A coordinate deregulation of microRNAs expressed in mucosa adjacent to tumor predicts relapse after resection in localized colon cancer.

Up to 20% of colorectal cancer (CRC) node-negative patients develop loco-regional or distant recurrences within 5 years from surgery. No predictive biomarker able to identify the node-negative subjects at high risk of relapse after curative treatment is presently available.Forty-eight localized (i.e. stage I-II) colon cancer patients who underwent radical tumor resection were considered. The expression of five miRNAs, involved in CRC progression, was investigated by qRT-PCR in both tumor tissue and matched normal colon mucosa.Interestingly, we found that the coordinate deregulation of four miRNAs (i.e. miR-18a, miR-21, miR-182 and miR-183), evaluated in the normal mucosa adjacent to tumor, is predictive of relapse within 55 months from curative surgery.Our results, if confirmed in independent studies, may help to identify high-risk patients who could benefit most from adjuvant therapy. Moreover, this work highlights the importance of extending the search for tissue biomarkers also to the tumor-adjacent mucosa.

PD-L1 overexpression in ampulla of Vater carcinoma and its pre-invasive lesions.

AIMS: PD-1/PD-L1 checkpoint immunotherapy has been proposed recently as a promising treatment in relapsed/refractory disease, used eventually in combination with traditional chemotherapy in different cancer settings. To date, no data are available concerning PD-L1 expression in ampulla of Vater carcinoma and its pre-invasive lesions. METHODS AND RESULTS: We assessed the immunohistochemical expression of PD-L1 in a series of 26 ampullary adenocarcinomas, 50 ampullary dysplastic lesions and 10 normal duodenal mucosa samples. Moreover, in all cases DNA mismatch repair proteins status was investigated. PD-L1 was expressed in seven of 26 (26.9%) invasive carcinomas and three of 50 (6.0%) dysplastic samples. Most of the PD-L1-positive tumours (seven of 10) were intestinal-type and poorly differentiated (G3). The number of PD-L1-positive stromal lymphoid cells was significantly higher in dysplastic and invasive lesions than in the normal samples (P = 0.011). Nineteen dysplastic lesions and eight invasive carcinomas did not show any evident epithelial or stromal PD-L1 expression. Four of the carcinomas were mismatch repair-deficient and two of these were PD-L1-positive. Furthermore, mismatch repair-deficient lesions showed a significantly higher average of PD-L1-positive stromal lymphoid cells than those of neoplastic PD-L1-negative samples (62.8 versus 21.6; P < 0.001). CONCLUSIONS: The present results suggest a role of the PD-1/PD-L1 axis in ampullary adenocarcinomas, and therefore this may also prompt consideration of checkpoint immunotherapy as a novel promising treatment for these tumours.

Impact of fecal immunochemical test-based screening programs on proximal and distal colorectal cancer surgery rates: A natural multiple-baseline experiment.

BACKGROUND: Colorectal cancer (CRC) screening programs based on the fecal immunochemical test (FIT) were found to reduce overall CRC surgery rates, but to the authors' knowledge data by subsite are lacking. The objective of the current study was to assess the impact of FIT-based screening on proximal and distal CRC surgical resection rates. METHODS: The Veneto region in Italy can be subdivided into 3 areas with staggered introduction of FIT-based screening programs: early (2002-2004), intermediate (2005-2007), and late (2008-2009) areas. Time series of proximal and distal CRC surgery were investigated in the 3 populations between 2001 and 2012 by Joinpoint regression analysis and segmented Poisson regression models. RESULTS: The impact of screening was similar in the study populations. Rates of distal CRC surgical resection were stable before screening, increased at the time of screening implementation (rate ratio [RR], 1.25; 95% confidence interval [95% CI], 1.14-1.37), and thereafter declined by 10% annually (RR, 0.90; 95% CI, 0.88-0.92). Rates of proximal CRC surgical resection increased by 4% annually before screening (RR, 1.04; 95% CI, 1.03-1.05) but, after a peak at the time of screening initiation, the trend was reversed. The percentage represented by proximal CRC surgery rose from 28% in 2001 to 41% in 2012. CONCLUSIONS: In this natural multiple-baseline experiment, consistent findings across each time series demonstrated that FIT-based screening programs have an impact both on proximal and distal CRC surgery rates. However, underlying preexisting epidemiological trends are leading to a rapidly increasing percentage of proximal CRC.

Trends in colorectal cancer surgical resection rates during the screening era: a retrospective study in Italy.

