IMMUNOREACT 7: Regular aspirin use is associated with immune surveillance activation in colorectal cancer.

BACKGROUND: Long-term daily use of aspirin reduces incidence and mortality due to colorectal cancer (CRC). This study aimed to analyze the effect of aspirin on the tumor microenvironment, systemic immunity, and on the healthy mucosa surrounding cancer. METHODS: Patients with a diagnosis of CRC operated on from 2015 to 2019 were retrospectively analyzed (METACCRE cohort). Expression of mRNA of immune surveillance-related genes (PD-L1, CD80, CD86, HLA I, and HLA II) in CRC primary cells treated with aspirin were extracted from Gene Expression Omnibus-deposited public database (GSE76583). The experiment was replicated in cell lines. The mucosal immune microenvironment of a subgroup of patients participating in the IMMUNOREACT1 (ClinicalTrials.gov NCT04915326) project was analyzed with immunohistochemistry and flow cytometry. RESULTS: In the METACCRE Cohort, 12% of 238 patients analyzed were aspirin users. Nodal metastasis was significantly less frequent (p = .008) and tumor-infiltrating lymphocyte infiltration was higher (p = .02) among aspirin users. In the CRC primary cells and selected cell lines, CD80 mRNA expression was increased following aspirin treatment (p = .001). In the healthy mucosa surrounding rectal cancer, the ratio of CD8/CD3 and epithelial cells expressing CD80 was higher in aspirin users (p = .027 and p = .034, respectively). CONCLUSIONS: These data suggested that regular aspirin use may have an active role in enhancing immunosurveillance against CRC.

Rectal sparing approach after preoperative radio - and/or Chemo-therapy (ReSARCh): a prospective, multicentre, observational study.

BACKGROUND: Rectal-sparing approaches for patients with rectal cancer who achieved a complete or major response following neoadjuvant therapy constitute a paradigm of a potential shift in the management of patients with rectal cancer, however their role remains controversial. The aim of this study was to investigate the feasibility of rectal-sparing approaches to preserve the rectum without impairing the outcomes. METHODS: This prospective, multicentre, observational study investigated the outcomes of patients with clinical stage II-III mid-low rectal adenocarcinoma treated with any neoadjuvant therapy, and either transanal local excision or watch-and-wait approach, based on tumor response (major or complete) and patient/surgeon choice. The primary endpoint of the study was rectum preservation at a minimum follow-up of two years. Secondary endpoints were overall, disease-free, local and distant recurrence-free, and stoma-free survival at three years. RESULTS: Of 178 patients enrolled in 16 centres, 112 (62.9%) were managed with local excision and 66 (37.1%) with watch-and-wait. At a median (interquartile range) follow-up of 36.1 (30.6-45.6) months, the rectum was preserved in 144 (80.9%) patients. The 3-year rectum-sparing, overall, disease-free, local recurrence-free, distant recurrence-free survival was 80.6% (95%CI 73.9-85.8), 97.6% (95%CI 93.6-99.1), 90.0% (95%CI 84.3-93.7), 94.7% (95%CI 90.1-97.2), and 94.6% (95%CI 89.9-97.2), respectively. The 3-year stoma-free survival was 95.0% (95%CI 89.5-97.6). The 3-year regrowth-free survival in the watch-and-wait group was 71.8% (95%CI 59.9-81.2). CONCLUSIONS: In rectal cancer patients with major or complete clinical response after neoadjuvant therapy, the rectum can be preserved in about 80% of cases, without compromise the outcomes.

Multiple colorectal adenomas syndrome: The role of MUTYH mutation and the polyps' number in clinical management and colorectal cancer risk.

