Concomitant (without adjuvant) temozolomide and radiation to treat glioblastoma: A retrospective study.

Between November 2004 and August 2006 we treated 35 patients with concomitant temozolomide (TMZ) and radiotherapy. Twelve patients had very large or multi-centric glioblastoma multiforme (GBM) with a poor performance status and received TMZ plus radiation doses of 45 to 50.4 Gy. Median survival of these patients was only 3.8 months and any benefit from treatment was small. Twenty three patients would have been eligible for randomisation in the EORTC/NCIC trial comparing combined and adjuvant TMZ plus radiation against radiotherapy alone. This group of patients received 60 Gy in 30 fractions plus comitant TMZ (75mg/m2) but no adjuvant chemotherapy. At a median follow-up of 26 months, 5 out of 23 patients are alive. The median survival time was 17 months (1.43 years 95% CI 0.96 to 1.55 years). 18% were alive at 2 years. Toxicity from temozolomide was infrequent. This series adds to indirect evidence that the concomitant rather than the adjuvant is the most efficacious part of the EORTC/NCIC schedule for this type of patient. Further trials should include a concomitant chemoradiotherapy regimen as well as a concomitant plus adjuvant chemotherapy

Racial differences in endometrial cancer molecular portraits in The Cancer Genome Atlas.

Endometrial cancer (EC) is now the most prevalent gynaecological malignancy in the Western world. Black or African American women (BoAA) have double the mortality of Caucasian women, and their tumours tend to be of higher grade. Despite these disparities, little is known regarding the mutational landscape of EC between races. Hence, we wished to investigate the molecular features of ECs within The Cancer Genome Atlas (TCGA) dataset by racial groupings. In total 374 Caucasian, 109 BoAA and 20 Asian patients were included in the analysis. Asian women were diagnosed at younger age, 54.2 years versus 64.5 years for Caucasian and 64.9 years for BoAA women (OR 3.432; p=0.011); BoAA women were more likely to have serous type tumors (OR 2.061; p=0.008). No difference in overall survival was evident. The most frequently mutated gene in Caucasian and Asian tumours was PTEN (63% and 85%), unlike BoAA cases where it was TP53 (49%). Mutation and somatic copy number alteration (SCNA) analysis revealed an enrichment of TP53 mutations in BoAAs; whereas POLE and RPL22 mutations were more frequent in Caucasians. Major recurrent SCNA racial differences were observed at chromosomes 3p, 8, 10, and 16, which clustered BoAA tumors into 4 distinct groups and Caucasian tumors into 5 groups. There was a significantly higher frequency of somatic mutations in DNA mismatch repair genes in Asian tumours, in particular PMS2 (p=0.0036). In conclusion, inherent racial disparities appear to be present in the molecular profile of EC, which could have potential implications on clinical management

Comet assay measures of DNA damage are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo

Bladder cancer patients suffer significant treatment failure, including high rates of recurrence and poor outcomes for advanced disease. If mechanisms to improve tumour cell treatment sensitivity could be identified and/or if tumour response could be predicted, it should be possible to improve local-control and survival. Previously, we have shown that radiation-induced DNA damage, measured by alkaline Comet assay (ACA), correlates bladder cancer cell radiosensitivity in vitro. In the present study we firstly show that modified-ACA measures of cisplatin and mitomycin-C-induced damage also correlate bladder cancer cell chemosensitivity in vitro, with essentially the same rank order for chemosensitivity as for radiosensitivity. Furthermore, ACA studies of radiation-induced damage in different cell-DNA substrates (nuclei, nucleoids & intact parent cells) suggest that it is a feature retained in the prepared nucleoids that is responsible for the relative damage sensitivity of bladder cancer cells, suggestive of differences in the organisation of DNA within resistant vs. sensitive cells. Secondly, we show that ACA analysis of biopsies from bladder tumours reveal that reduced DNA damage sensitivity associates with poorer treatment outcomes, notably that tumours with a reduced damage response show a significant association with local recurrence of non-invasive disease and that reduced damage response was a better predictor of recurrence than the presence of high-risk histology in this cohort. In conclusion, this study demonstrates that mechanisms governing treatment-induced DNA damage are both central to and predictive of bladder cancer cell treatment sensitivity and exemplifies a link between DNA damage resistance and both treatment response and tumour aggression