The prognostic value of FET PET at radiotherapy planning in newly diagnosed glioblastoma

BACKGROUND: Glioblastoma patients show a great variability in progression free survival (PFS) and overall survival (OS). To gain additional pretherapeutic information, we explored the potential of O-(2-(18)F-fluoroethyl)-L-tyrosine (FET) PET as an independent prognostic biomarker. METHODS: We retrospectively analyzed 146 consecutively treated, newly diagnosed glioblastoma patients. All patients were treated with temozolomide and radiation therapy (RT). CT/MR and FET PET scans were obtained postoperatively for RT planning. We used Cox proportional hazards models with OS and PFS as endpoints, to test the prognostic value of FET PET biological tumor volume (BTV). RESULTS: Median follow-up time was 14 months, and median OS and PFS were 16.5 and 6.5 months, respectively. In the multivariate analysis, increasing BTV (HR = 1.17, P < 0.001), poor performance status (HR = 2.35, P < 0.001), O(6)-methylguanine-DNA methyltransferase protein status (HR = 1.61, P = 0.024) and higher age (HR = 1.32, P = 0.013) were independent prognostic factors of poor OS. For poor PFS, only increasing BTV (HR = 1.18; P = 0.002) was prognostic. A prognostic index for OS was created based on the identified prognostic factors. CONCLUSION: Large BTV on FET PET is an independent prognostic factor of poor OS and PFS in glioblastoma patients. With the introduction of FET PET, we obtain a prognostic index that can help in glioblastoma treatment planning. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00259-016-3494-2) contains supplementary material which is available to authorized users

Angiotensinogen and HLA class II predict bevacizumab response in recurrent glioblastoma patients

Background Bevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers for bevacizumab response in recurrent glioblastoma patients. Methods The study included a total of 82 recurrent glioblastoma patients treated with bevacizumab combination therapy whom were both response and biomarker evaluable. Gene expression of tumor tissue was analyzed by using a customized NanoString platform covering 800 genes. Candidate gene predictors associated with response were analyzed by multivariate logistic and Cox regression analysis. Results Two genes were independently associated with response: Low expression of angiotensinogen (2‐fold decrease in AGT; OR = 2.44; 95% CI: 1.45–4.17; P = 0.0009) and high expression of a HLA class II gene (2‐fold increase in HLA‐DQA1; OR = 1.22; 95% CI: 1.01–1.47; P = 0.04). These two genes were included in a model that is able predict response to bevacizumab combination therapy in clinical practice. When stratified for a validated prognostic index, the predictive model for response was significantly associated with improved overall survival. Conclusion Two genes (low angiotensinogen and high HLA‐class II expression) were predictive for bevacizumab response and were included in a predictive model for response. This model can be used in clinical practice to identify patients who will benefit from bevacizumab combination therapy

Clinical performance and acceptability of self-collected vaginal and urine samples compared with clinician-taken cervical samples for HPV testing among women referred for colposcopy. A cross-sectional study

Objectives To increase effectiveness of the cervical cancer screening program, self-sampling can be an option. Both self-collected vaginal samples (SCV) and urine samples may be useful alternatives to clinician-taken cervical samples (CS).Design Cross-sectional study.Setting Colposcopy clinic.Participants Women (n=305) referred to colposcopy after abnormal cervical screening result or conditions like postcoital bleeding.Intervention All women self-collected a urine and a vaginal sample prior to colposcopy, where a CS and biopsies were taken. All samples were tested for high-risk human papillomavirus (HPV) using the Cobas HPV assay. The gold standard was histology diagnoses (CIN2+/CIN3+) from biopsies obtained at the same examination.Primary outcome Absolute and relative sensitivity and specificity of HPV testing on SCV and urine to detect CIN2+/CIN3+ compared with the CS.Secondary outcome The acceptability by women of self-sampling.Results Both the vaginal and urine sample were comparable to the CS in identifying severe intraepithelial neoplasia (CIN2+/CIN3+). Absolute sensitivity ranged from 93% for urine samples to 96% for SCV for detecting CIN2+, which is comparable to the sensitivity of CS (overlapping 95% CI).The relative sensitivity for detecting CIN2+ was 1.00 (95% CI 0.96 to 1.04) for SCV and 0.96 (95% CI 0.91 to 1.03) for urine samples. At CIN3+, the relative sensitivity was 1.00 (95% CI 0.96 to 1.08) and 0.97 (95% CI 0.89 to 1.07) for SCV and urine samples, respectively. There were no statistical differences between the self-collected samples and the CS (McNemar’s test &gt;0.05). The relative specificity was also similar (1.03 (95% CI 0.95 to 1.12) for SCV and 0.98 (95% CI 0.89 to 1.09) for urine samples) (McNemar’s test &gt;0.05).The acceptability of self-sampling was evaluated by questionnaire. The women found the instructions on sample collection easy to understand and were positive about self-sampling with a preference for the urine sample.Conclusion Self-sampling by SCV and urine is a clinically safe alternative to CS with a high degree of acceptability

Assessment of Quantitative and Allelic <i>MGMT</i> Methylation Patterns as a Prognostic Marker in Glioblastoma

Methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is a predictive and prognostic marker in newly diagnosed glioblastoma patients treated with temozolomide but how MGMT methylation should be assessed to ensure optimal detection accuracy is debated. We developed a novel quantitative methylation-specific PCR (qMSP) MGMT assay capable of providing allelic methylation data and analyzed 151 glioblastomas from patients receiving standard of care treatment (Stupp protocol). The samples were also analyzed by immunohistochemistry (IHC), standard bisulfite pyrosequencing, and genotyped for the rs1690252 MGMT promoter single nucleotide polymorphism. Monoallelic methylation was observed more frequently than biallelic methylation, and some cases with monoallelic methylation expressed the MGMT protein whereas others did not. The presence of MGMT methylation was associated with better overall survival (p = 0.006; qMSP and p = 0.002; standard pyrosequencing), and the presence of the protein was associated with worse overall survival (p = 0.009). Combined analyses of qMSP and standard pyrosequencing or IHC identified additional patients who benefited from temozolomide treatment. Finally, low methylation levels were also associated with better overall survival (p = 0.061; qMSP and p = 0.02; standard pyrosequencing). These data support the use of both MGMT methylation and MGMT IHC but not allelic methylation data as prognostic markers in patients with temozolomide-treated glioblastoma