BACKGROUND & AIMS: Multiple colorectal adenomas (MCRAs) can result from APC (AFAP) or biallelic MUTYH (MAP) mutations, but most patients are wild type and referred to as non-APC/MUTYH polyposis (NAMP). We aim to examine the risk of colorectal cancer (CRC) and the role of endoscopy in managing patients with MCRAs, with a specific focus on clinical features and genotype. METHODS: Records of MRCAs between 2000 and 2022 were retrospectively analysed. Patients were divided according to the genotype (MAP vs. NAMP) and the number of categorised polyps' burden (group 1: 10-24, group 2: 25-49, and group 3: 50-99 adenomas). Predictors of outcome were CRC-free survival (CRC-FS) and Surgery free-survival (S-FS). RESULTS: 220 patients were enrolled (NAMP n = 178(80.0%)). CRC at diagnosis was more frequent in group 3 (p = 0.01), without significant differences between the genotypes (p = 0.20). At a follow-up of 83(41-164) months, 15(7%) patients developed CRC during surveillance. CRC-FS was not correlated to genotype (p = 0.07) or polyps' number (p = 0.33), while S-FS was similar in MAP and NAMP (p = 0.22) and lower in groups 2 and 3 (p = 0.0001). CONCLUSIONS: MAP and NAMP have the same CRC risk and no difference in treatment. Endoscopic surveillance compared favorably with surgery in avoiding CRC risk, even in patients with more severe colorectal polyposis.

Leaving behind a diseased small bowel during surgery for Crohn's disease: Long-term outcomes.

PURPOSES: Stricture is a common complication of Crohn's disease (CD) and may be treated with bowel-sparing procedures. Our study analyzed what happens in terms of intestinal and systemic inflammation when the diseased bowel is left behind following surgery. METHODS: In this retrospective study, we enrolled 42 consecutive patients who underwent strictureplasty (alone or with resection) for stricturing CD. Control patients who underwent complete diseased bowel resection were identified and propensity score-matched for the sex, age, and history of abdominal surgery. Biohumoral values were collected at follow-up examinations at 1, 6, and 12 months after surgery. Magnetic resonance imaging (MRI) was performed before and after strictureplasty in 19 patients. RESULTS: In the strictureplasty group, fecal calprotectin levels were decreased at 12 months (p = 0.03), whereas in the resectiongroup, they were decreased at 6 months (p = 0.02). On MRI, the ADC [apparent diffusion coefficient] (p < 0.001), wall thickness (p = 0.046) and Magnetic Resonance Index of Activity (MaRIA) (p < 0.001) and Clermont (p < 0.001) scores were improved after strictureplasty. Surgical recurrence was more frequent in the strictureplasty group than in the resection group (p = 0.003). CONCLUSIONS: Our retrospective study showed that even if the diseased bowel was left behind after surgery, the intestinal inflammatory activity still decreased. However, the permanence of the diseased bowel still increased the risk of reoperation, probably because of the fibrotic nature of the stenosis and the multifocality of CD.

Predictors of urinary tract infection after lower gastrointestinal surgery.

BACKGROUND: Urinary tract infections (UTIs) cause postoperative morbidity in patients undergoing lower gastrointestinal (GI) surgery that can prolong postoperative hospital stays. In patients with a fever of unknown origin (FUO), clinicians ignore what to do while waiting for the results of the urine culture test. This study aimed to develop a nomogram predicting UTI in the case of postoperative FUO. METHODS: This observational, retrospective study included all consecutive patients from 1 November 2020 to 1 November 2021 undergoing lower-GI surgery at the Chirurgia Generale 3, University Hospital of Padua, Italy. A nomogram was created and externally validated in 90 consecutive patients undergoing urine culture tests for FUO at the Chirurgia Oncologica Unit, Veneto Institute of Oncology. RESULTS: In the development cohort, 109 (N = 109) patients performed a urine culture test for FUO, and 39 were diagnosed with UTI. In a multivariate analysis of patients who underwent urine culture tests for FUO, UTI was associated with female sex, older age, and duration of catheterization at the date of the urine culture test. We developed a nomogram to predict UTI in surgical patients with a C-index of 0.76. In the validation cohort, 90 consecutive patients, who had lower-GI surgery, underwent a urine culture test for FUO and were tested with this nomogram. In the validation cohort, the C-index of the nomogram for predicting a positive urine culture test was 0.71. CONCLUSIONS AND RELEVANCE: UTIs are a common problem in patients undergoing lower-GI surgery. A nomogram including the major risk factors may help to reduce the inappropriate use of antibiotics during the period awaiting the result of the urine culture test.

