliomas with IDHwild-type and those with ATRX retention. However, in multivariate analysis only patient age, IDH1/2 mutation status, MGMT promoter methylation status, and WHO grade IV are relevant for predicting survival.

ObjectiveThe aim of this work is to define competencies and entrustable professional activities (EPAs) to be imparted within the framework of surgical neuro-oncological residency and fellowship training as well as the education of medical students. Improved and specific training in surgical neuro-oncology promotes neuro-oncological expertise, quality of surgical neuro-oncological treatment and may also contribute to further development of neuro-oncological techniques and treatment protocols. Specific curricula for a surgical neuro-oncologic education have not yet been established.MethodsWe used a consensus-building approach to propose skills, competencies and EPAs to be imparted within the framework of surgical neuro-oncological training. We developed competencies and EPAs suitable for training in surgical neuro-oncology.ResultIn total, 70 competencies and 8 EPAs for training in surgical neuro-oncology were proposed. EPAs were defined for the management of the deteriorating patient, the management of patients with the diagnosis of a brain tumour, tumour-based resections, function-based surgical resections of brain tumours, the postoperative management of patients, the collaboration as a member of an interdisciplinary and/or -professional team and finally for the care of palliative and dying patients and their families.Conclusions and RelevanceThe present work should subsequently initiate a discussion about the proposed competencies and EPAs and, together with the following discussion, contribute to the creation of new training concepts in surgical neuro-oncology.

Background Various prognostic factors have been suggested in meningioma patients including WHO grading, brain invasion and bone involvement, for instance. Brain invasion was included as an independent criterion in the recent WHO classification. However, assessability of brain or bone involvement is often limited or varies between histopathologic, operative and imaging reports. Objective of our study was to investigate prognostic values including brain and bone involvement according to different clinical approaches. Methods A cohort of 111 patients was treated with primary, adjuvant or salvage irradiation between 2008 and 2017 using intensity-modulated radiotherapy. Positron-emission tomography (PET) was available for treatment planning in 81% of patients. Clinical data were extracted from the medical reports. Brain and bone involvement were stratified separately according to histopathologic, operative and imaging reports as well as judged in synopsis. Results WHO grade I tumours, lower estimated proliferation index, primary versus recurrence treatment and localization (i.e. skull base, optic nerve sheath) were beneficial prognostic factors for local control. Judgement of brain and bone invasion partly differed between diagnostic modalities. In synopsis, brain or bone invasion did not show a significant influence on local control rates. Conclusions Several previously described prognostic factors could be reproduced. However, partly divergent histopathological, surgical and image-based judgements could be found in regard to brain and bone invasion and all methods imply limitations. Therefore, we suggest a particular, complemental synopsis judgement. In synopsis, brain or bone involvement did not coherently impair local control in our irradiated patients. This might be explained by elaborate radiation techniques and PET-based treatment planning.

The development of somatostatin analogs for the treatment of pituitary Cushing’s disease has been based on somatostatin receptor expression analyses of small cohorts of pituitary adenomas. Additionally, the classification of pituitary adenomas has recently changed. To enable progress with this treatment option, we assessed somatostatin receptors in a large cohort of corticotroph and other pituitary adenomas according to the new WHO classification of endocrine tumors. Paraffin-embedded tumor samples of 88 corticotroph pituitary adenomas and 30 nonadenomatous pituitary biopsies were analyzed after processing into tissue microarrays and immunohistochemical staining for SSTR 1, SSTR2A, SSTR3, SSTR4, and SSTR5. For comparison, 159 other noncorticotroph pituitary adenomas were analyzed. SSTR3 expression was higher in corticotroph adenomas compared to PIT-1-positive, gonadotroph, and nonfunctioning pituitary adenomas (p<0.0001, p=0.0280, and p<0.0001, respectively). This was also the case for the expression of SSTR5 (p=0.0003, p<0.0001, and p<0.0001, respectively). SSTR2A expression was higher compared to gonadotroph and nonfunctioning pituitary adenomas (p=0.0217 and 0.0126, respectively) while PIT-1-positive adenomas showed even higher SSTR2A expression (p<0.0001). SSTR2A and SSTR5 were both expressed higher in nonadenomatous pituitary biopsies than in pituitary adenomas (p=0.0126 and p=0.0008, respectively). There are marked expression differences of SSTR1-5 as well as changes in expression in recurrent disease that need to be addressed when looking for other possible substances for the treatment of Cushing’s disease. SSTR2A, SSTR3, and SSTR5 seem to be most suitable biomarkers for a targeted therapy with somatostatin analogs.

