A Genetic Vaccine Encoding Shared Cancer Neoantigens to Treat Tumors with Microsatellite Instability.

Tumors with microsatellite instability (MSI) are caused by a defective DNA mismatch repair system that leads to the accumulation of mutations within microsatellite regions. Indels in microsatellites of coding genes can result in the synthesis of frameshift peptides (FSP). FSPs are tumor-specific neoantigens shared across patients with MSI. In this study, we developed a neoantigen-based vaccine for the treatment of MSI tumors. Genetic sequences from 320 MSI tumor biopsies and matched healthy tissues in The Cancer Genome Atlas database were analyzed to select shared FSPs. Two hundred nine FSPs were selected and cloned into nonhuman Great Ape Adenoviral and Modified Vaccinia Ankara vectors to generate a viral-vectored vaccine, referred to as Nous-209. Sequencing tumor biopsies of 20 independent patients with MSI colorectal cancer revealed that a median number of 31 FSPs out of the 209 encoded by the vaccine was detected both in DNA and mRNA extracted from each tumor biopsy. A relevant number of peptides encoded by the vaccine were predicted to bind patient HLA haplotypes. Vaccine immunogenicity was demonstrated in mice with potent and broad induction of FSP-specific CD8 and CD4 T-cell responses. Moreover, a vaccine-encoded FSP was processed by human antigen-presenting cells and was subsequently able to activate human CD8 T cells. Nous-209 is an "off-the-shelf" cancer vaccine encoding many neoantigens shared across sporadic and hereditary MSI tumors. These results indicate that Nous-209 can induce the optimal breadth of immune responses that might achieve clinical benefit to treat and prevent MSI tumors. SIGNIFICANCE: These findings demonstrate the feasibility of an "off-the-shelf" vaccine for treatment and prevention of tumors harboring frameshift mutations and neoantigenic peptides as a result of microsatellite instability

Practice of proctology among general surgery residents and young specialists in Italy: a snapshot survey

Anal diseases are very common and, in most of the cases, require surgery of minor or medium complexity, and, therefore, are among the most accessible diseases for surgeons in training. Aim of this study is to investigate the status of the training in proctology in Italy. A 31-items questionnaire was administered to residents and young specialists (<= 2 years) in general surgery, using mailing lists, and the social media accounts of the Italian Society of Colorectal Surgery. Answers from 338 respondents (53.8% males) were included in the final analysis. Overall, 252 respondents (74.5%) were residents and 86 (25.5%) young specialists. Two hundred and fifty-five (75.4%) respondents practiced proctology for the first time early on during their postgraduate training, but only 19.5% did it continuously for >= 24 months. Almost all respondents (334; 98.8%) had the chance to participate in proctological procedures, 205 (60.5%) as first surgeon. This percentage decreases according to the complexity of the surgery. In fact, only 11 (3.3%) and 24 (7.1%) of the respondents were allowed to be the first surgeon in more complex proctological diseases such as surgery for rectal prolapse and fecal incontinence. The present survey suggests that, in Italy, most surgeons in training deal with anal diseases. However, only few of them could achieve sufficient professional skills in the management of proctological diseases to be able to practice autonomously as young specialists