BACKGROUND: Faecal immunochemical test (FIT)-based screening is effective in reducing colorectal cancer (CRC) incidence, but its sensitivity for proximal lesions remains low. OBJECTIVES: We compared age-adjusted CRC surgical resection rates across anatomic sites (proximal colon, distal colon, rectum), age groups and sex over 20 years in a large Italian population. We particularly focused on changes in trends following FIT-screening implementation in the target population (50-69 years). DESIGN: This retrospective study analysed data from the Veneto Region's administrative Hospital Discharge Dataset, involving over 54 000 patients aged 40-89 (43.4% female) who underwent CRC surgery between 2002 and 2021. RESULTS: Overall, surgery rates increased until 2007 (annual percentage changes: 2.5% in males, 2.9% in females) and then declined (-4.2% in males, -3.4% in females). This decline was steeper for distal and rectal cancers compared with proximal cancer, suggesting a shift towards more right-sided CRC surgery.In males, the prescreening increase in proximal surgery was reversed after screening implementation (slope change: -6%) while the prescreening decline accelerated for distal (-4%) and rectal (-3%) surgeries. In females, stable prescreening trends shifted downward for all sites (-5% for proximal, -8% for distal and -7% for rectal surgery). However, the change in trends between prescreening and postscreening periods was not different across anatomic sites for either sex (all slope change differences in pairwise comparisons were not statistically significant). CONCLUSION: The shift towards proximal surgery may not be entirely due to the FIT's low sensitivity but may reflect an underlying upward trend in proximal cancers independent of screening.

Rectal Sparing Approach after preoperative Radio- and/or Chemo-therapy (ReSARCh): a prospective, multicenter, 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, multicenter, 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 2 years. Secondary endpoints were overall, disease-free, local and distant recurrence-free, and stoma-free survival at 3 years. RESULTS: Of the 178 patients enrolled in 16 centers, 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 survival, disease-free survival, local recurrence-free survival, and 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 compromising the outcomes.

Factors affecting the treatment of multiple colorectal adenomas.

BACKGROUND: Currently, no guidelines exist for the treatment of patients with multiple colorectal adenomas (MCRAs) (>10 but <100 synchronous nondiminutive polyps of the large bowel). This retrospective study aimed to investigate the clinical and molecular factors related to different treatments for MCRAs. METHODS: Patients with MCRAs were consecutively enrolled from January 2003 to June 2011. Sequencing of their APC and MutYH genes was performed. The clinical, molecular, and family histories of the patients were collected using the Progeny database. The patient treatments were divided into three groups of increasing clinical weight: endoscopic polypectomy, segmental resection, and total colectomy. A logistic regression analysis of clinicomolecular factors related to different treatment options was performed. RESULTS: The study comprised 80 patients (32 women, 40%) with a median age of 53 years (range 13-74 years). The median number of polyps was 33 (range 10-90).The cases included 62 diffuse polyposis, 18 segmental polyposis coli and synchronous colorectal carcinomas (CRC; 34 cases, 43%). The pathogenetic mutations were biallelic MutYH (n = 19, 24%) and APC (n = 4, 5%). The mean follow-up period was 74 months (median 43 months, range 1-468 months). Endoscopic polypectomy was performed in 25 cases (31%), segmental resection in 16 cases (20%), and total colectomy in 39 cases (49%). The logistics regression analysis, considering all the patients, showed that the number of polyps, the presence of CRC, and mutation were correlated with more intensive treatment. For the patients without CRC, only the number of polyps was correlated with the severity of the treatment (p > 0.0166). "On the ROC (receiver operating characteristic) curve, 25 was the number of polyps that best discriminated between surgical and endoscopic therapy. CONCLUSIONS: The majority of patients with MCRAs undergo surgery. For patients without CRC, only the number of polyps, and not the presence of a disease-causing mutation, is correlated with increased heaviness of treatment. Patients with more than 25 polyps are more likely to undergo a surgical resection.

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.

Analysis of morbidity and mortality, quality of life and bowel function after total colectomy with ileorectal anastomosis versus right and left hemicolectomy: A study to optimise the treatment of lynch syndrome and attenuated polyposis coli.