Acetylsalicylic acid has been linked to a lower risk for different cancer types, presumably through its inhibitory effect on cyclooxygenase 2. This has also been investigated in vestibular schwannomas with promising results suggesting an antiproliferative effect and recently the intake has been recommended for vestibular schwannomas as a conservative treatment option. We constructed tissue microarrays from paraffin-embedded tissue samples of 1048 vestibular schwannomas and analyzed the expression of cyclooxygenase 2 and the proliferation marker MIB1 (Molecular Immunology Borstel) via immunohistochemistry together with clinical data (age, gender, tumor extension, prior radiotherapy, neurofibromatosis type 2, tumor recurrence, cyclooxygenase 2 responsive medication). Univariate analysis showed that cyclooxygenase 2 expression was increased with age, female gender, prior radiotherapy and larger tumor extension. MIB1 expression was also associated with higher cyclooxygenase 2 expression. Schwannomas of neurofibromatosis type 2 patients had lower cyclooxygenase 2 levels. Use of acetylsalicylic acid, non-steroidal anti-inflammatory drugs, glucocorticoids or other immunosuppressants did not show differences in cyclooxygenase 2 or MIB1 expression. Instead, cyclooxygenase 2 expression increases with tumor extension while MIB1 expression is not associated with tumor size. Overall, cyclooxygenase 2 expression is associated with proliferation but not influenced by regular intake of acetylsalicylic acid or other cyclooxygenase 2-responsive medications. Acetylsalicylic acid intake does not alter cyclooxygenase 2 expression and has no antiproliferative effect in vestibular.

The detection of the infiltrative growth of meningiomas into CNS tissue has been integrated into the WHO classification as a stand-alone marker for atypical meningioma. However, its prognostic impact has been questioned. Infiltrative growth can also be detected intraoperatively. The prognostic impact of the intraoperative detection of the central nervous system tissue invasion of meningiomas was analyzed and compared to the histopathological assessment. The clinical data of 1517 cases with follow-up data regarding radiographic recurrence was collected. Histopathology and operative reports were reviewed and invasive growth was seen during resection in 23.7% (n = 345) while histopathology detected it in 4.8% (n = 73). The histopathological and intraoperative assessments were compatible in 63%. The prognostic impact of histopathological and intraoperative assessment was significant in the univariate but not in the multivariate analysis. Both methods of assessment combined reached statistical significance in the multivariate analysis (p = 0.0409). A score including all independent prognostic factors divided the cohort into three prognostic subgroups with a risk of recurrence of 33.8, 64.7 and 88.5%, respectively. The intraoperative detection of the infiltrative growth of primary meningiomas into the central nervous system tissue can complement the histopathological assessment of CNS invasion. The combined assessment is an independent prognostic factor regarding tumor recurrence and allows a risk-adapted tumor stratification.

Background As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response. Methods This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively. Results Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P  = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P  = 0.21). In subgroup serum analyses, significant changes in VEGF-A ( P  = 0.017), VEGFR2 ( P  = 0.012) and VEGF-D ( P  < 0.001) serum levels were observed. Conclusions Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted. Trial registration This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.

Melanoma brain metastases (MBM) are associated with a dismal prognosis. Few clinical trials evaluated the impact of immunotherapy (IT) and targeted therapy (TT) alone or in combination with surgery and radiotherapy in this population. Retrospective analysis of data from 163 patients diagnosed with MBM between January 2014 and December 2016. Prognostic factors of overall survival were analyzed using Kaplan-Meier survival curves, classification and regression tree and multivariate Cox regression analysis. The median follow-up was 25 months; median overall survival (mOS) for all patients was 7 months. For patients receiving IT, the mOS was 13 months and 7 months for patients receiving TT or chemotherapy (CT). The mOS for patients treated with surgery/radiosurgery in combination with IT, TT and CT was 25, 14 and 11 months, respectively. New systemic therapies, especially IT, improve mOS in patients with MBM, particularly when combined with surgery/radiosurgery upfront.

Purpose: To assess the predictive value of MRI gadolinium enhancement as a prognostic factor in the 2016 CNS WHO integrated glioma groups. Methods: 450 glioma patients were retrospectively assessed using gadolinium enhancement, survival, and relevant prognostic molecular data [isocitrate dehydrogenase (IDH); alpha-thalassemia/mental retardation syndrome X-linked (ATRX); chromosome 1p/19q loss of heterozygosity; and O6-methylguanine DNA methyltransferase (MGMT)]. Kaplan-Meier method was used to assess univariate survival data. Multivariate Cox proportional hazards model was performed on significant results from the univariate analysis. Results: There were significant differences in survival between patient age (p < 0.0001), WHO glioma grades (p < 0.0001), and integrated molecular profiles (p < 0.0001). Patients with IDH1/2 mutation, loss of ATRX expression, and methylated MGMT promoter showed significantly better survival than those with the IDH wild type (p < 0.0001), retained ATRX expression (p < 0.0001), and unmethylated MGMT promoter (p = 0.019). Survival was significantly better in patients without gadolinium enhancement (p = 0.009) who were in the IDH wild type glioma and glioma with retained ATRX expression groups (p = 0.018 and 0.030, respectively). Conclusion: In univariate analysis, the presence of gadolinium enhancement on preoperative MRI scans is an unfavorable factor for survival. Regarding the molecular subgroups, gadolinium enhancement is an unfavorable prognostic factor in gliomas with IDH wild type and those with ATRX retention. However, in multivariate analysis only patient age, IDH1/2 mutation status, MGMT promoter methylation status, and WHO grade IV are relevant for predicting survival.