International evaluation of the psychometrics of health-related quality of life questionnaires for use among long-term survivors of testicular and prostate cancer

Background: Understanding of the physical, functional and psychosocial health problems and needs of cancer survivors requires cross-national and cross-cultural standardization of health-related quality of life (HRQoL) questionnaires that capture the full range of issues relevant to cancer survivors. To our knowledge, only one study has investigated in a comprehensive way whether a questionnaire used to evaluate HRQoL in cancer patients under active treatment is also reliable and valid when used among (long-term) cancer survivors. In this study we evaluated, in an international context, the psychometrics of HRQoL questionnaires for use among long-term, disease-free, survivors of testicular and prostate cancer. Methods: In this cross-sectional study, we recruited long-term survivors of testicular and prostate cancer from Northern and Southern Europe and from the United Kingdom who had participated in two phase III EORTC clinical trials. Participants completed the SF-36 Health Survey, the EORTC QLQ-C30 questionnaire, the QLQ-PR25 (for prostate cancer) or the QLQ-TC26 (for testicular cancer) questionnaires, and the Impact of Cancer questionnaire. Testicular cancer survivors also completed subscales from the Nordic Questionnaire for Monitoring the Age Diverse Workforce. Results: Two hundred forty-two men (66% response rate) were recruited into the study. The average time since treatment was more than 10 years. Overall, there were few missing questionnaire data, although scales related to sexuality, satisfaction with care and relationship concern

Functionally Redundant RXLR Effectors from <em>Phytophthora infestans</em> Act at Different Steps to Suppress Early flg22-Triggered Immunity

Genome sequences of several economically important phytopathogenic oomycetes have revealed the presence of large families of so-called RXLR effectors. Functional screens have identified RXLR effector repertoires that either compromise or induce plant defense responses. However, limited information is available about the molecular mechanisms underlying the modes of action of these effectors in planta. The perception of highly conserved pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs), such as flg22, triggers converging signaling pathways recruiting MAP kinase cascades and inducing transcriptional re-programming, yielding a generic anti-microbial response. We used a highly synchronizable, pathogen-free protoplast-based assay to identify a set of RXLR effectors from Phytophthora infestans (PiRXLRs), the causal agent of potato and tomato light blight that manipulate early stages of flg22-triggered signaling. Of thirty-three tested PiRXLR effector candidates, eight, called Suppressor of early Flg22-induced Immune response (SFI), significantly suppressed flg22-dependent activation of a reporter gene under control of a typical MAMP-inducible promoter (pFRK1-Luc) in tomato protoplasts. We extended our analysis to Arabidopsis thaliana, a non-host plant species of P. infestans. From the aforementioned eight SFI effectors, three appeared to share similar functions in both Arabidopsis and tomato by suppressing transcriptional activation of flg22-induced marker genes downstream of post-translational MAP kinase activation. A further three effectors interfere with MAMP signaling at, or upstream of, the MAP kinase cascade in tomato, but not in Arabidopsis. Transient expression of the SFI effectors in Nicotiana benthamiana enhances susceptibility to P. infestans and, for the most potent effector, SFI1, nuclear localization is required for both suppression of MAMP signaling and virulence function. The present study provides a framework to decipher the molecular mechanisms underlying the manipulation of host MAMP-triggered immunity (MTI) by P. infestans and to understand the basis of host versus non-host resistance in plants towards P. infestans

Bringing onco‐innovation to Europe’s healthcare systems: The potential of biomarker testing, real world evidence, tumour agnostic therapies to empower personalised medicine

Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre‐eminently in many cancers, but also in an ever‐wider range of conditions— notably BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, the implementation of genetic testing in clinical routine setting is still challenging. Development is impeded by country‐related heterogeneity, data deficiencies, and lack of policy alignment on standards, approval—and the role of real‐world evidence in the process—and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe’s industrial competitiveness and innovation require an appropriate policy framework—starting with an update to outdated recommendations. We show herein the main issues and proposals that emerged during the previous advisory boards organised by the European Alliance for Personalized Medicine which mainly focus on possible scenarios of harmonisation of both oncogenetic testing and management of cancer patients

Gleason score and margin status are the strongest predictors for benefit of radiotherapy after radical prostatectomy.

Introduction and Objective: A randomized trial (EORTC 22911) recently showed that postoperative radiotherapy after radical prostatectomy showing pT3a/b with or without positive margins reduces the risk of biochemical and local recurrence. A pathological review of prostatectomy specimens was performed to analyse predictors of this beneficial effect. Methods: After radical prostatectomy 503 patients were randomly assigned to a control arm and 502 to immediate postoperative radiotherapy. All eligible patients had pN0M0 disease and local pathology had shown pT3a/b disease and/or positive surgical margins. A total of 552 prostatectomy specimens (280 control arm, 272 test arm) of 12 major centers was reviewed by a single pathologist for stage, margins and Gleason score. The findings of review were related to biochemical recurrence in each of the trial arms by log-rank test for heterogeneity (α=0.05). Results: Agreement of local pathologists and review pathologist was high (kappa 0.83) for seminal vesicle involvement, but low (kappa 0.33, resp. 0.45) for extracapsular extension and margin status. Review pathology of surgical margins was a stronger predictor of biochemical recurrence than local pathology (HR=2.16, P=0.0002 versus HR=1.08, P>0.1). The data also suggested that the margin status assessed by the review pathologist was a stronger predictive factor of treatment benefit than the local pathology. These data confirm earlier findings that the margin status modulates the extent of the treatment benefit. We also developed a multivariate prognostic model in the control arm that showed Gleason sum, margin positivity assessed by the review pathologist and post operative PSA value (> 2 ng/ml vs <=2 ng/ml) to be the three strongest predictors of biochemical PFS. A prognostic classification could be derived from the model, that was predictive of treatment benefit (P=0.04) and suggested that the “good risk” patients might not truly benefit from post-operative irradiation. Those patients are essentially patients with pT2a-pT3 disease, Gleason sum <8, negative margins and post-operative PSA <= 2 ng/ml. Conclusions: Gleason score, margin status, and post-operative PSA are the strongest predictors of outcome and radiotherapy benefit after radical prostatectomy. Review pathology assessment of the margins, however, is needed

Impact of pathology review of stage and margin status of radical prostatectomy specimens (EORTC trial 22911).

International audiencePathological staging and surgical margin status of radical prostatectomy specimens are next to grading the most important prognosticators for recurrence. A central review of pathological stage and surgical margin status was performed on a series of 552 radical prostatectomy specimens of patients, participating in the European Organisation for Research and Treatment of Cancer trial 22911. Inclusion criteria of the trial were pathological stage pT3 and/or positive surgical margin at local pathology. All specimens were totally embedded. Data of the central review were compared with those of local pathologists and related to clinical follow-up. Although a high concordance between review pathology and local pathologists existed for seminal vesicle invasion (94%, kappa=0.83), agreement was much less for extraprostatic extension (57.5%, kappa=0.33) and for surgical margin status (69.4%, kappa=0.45). Review pathology of surgical margin status was a stronger predictor of biochemical progression-free survival in univariate analysis [hazard ratio (HR)=2.16 and p=0.0002] than local pathology (HR=1.08 and p>0.1). The review pathology demonstrated a significant difference between those with and without extraprostatic extension (HR=1.83 and p=0.0017), while local pathology failed to do so (HR=1.05 and p>0.8). The observations suggest that review of pathological stage and surgical margin of radical prostatectomy strongly improves their prognostic impact in multi-institutional studies or trials