Pierluigi Pilati

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. 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. 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 CD8β 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. 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.

Objective This study compared all patients undergoing surgery for colorectal cancer in 20 hospitals of Northern Italy in 2019 versus 2020, in order to evaluate whether COVID-19-related delays in the execution of colorectal cancer screening resulted in more advanced cancers at diagnosis and worse clinical outcomes. Design A retrospective multicentric cohort analysis of patients who underwent surgery for colorectal cancer in March-December 2019 (2019) versus March-December 2020 (2020). The independent predictors of disease stage (oncologic stage, associated symptoms, clinical T4 stage, metastasis) and postoperative outcome (surgical complications, palliative surgery, 30-day death) were evaluated using logistic regression. Results The sample consisted of 1755 patients operated in 2019, and 1481 in 2020 (both mean ages 69.6 years). The proportions of cancers with symptoms, clinical T4 stage, liver and lung metastases in 2019 and 2020 were, respectively: 80.8% vs 84.5%; 6.2% vs 8.7%; 10.2% vs 10.3%; and 3.0% vs 4.4%. The proportions of surgical complications, palliative surgery, and death in 2019 and 2020 were, respectively: 34.4%vs 31.9%; 5.0% vs 7.5%; and 1.7% vs 2.4%. At multivariate analysis, as compared with 2019, cancers in 2020 were significantly more likely to be symptomatic (Odds Ratio - OR: 1.36, 95% Confidence Interval - CI: 1.09-1.69), in clinical T4 stage (OR: 1.38; 1.03-1.85), with multiple liver metastases (OR: 2.21; 1.24-3.94), but less likely to cause surgical complications (OR: 0.79; 0.68-0.93). Conclusions Colorectal cancer patients who had surgery between March and December 2020 had an increased risk of more advanced disease in terms of associated symptoms, cancer location, clinical T4 stage, and number of liver metastases. What is already known about this subject?A specific search regarding the correlation between colorectal cancer oncologic outcomes and COVID-19 showed a few modeling studies which reported the predictions of the potential impact of the diagnostic delays (due to the reduction of the screening programs) on the survival of patients affected by colorectal cancer. However, no study reported any real-life evidence regarding the correlation between the COVID-19 outbreak and the deteriorations of the oncologic outcomes of patients with colorectal cancer. What are the new findings?The present study showed that patients who had surgery for colorectal cancer between March and December 2020 had an increased risk of more advanced disease in terms of associated symptoms, cancer location, clinical T4 stage, and number of liver metastases, than patients who had surgery between March and December 2019. How might it impact on clinical practice in the foreseeable future?The present study confirmed that the backlogs of the screening programs have had, and probably will have, detrimental effects on the oncologic outcomes of patients affected by colorectal cancer. Increased resources should be placed in order to reactivate and enhance the screening programs, and to reduce the risk of colorectal cancer patients to be diagnosed with advanced cancer in the next future.

Three‐dimensional (3D) cancer models are overlooking the scientific landscape with the primary goal of bridging the gaps between two‐dimensional (2D) cell lines, animal models and clinical research. Here, we describe an innovative tissue engineering approach applied to colorectal cancer (CRC) starting from decellularized human biopsies in order to generate an organotypic 3D‐bioactive model. This in vitro 3D system recapitulates the ultrastructural environment of native tissue as demonstrated by histology, immunohistochemistry, immunofluorescence and scanning electron microscopy analyses. Mass spectrometry of proteome and secretome confirmed a different stromal composition between decellularized healthy mucosa and CRC in terms of structural and secreted proteins. Importantly, we proved that our 3D acellular matrices retained their biological properties: using CAM assay, we observed a decreased angiogenic potential in decellularized CRC compared with healthy tissue, caused by direct effect of DEFA3. We demonstrated that following a 5 days of recellularization with HT‐29 cell line, the 3D tumor matrices induced an over‐expression of IL‐8, a DEFA3‐mediated pathway and a mandatory chemokine in cancer growth and proliferation. Given the biological activity maintained by the scaffolds after decellularization, we believe this approach is a powerful tool for future pre‐clinical research and screenings.