Pediatric Injury Surveillance From Uncoded Emergency Department Admission Records in Italy: Machine Learning-Based Text-Mining Approach.

BACKGROUND: Unintentional injury is the leading cause of death in young children. Emergency department (ED) diagnoses are a useful source of information for injury epidemiological surveillance purposes. However, ED data collection systems often use free-text fields to report patient diagnoses. Machine learning techniques (MLTs) are powerful tools for automatic text classification. The MLT system is useful to improve injury surveillance by speeding up the manual free-text coding tasks of ED diagnoses. OBJECTIVE: This research aims to develop a tool for automatic free-text classification of ED diagnoses to automatically identify injury cases. The automatic classification system also serves for epidemiological purposes to identify the burden of pediatric injuries in Padua, a large province in the Veneto region in the Northeast Italy. METHODS: The study includes 283,468 pediatric admissions between 2007 and 2018 to the Padova University Hospital ED, a large referral center in Northern Italy. Each record reports a diagnosis by free text. The records are standard tools for reporting patient diagnoses. An expert pediatrician manually classified a randomly extracted sample of approximately 40,000 diagnoses. This study sample served as the gold standard to train an MLT classifier. After preprocessing, a document-term matrix was created. The machine learning classifiers, including decision tree, random forest, gradient boosting method (GBM), and support vector machine (SVM), were tuned by 4-fold cross-validation. The injury diagnoses were classified into 3 hierarchical classification tasks, as follows: injury versus noninjury (task A), intentional versus unintentional injury (task B), and type of unintentional injury (task C), according to the World Health Organization classification of injuries. RESULTS: The SVM classifier achieved the highest performance accuracy (94.14%) in classifying injury versus noninjury cases (task A). The GBM method produced the best results (92% accuracy) for the unintentional and intentional injury classification task (task B). The highest accuracy for the unintentional injury subclassification (task C) was achieved by the SVM classifier. The SVM, random forest, and GBM algorithms performed similarly against the gold standard across different tasks. CONCLUSIONS: This study shows that MLTs are promising techniques for improving epidemiological surveillance, allowing for the automatic classification of pediatric ED free-text diagnoses. The MLTs revealed a suitable classification performance, especially for general injuries and intentional injury classification. This automatic classification could facilitate the epidemiological surveillance of pediatric injuries by also reducing the health professionals' efforts in manually classifying diagnoses for research purposes.

IMMUNOREACT 6: weak immune surveillance characterizes early-onset rectal cancer.

BACKGROUND: Colon cancer in young patients is often associated with hereditary syndromes; however, in early-onset rectal cancer, mutations of these genes are rarely observed. The aim of this study was to analyse the features of the local immune microenvironment and the mutational pattern in early-onset rectal cancer. METHODS: Commonly mutated genes were analysed within a rectal cancer series from the University Hospital of Padova. Mutation frequency and immune gene expression in a cohort from The Cancer Genome Atlas ('TCGA') were compared and immune-cell infiltration levels in the healthy rectal mucosa adjacent to rectal cancers were evaluated in the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 ('IMMUNOREACT') series. RESULTS: In the authors' series, the mutation frequency of BRAF, KRAS, and NRAS, as well as microsatellite instability frequency, were not different between early- and late-onset rectal cancer. In The Cancer Genome Atlas series, among the genes with the most considerable difference in mutation frequency between young and older patients, seven genes are involved in the immune response and CD69, CD3, and CD8ß expression was lower in early-onset rectal cancer. In the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 series, young patients had a lower rate of CD4+ T cells, but higher T regulator infiltration in the rectal mucosa. CONCLUSION: Early-onset rectal cancer is rarely associated with common hereditary syndromes. The tumour microenvironment is characterized by a high frequency of mutations impairing the local immune surveillance mechanisms and low expression of immune editing-related genes. A constitutively low number of CD4 T cells associated with a high number of T regulators indicates an imbalance in the immune surveillance mechanisms.

IMMUNOREACT 5: female patients with rectal cancer have better immune editing mechanisms than male patients - a cohort study.

