Damien Carignan

Purpose of the researchPulmonary seed migration is a rare complication of low‑dose‑rate prostate brachytherapy. This retrospective study evaluated whether it is associated with an increased risk of lung cancer.Patients and MethodsWe conducted a single‑center cohort study of patients treated with low‑dose‑rate prostate brachytherapy between 2004 and 2015 who experienced seed migration, assessed 30 days post‑implant. The primary endpoint was lung cancer incidence, based on clinical and radiological data. We estimated cumulative incidences at 5, 10, and 20 years, and analyzed the anatomical correspondence between migrated seeds and tumours. We evaluated predictors of lung cancer using univariate Fine‑Gray regression accounting for competing risks. We followed the Strengthening the reporting of observational studies in epidemiology guidelines and received ethics approval.ResultsAmong 1,386 patients, 98 (7.1%) experienced seed migration, corresponding to 125 of 71,316 seeds (0.18%), and were included in the analysis. Mean age was 62 years, and median follow‑up was 178 months. On day 30 post‑implant, most migrated seeds were detected in the thorax. Five patients developed lung cancer, all with a smoking history. Tumours occurred 6.3 to 20.3 years after implantation. Cumulative incidence of lung cancer was 0% at 5 years, 2.84% at 10 years, and 6.38% at 20 years. Only one tumour was in direct contact with a migrated seed. On univariate competing‑risk analysis, age was the only variable significantly associated with lung cancer risk.ConclusionIn this cohort with extended follow‑up, pulmonary seed migration after low‑dose‑rate prostate brachytherapy was not associated with an increased risk of lung cancer beyond that expected based on age and smoking status.

Background: Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and treatment outcomes and toxicity in brachytherapy‐treated patients.Purpose: To evaluate the association of inherited germline variations in DNA repair‐associated genes with tumor control and treatment toxicity in patients treated with low‐dose‐rate prostate brachytherapy (LDRB).Material and Methods: The cohort consists of 475 I‐125 LDRB patients with a median follow‐up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan–Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity.Results: After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HR_adj.) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC₉₅ = 3.9‐32.0; P < .0001; q < 0.001). The Kaplan–Meier survival curve revealed a mean BCR‐free survival time reduced from 213 ± 7 to 99 ± 12 months (log‐rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b‐coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01).Conclusions: This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.

Flexuous rod-shaped nanoparticles made of the coat protein (CP) of papaya mosaic virus (PapMV) have been shown to trigger innate immunity through engagement of toll-like receptor 7 (TLR7). PapMV nanoparticles can also serve as a vaccine platform as they can increase the immune response to fused peptide antigens. Although this approach shows great potential, fusion of antigens directly to the CP open reading frame (ORF) is challenging because the fused peptides can alter the structure of the CP and its capacity to self assemble into nanoparticles—a property essential for triggering an efficient immune response to the peptide. This represents a serious limitation to the utility of this approach as fusion of small peptides only is tolerated. We have developed a novel approach in which peptides are fused directly to pre-formed PapMV nanoparticles. This approach is based on the use of a bacterial transpeptidase (sortase A; SrtA) that can attach the peptide directly to the nanoparticle. An engineered PapMV CP harbouring the SrtA recognition motif allows efficient coupling. To refine our engineering, and to predict the efficacy of coupling with SrtA, we modeled the PapMV structure based on the known structure of PapMV CP and on recent reports revealing the structure of two closely related potexviruses: pepino mosaic virus (PepMV) and bamboo mosaic virus (BaMV). We show that SrtA can allow the attachment of long peptides [Influenza M2e peptide (26 amino acids) and the HIV-1 T20 peptide (39 amino acids)] to PapMV nanoparticles. Consistent with our PapMV structural model, we show that around 30% of PapMV CP subunits in each nanoparticle can be fused to the peptide antigen. As predicted, engineered nanoparticles were capable of inducing a strong antibody response to the fused antigen. Finally, in a challenge study with influenza virus, we show that mice vaccinated with PapMV-M2e are protected from infection. This technology will allow the development of vaccines harbouring long peptides containing several B and/or T cell epitopes that can contribute to a broad and robust protection from infection. The design can be fast, versatile and can be adapted to the development of vaccines for many infectious diseases as well as cancer vaccines.