Background Pancreatoduodenectomy is a surgical procedure used to treat diseases of the pancreatic head and, less often, the duodenum. The most common disease treated is cancer, but pancreatoduodenectomy is also used for people with traumatic lesions and chronic pancreatitis. Following pancreatoduodenectomy, the pancreatic stump must be connected with the small bowel where pancreatic juice can play its role in food digestion. Pancreatojejunostomy (PJ) and pancreatogastrostomy (PG) are surgical procedures commonly used to reconstruct the pancreatic stump after pancreatoduodenectomy. Both of these procedures have a non‐negligible rate of postoperative complications. Since it is unclear which procedure is better, there are currently no international guidelines on how to reconstruct the pancreatic stump after pancreatoduodenectomy, and the choice is based on the surgeon's personal preference. Objectives To assess the effects of pancreaticogastrostomy compared to pancreaticojejunostomy on postoperative pancreatic fistula in participants undergoing pancreaticoduodenectomy. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 9), Ovid MEDLINE (1946 to 30 September 2016), Ovid Embase (1974 to 30 September 2016) and CINAHL (1982 to 30 September 2016). We also searched clinical trials registers (ClinicalTrials.gov and WHO ICTRP) and screened references of eligible articles and systematic reviews on this subject. There were no language or publication date restrictions. Selection criteria We included all randomized controlled trials (RCTs) assessing the clinical outcomes of PJ compared to PG in people undergoing pancreatoduodenectomy. Data collection and analysis We used standard methodological procedures expected by The Cochrane Collaboration. We performed descriptive analyses of the included RCTs for the primary (rate of postoperative pancreatic fistula and mortality) and secondary outcomes (length of hospital stay, rate of surgical re‐intervention, overall rate of surgical complications, rate of postoperative bleeding, rate of intra‐abdominal abscess, quality of life, cost analysis). We used a random‐effects model for all analyses. We calculated the risk ratio (RR) for dichotomous outcomes, and the mean difference (MD) for continuous outcomes (using PG as the reference) with 95% confidence intervals (CI) as a measure of variability. Main results We included 10 RCTs that enrolled a total of 1629 participants. The characteristics of all studies matched the requirements to compare the two types of surgical reconstruction following pancreatoduodenectomy. All studies reported incidence of postoperative pancreatic fistula (the main complication) and postoperative mortality. Overall, the risk of bias in included studies was high; only one included study was assessed at low risk of bias. There was little or no difference between PJ and PG in overall risk of postoperative pancreatic fistula (PJ 24.3%; PG 21.4%; RR 1.19, 95% CI 0.88 to 1.62; 7 studies; low‐quality evidence). Inclusion of studies that clearly distinguished clinically significant pancreatic fistula resulted in us being uncertain whether PJ improved the risk of pancreatic fistula when compared with PG (19.3% versus 12.8%; RR 1.51, 95% CI 0.92 to 2.47; very low‐quality evidence). PJ probably has little or no difference from PG in risk of postoperative mortality (3.9% versus 4.8%; RR 0.84, 95% CI 0.53 to 1.34; moderate‐quality evidence). We found low‐quality evidence that PJ may differ little from PG in length of hospital stay (MD 1.04 days, 95% CI ‐1.18 to 3.27; 4 studies, N = 502) or risk of surgical re‐intervention (11.6% versus 10.3%; RR 1.18, 95% CI 0.86 to 1.61; 7 studies, N = 1263). We found moderate‐quality evidence suggesting little difference between PJ and PG in terms of risk of any surgical complication (46.5% versus 44.5%; RR 1.03, 95% CI 0.90 to 1.18; 9 studies, N = 1513). PJ may slightly improve the risk of postoperative bleeding (9.3% versus 13.8%; RR 0.69, 95% CI: 0.51 to 0.93; low‐quality evidence; 8 studies, N = 1386), but may slightly worsen the risk of developing intra‐abdominal abscess (14.7% versus 8.0%; RR 1.77, 95% CI 1.11 to 2.81; 7 studies, N = 1121; low quality evidence). Only one study reported quality of life (N = 320); PG may improve some quality of life parameters over PJ (low‐quality evidence). No studies reported cost analysis data. Authors' conclusions There is no reliable evidence to support the use of pancreatojejunostomy over pancreatogastrostomy. Future large international studies may shed new light on this field of investigation.

BACKGROUND: The number of studies on the association between clock genes’ polymorphisms and cancer susceptibility has increased over the last years but the results are often conflicting and no comprehensive overview and quantitative summary of the evidence in this field is available.