Development and external validation of a clinical prediction model for survival in patients with IDH wild-type glioblastoma.

OBJECTIVE: Prognostication of glioblastoma survival has become more refined due to the molecular reclassification of these tumors into isocitrate dehydrogenase (IDH) wild-type and IDH mutant. Since this molecular stratification, however, robust clinical prediction models relevant to the entire IDH wild-type glioblastoma patient population are lacking. This study aimed to provide an updated model that predicts individual survival prognosis in patients with IDH wild-type glioblastoma. METHODS: Databases from Germany and the Netherlands provided data on 1036 newly diagnosed glioblastoma patients treated between 2012 and 2018. A clinical prediction model for all-cause mortality was developed with Cox proportional hazards regression. This model included recent glioblastoma-associated molecular markers in addition to well-known classic prognostic variables, which were updated and refined with additional categories. Model performance was evaluated according to calibration (using calibration plots and calibration slope) and discrimination (using a C-statistic) in a cross-validation procedure by country to assess external validity. RESULTS: The German and Dutch patient cohorts consisted of 710 and 326 patients, respectively, of whom 511 (72%) and 308 (95%) had died. Three models were developed, each with increasing complexity. The final model considering age, sex, preoperative Karnofsky Performance Status, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and adjuvant therapeutic regimen showed an optimism-corrected C-statistic of 0.73 (95% confidence interval 0.71-0.75). Cross-validation between the national cohorts yielded comparable results. CONCLUSIONS: This prediction model reliably predicts individual survival prognosis in patients with newly diagnosed IDH wild-type glioblastoma, although additional validation, especially for long-term survival, may be desired. The nomogram and web application of this model may support shared decision-making if used properly.

Age-stratified clinical performance and survival of patients with IDH-wildtype glioblastoma homogeneously treated by radiotherapy with concomitant and maintenance temozolomide.

OBJECTIVE: Isocitrate dehydrogenase (IDH)-wildtype glioblastomas are the most malignant glial tumours. Median survival is only 14-16 months after diagnosis, with patients aged ≥ 65 years reportedly showing worse outcome. This study aimed to further evaluate the prognostic role of age in a homogenously treated patient cohort. METHODS: The study includes 132 IDH-wildtype glioblastoma patients treated between 2013 and 2017 with open resection followed by radiotherapy with concomitant and maintenance temozolomide. Patients were dichotomized into a non-elderly (< 65 years) and an elderly (≥ 65 years) group. Extent of resection and the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status were determined for each tumour. Clinical and radiological follow-up data were obtained at 6 weeks after the end of radiation therapy and thereafter in 3-month intervals. Progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate cox regression analyses. RESULTS: The elderly group consisted of 58 patients (median age: 70.5 years) and the non-elderly group of 74 patients (median age: 55 years). Median pre- and postoperative operative Karnofsky Performance Scale (KPS), Eastern Cooperative Oncology Group (ECOG) score and National Institutes of Stroke Scale (NIHSS) were not significantly different between the groups, but KPS and ECOG scores became significantly worse in the elderly group at 6 weeks after termination of radiation therapy. Neither PFS nor OS differed significantly between the age groups. Patients with MGMT promoter-methylated tumours survived longer. CONCLUSION: Elderly patients in good pre- and postoperative clinical conditions may show similar outcome as younger patients when treated according to standard of care. However, elderly patients may suffer more frequently from clinical deterioration following chemoradiotherapy. In both age groups, MGMT promoter methylation was linked to longer PFS and OS.

Gene expression analysis reveals evidence for increased expression of cell cycle-associated genes and Gq-protein-protein kinase C signaling in cold thyroid nodules.

In contrast to the molecular etiology of autonomously functioning thyroid nodules, the molecular cause of cold thyroid nodules (CTNs), their benign, functional inactive counterparts, are so far largely unknown. Because of the partially dedifferentiated phenotype of CTNs, alterations in signaling cascades that favor proliferation, but not differentiation, are likely candidates for tumor induction and progression. The importance of RAS mutations for the development of benign nodules with follicular histology is still in question. However, differentially expressed genes in the context of their signaling cascades could define aberrant signaling in CTNs. Therefore, we investigated gene expression in 22 CTNs and their normal surrounding tissue using Affymetrix GeneChips. Most prominently, data analysis revealed an increased expression of cell cycle-associated genes and a special relevance of protein kinase C signaling, whereas no evidence of RAS-MAPK signaling in CTNs was found. Moreover, we determined 31 differentially regulated genes in CTNs, including several histone mRNAs. Taken together, these results explain recent findings showing an increased proliferation in CTNs and draw attention to protein kinase C signaling, but away from RAS-MAPK signaling, as being involved in the etiology of CTNs.