BACKGROUND: The optimal surgical treatment for colonic colorectal carcinoma (CRC) in Lynch Syndrome (LS) and attenuated polyposis coli (A-FAP phenotype) patients is still debated, since there is a high risk of metachronous colonic adenomas and carcinoma after primary surgery. The aim of this study was to compare surgical outcome, functional data, and Quality of Life (QoL) after total colectomy with ileorectal anastomosis (TC-IRA) compared to right (RH) or left hemicolectomy/sigmoidectomy (LH/SI). METHODS: Patients who underwent TC-IRA (ileorectal anastomosis from 8 to 15 cm from the anal verge) for CRC and/or polyposis at our Surgical Department between 2001 and 2017 were included in the study group, and were matched one-to-one by baseline and clinical characteristics with a control group of RH and LH/SI. Morbidity and mortality data were collected (Clavien-Dindo classification). International validated questionnaires were used to investigate QoL and bowel function. RESULTS: Fifty-five patients were enrolled in each group. No differences were found on length of hospital stay, Clavien-Dindo grade III-IV complications and mortality (p > 0.05). TC-IRA showed a longer operative time than RH and LH/SI (p < 0.0001) and a major blood loss than RH (p < 0.0001). Worse bowel function and worse QoL, only for the bowel-related items, were recorded in TC-IRA group. The general QoL was similar among the groups. CONCLUSIONS: TC-IRA and segmental resection have similar morbidity and mortality. The worse bowel function in TC-IRA group does not impact on the general QoL. These data can be useful in the setting of risk-reducing surgery decision in LS and A-FAP patients.

MiR-21 up-regulation in ampullary adenocarcinoma and its pre-invasive lesions.

Poor information is available on the molecular landscape characterizing the carcinogenetic process leading to ampullary carcinoma. MiR-21 is one of the most frequently up-regulated miRNAs in pancreatic adenocarcinoma, a tumor sharing similar molecular features with ampullary adenocarcinomas (AVCs), above all with the pancreatic-biliary type. We profiled, by in situ hybridization (ISH), miR-21 expression in a series of 26 AVCs, 50 ampullary dysplastic lesions (35 low-grade [LG-IEN] and 15 high-grade [HG-IEN]) and 10 normal duodenal mucosa samples. The same series was investigated by immunohistochemistry for ß-catenin, p53 and HER2 expression. HER2 gene amplification was evaluated by chromogenic in situ hybridization. To validate miR-21 ISH results we performed miR-21 qRT-PCR analysis in a series of 10 AVCs and their matched normal samples. All the normal control samples showed a negative or faint miR-21 expression, whereas a significant miR-21 up-regulation was observed during the carcinogenetic cascade (p < 0.001), with 21/26 (80.8%) of cancer samples showing a miR-21 overexpression. In comparison to control samples, a significant overexpression was found in samples of LG-IEN (p = .0003), HG-IEN (p = .0001), and AVCs (p < 0.0001). No significant difference in miR-21 overexpression was observed between LG-IEN, HG-IEN and AVCs. By qRT-PCR analysis, AVCs showed a 1.7-fold increase over the controls (p = .003). P53 was frequently dysregulated in both dysplastic and carcinoma samples (44 out of 76; 57.9%). A 20% (10/50) of dysplastic lesions and 11% (3/26) of carcinomas were characterized by a nuclear localization of ß-catenin. Only 2 AVCs (7.7%; both intestinal-type) showed a HER2 overexpression (both 2+), which corresponded to a HER2 gene amplification at CISH analysis. This is the first study demonstrating a miRNA dysregulation in the whole spectrum of ampullary carcinogenesis. MiR-21 overexpression is an early molecular event during ampullary carcinogenesis and its levels increase with the neoplastic progression.

Reduced Plasma Levels of Very-Long-Chain Dicarboxylic Acid 28:4 in Italian and Brazilian Colorectal Cancer Patient Cohorts.

BACKGROUND: There are currently no blood-based biomarkers for early diagnosis of colorectal cancer. Previous research has suggested that very-long-chain dicarboxylic acid (VLCDCA) 28:4 might be such a biomarker. METHODS: Using high-resolution mass spectrometry, we analyzed VLCDCA 28:4 in the plasma of colorectal cancer patients in Italian [n = 62] and Brazilian [n = 52] cohorts. Additionally, we investigated individuals diagnosed with familial adenomatous polyposis (FAP; n = 27), one of the most important clinical forms of inherited susceptibility to colorectal cancer. Results: Decrements in plasma levels of VLCDCA 28:4 were monitored in colorectal cancer patients. These decreases were independent of the stage of tumor development and the individual's age. However, no decrements in VLCDCA 28:4 were monitored in FAP patients. CONCLUSIONS: The plasma levels of VLCDCA 28:4 represent a potential biomarker of sporadic colorectal cancer. In addition, it is possible that resupply of this anti-inflammatory lipid may represent a new therapeutic strategy for CRC and inflammatory disorders.