A Comparison between Patient-and Physician-Reported Late Radiation Toxicity in Long-Term Prostate Cancer Survivors

Patient-reported outcome measures (PROMs) are advocated for the monitoring of toxicity after radiotherapy. However, studies comparing physician-and patient-reported toxicity show low concordance. In this study, we compared physician-and patient-reported toxicity in long-term prostate cancer survivors after radiotherapy, and we determined the correlation with a presumable risk factor for late toxicity: γ-H2AX foci decay ratio (FDR). Patients formerly included in a prospective study were invited to participate in this new study, comprising one questionnaire and one call with a trial physician assistant. Concordance was calculated for seven symptoms. Gamma-H2AX FDRs were determined in ex vivo irradiated lymphocytes in a previous analysis. Associations between FDR and long-term prevalence of toxicity were assessed using univariable logistic regression analyses. The 101 participants had a median follow-up period of 9 years. Outcomes were discordant in 71% of symptomatic patients; in 21%, the physician-assessed toxicity (using CTCAE) was higher, and, in 50%, the patients reported higher toxicity. We did not find a correlation between presence of toxicity at long-term follow-up and FDR. In conclusion, patients assigned greater severity to symptoms than the trial physician assistant did. Consideration of both perspectives may be warranted to provide the best care

Development of a cell line-based in vitro assay for assessment of Diphtheria, Tetanus and acellular Pertussis (DTaP)-induced inflammasome activation.

Safety and potency assessment for batch release testing of established vaccines still relies partly on animal tests. An important avenue to move to batch release without animal testing is the consistency approach. This approach is based on thorough characterization of the vaccine to identify critical quality attributes that inform the use of a comprehensive set of non-animal tests to release the vaccine, together with the principle that the quality of subsequent batches follows from their consistent production. Many vaccine antigens are by themselves not able to induce a protective immune response. The antigens are therefore administered together with adjuvant, most often by adsorption to aluminium salts. Adjuvant function is an important component of vaccine potency, and an important quality attribute of the final product. Aluminium adjuvants are capable of inducing NLRP3 inflammasome activation. The aim of this study was to develop and evaluate an in vitro assay for NLRP3 inflammasome activation by aluminium-adjuvanted vaccines. We evaluated the effects of Diphtheria-Tetanus-acellular Pertussis combination vaccines from two manufacturers and their respective adjuvants, aluminium phosphate (AP) and aluminium hydroxide (AH), in an in vitro assay for NLRP3 inflammasome activation. All vaccines and adjuvants tested showed a dose-dependent increase in IL-1β production and a concomitant decrease in cell viability, suggesting NLRP3 inflammasome activation. The results were analysed by benchmark dose modelling, showing a similar 50% effective dose (ED50) for the two vaccine batches and corresponding adjuvant of manufacturer A (AP), and a similar ED50 for the two vaccine batches and corresponding adjuvant of manufacturer B (AH). This suggests that NLRP3 inflammasome activation is determined by the adjuvant only. Repeated freeze-thaw cycles reduced the adjuvant biological activity of AH, but not AP. Inflammasome activation may be used to measure adjuvant biological activity as an important quality attribute for control or characterization of the adjuvant

Gamma-H2AX Foci Decay Ratio as a Stronger Predictive Factor of Late Radiation Toxicity Than Dose-Volume Parameters in a Prospective Cohort of Prostate Cancer Patients

Purpose: Late radiation toxicity is a major dose-limiting factor in curative cancer radiation therapy. Previous studies identified several risk factors for late radiation toxicity, including both dose-volume factors and genetic predisposition. Herein, we investigated the contribution of genetic predisposition, particularly compared with dose-volume factors, to the risk of late radiation toxicity in patients treated with highly conformal radiation therapy. Methods and Materials: We included 179 patients with prostate cancer who underwent treatment with curative external beam radiation therapy between 2009 and 2013. Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 4.0. Transcriptional responsiveness of homologous recombination repair genes and γ-H2AX foci decay ratios (FDRs) were determined in ex vivo irradiated lymphocytes in a previous analysis. Dose-volume parameters were retrieved by delineating the organs at risk (OARs) on CT planning images. Associations between risk factors and grade ≥2 urinary and bowel late radiation toxicities were assessed using univariable and multivariable logistic regression analyses. The analyses were performed using the highest toxicity grade recorded during the follow-up per patient. Results: The median follow-up period was 31 months. One hundred and one patients (56%) developed grade ≥2 late radiation toxicity. Cumulative rates for urinary and bowel grade ≥2 late toxicities were 46% and 17%, respectively. In the multivariable analysis, factors significantly associated with grade ≥2 late toxicity were transurethral resection of the prostate (P = .013), γ-H2AX FDR 11.52% (P = .017). Conclusions: Our results suggest that impaired DNA double-strand break repair in lymphocytes, as quantified by γ-H2AX FDR, is the most critical determining factor of late radiation toxicity. The limited influence of dose-volume parameters could be due to the use of increasingly conformal techniques, leading to improved dose-volume parameters of the organs at risk