BACKGROUND: Studies evaluating sex differences in colorectal cancer (CRC) tumor microenvironment are limited, and no previous study has focused on rectal cancer patients' constitutive immune surveillance mechanisms. The authors aimed to assess gender-related differences in the immune microenvironment of rectal cancer patients. METHODS: A systematic review and meta-analysis were conducted up to 31 May 2021, including studies focusing on gender-related differences in the CRC tumor microenvironment. Data on the mutational profile of rectal cancer were extracted from the Cancer Genome Atlas (TCGA). A subanalysis of the two IMMUNOREACT trials (NCT04915326 and NCT04917263) was performed, aiming to detect gender-related differences in the immune microenvironment of the healthy mucosa in patients with early (IMMUNOREACT 1 cohort) and locally advanced rectal cancer following neoadjuvant therapy (IMMUNOREACT 2 cohort). In the retrospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 442 patients (177 female and 265 male), while in the retrospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), we enrolled 264 patients (80 female and 184 male). In the prospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 72 patients (26 female and 46 male), while in the prospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), the authors enrolled 105 patients (42 female and 63 male). RESULTS: Seven studies reported PD-L1 expression in the CRC microenvironment, but no significant difference could be identified between the sexes. In the TGCA series, mutations of SYNE1 and RYR2 were significantly more frequent in male patients with rectal cancer. In the IMMUNOREACT 1 cohort, male patients had a higher expression of epithelial cells expressing HLA class I, while female patients had a higher number of activated CD4+Th1 cells. Female patients in the IMMUNOREACT 2 cohort showed a higher infiltration of epithelial cells expressing CD86 and activated cytotoxic T cells (P=0.01). CONCLUSIONS: Male patients have more frequent oncogene mutations associated with a lower expression of T-cell activation genes. In the healthy mucosa of female patients, more Th1 cells and cytotoxic T cells suggest a potentially better immune response to the tumor. Sex should be considered when defining the treatment strategy for rectal cancer patients or designing prognostic scores.

Vedolizumab is superior to infliximab in biologic naïve patients with ulcerative colitis.

There are no prospective, head-to-head, controlled trials comparing the efficacy and safety of Infliximab (IFX) and Vedolizumab (VDZ) for the treatment of moderate-to-severe ulcerative colitis (UC), while only a few real-life retrospective studies have been published so far. We assessed the efficacy of IFX vs. VDZ in two cohorts of biologic-naïve outpatients with moderate-to-severe UC or mild, but refractory, disease. Data were extracted from patients' files and reviewed. The duration of follow-up (FU) was 52 weeks. The primary endpoint was the clinical remission (CR) at the end of FU. Secondary endpoints were: drug persistency, time to obtain CR, clinical response at the end of the induction phase (IP), steroid-free CR (compared to patients who used steroids at baseline) at the end of FU, need for drug optimization, adverse events (AEs), and normalization of C-reactive protein (CRP). We also analyzed the causes of dropping out (primary non-response), or secondary loss of response (immunogenic or not), for each group. We enrolled 82 patients (50 IFX and 32 VDZ) who met the inclusion criteria. At the end of FU, CR was obtained in 32% of the patients on IFX and 75% on VDZ (p = 0.0003). Drug persistency was superior for VDZ compared to IFX (78% vs. 52%, p = 0.033). Clinical response at the end of induction was reached in 54% and in 81% in the IFX and VDZ group, respectively (p = 0.014). Steroid-free clinical remission at the end of FU was 62% and 94% in the IFX vs. VDZ group, respectively (p = 0.036). The need for drug optimization was higher for VDZ than for IFX (28% vs. 57%, p = 0.009), while the time to obtain CR, the incidence of AEs, mean duration of FU, and rate of CRP normalization at the end of IP were comparable between the two groups. There was a prevalence of patients dropping out because of primary non-response in IFX group (p = 0.027), while the incidence of secondary loss of response was similar in the two groups. At the multivariate analysis, CRP and Partial Mayo Score (PMS) at T0 did not correlate with CR at the end of FU in both groups. In this retrospective, real world data study in biologic-naïve patients, VDZ was superior to IFX in CR, clinical response rate at the end of IP, drug persistency, steroid-free remission, and need for optimization at the end of FU.