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Background: Wnt/β-catenin signalling impairment accounts for 85% of colorectal cancers (CRCs), including sporadic and familial adenomatous polyposis (FAP) settings. An altered PI3K/mTOR pathway and gut microbiota also contribute to CRC carcinogenesis. We studied the interplay between the two pathways and the microbiota composition within each step of CRC carcinogenesis. Methods: Proteins and target genes of both pathways were analysed by RT-qPCR and IHC in tissues from healthy faecal immunochemical test positive (FIT+, n = 17), FAP (n = 17) and CRC (n = 15) subjects. CRC-related mutations were analysed through NGS and Sanger. Oral, faecal and mucosal microbiota was profiled by 16 S rRNA-sequencing. Results: We found simultaneous hyperactivation of Wnt/β-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs. Wnt/β-catenin molecular markers positively correlated with Clostridium_sensu_stricto_1 and negatively with Bacteroides in FAP faecal microbiota. Alistipes, Lachnospiraceae, and Ruminococcaceae were enriched in FAP stools and adenomas, the latter also showing an overabundance of Lachnoclostridium, which positively correlated with cMYC. In impaired-mTOR-mutated CRC tissues, p-S6R correlated with Fusobacterium and Dialister, the latter also confirmed in the faecal-ecosystem. Conclusions: Our study reveals an interplay between Wnt/β-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment. [ABSTRACT FROM AUTHOR]

Locally Recurrent Rectal Cancer (LRRC) remains a major clinical concern; it rapidly invades pelvic organs and nerve roots, causing severe symptoms. Curative-intent salvage therapy offers the only potential for cure but it has a higher chance of success when LRRC is diagnosed at an early stage. Imaging diagnosis of LRRC is very challenging due to fibrosis and inflammatory pelvic tissue, which can mislead even the most expert reader. This study exploited a radiomic analysis to enrich, through quantitative features, the characterization of tissue properties, thus favoring an accurate detection of LRRC by Computed Tomography (CT) and 18 F-FDG-Positron Emission Tomography/CT (PET/CT). Of 563 eligible patients undergoing radical resection (R0) of primary RC, 57 patients with suspected LRRC were included, 33 of which were histologically confirmed. After manually segmenting suspected LRRC in CT and PET/CT, 144 Radiomic Features (RFs) were generated, and RFs were investigated for univariate significant discriminations (Wilcoxon rank-sum test, p < 0.050) of LRRC from NO LRRC. Five RFs in PET/CT (p < 0.017) and two in CT (p < 0.022) enabled, individually, a clear distinction of the groups, and one RF was shared by PET/CT and CT. As well as confirming the potential role of radiomics to advance LRRC diagnosis, the aforementioned shared RF describes LRRC as tissues having high local inhomogeneity due to the evolving tissue's properties. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the pathological complete response (pCR) rate of locally advanced rectal cancer (LARC) after adaptive high-dose neoadjuvant chemoradiation (CRT) based on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT). Methods: The primary endpoint was the pCR rate. Secondary endpoints were the predictive value of 18 F-FDG-PET/CT on pathological response and acute and late toxicity. All patients performed 18 F-FDG-PET/CT at baseline (PET0) and after 2 weeks during CRT (PET1). The metabolic PET parameters were calculated both at the PET0 and PET1. The total CRT dose was 45 Gy to the pelvic lymph nodes and 50 Gy to the primary tumor, corresponding mesorectum, and to metastatic lymph nodes. Furthermore, a sequential boost was delivered to a biological target volume defined by PET1 with an additional dose of 5 Gy in 2 fractions. Capecitabine (825 mg/m2 twice daily orally) was prescribed for the entire treatment duration. Results: Eighteen patients (13 males, 5 females; median age 55 years [range, 41–77 years]) were enrolled in the trial. Patients underwent surgical resection at 8–9 weeks after the end of neoadjuvant CRT. No patient showed grade > 1 acute radiation-induced toxicity. Seven patients (38.8%) had TRG = 0 (complete regression), 5 (27.0%) showed TRG = 2, and 6 (33.0%) had TRG = 3. Based on the TRG results, patients were classified in two groups: TRG = 0 (pCR) and TRG = 1, 2, 3 (non pCR). Accepting p < 0.05 as the level of significance, at the Kruskal–Wallis test, the medians of baseline-MTV, interim-SUVmax, interim-SUVmean, interim-MTV, interim-TLG, and the MTV reduction were significantly different between the two groups. 18 F-FDG-PET/CT was able to predict the pCR in 77.8% of cases through compared evaluation of both baseline PET/CT and interim PET/CT. Conclusions: Our results showed that a dose escalation on a reduced target in the final phase of CRT is well tolerated and able to provide a high pCR rate. [ABSTRACT FROM AUTHOR]

Purpose: The impact of anastomotic leaks (AL) on oncological outcomes after low anterior resection for mid-low rectal cancer is still debated. The aim of this study was to evaluate overall survival (OS), disease-free survival (DFS), and local and distant recurrence in patients with AL following low anterior resection. Methods: This is an extension of a multicentre RCT (NCT01110798). Kaplan–Meier method and the log-rank test were used to estimate and compare the 3-, 5-, and 10-year OS and DFS, and local and distant recurrence in patients with and without AL. Predictors of OS and DFS were evaluated using the Cox regression analysis as secondary aim. Results: Follow-up was available for 311 patients. Of them, 252 (81.0%) underwent neoadjuvant chemoradiotherapy and 138 (44.3%) adjuvant therapy. AL occurred in 63 (20.3%) patients. At a mean follow-up of 69.5 ± 31.9 months, 23 (7.4%) patients experienced local recurrence and 49 (15.8%) distant recurrence. The 3-, 5-, and 10-year OS and DFS were 89.2%, 85.3%, and 70.2%; and 80.7%, 75.1%, and 63.5% in patients with AL, and 88.9%, 79.8% and 72.3%; and 83.7, 74.2 and 62.8%, respectively in patients without (p = 0.89 and p = 0.84, respectively). At multivariable analysis, AL was not an independent predictor of OS (HR 0.65, 95%CI 0.34–1.28) and DFS (HR 0.70, 95%CI 0.39–1.25), whereas positive circumferential resection margins and pathological stage impaired both. Conclusions: In the context of modern multimodal rectal cancer treatment, AL does not affect long-term OS, DFS, and local and distant recurrence in patients with mid-low rectal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is the second most malignant tumor per number of deaths after lung cancer and the third per number of new cases after breast and lung cancer. The correct and rapid identification (i.e., segmentation of the cancer regions) is a fundamental task for correct patient diagnosis. In this study, we propose a novel automated pipeline for the segmentation of MRI scans of patients with LARC in order to predict the response to nCRT using radiomic features. This study involved the retrospective analysis of T2-weighted MRI scans of 43 patients affected by LARC. The segmentation of tumor areas was on par or better than the state-of-the-art results, but required smaller sample sizes. The analysis of radiomic features allowed us to predict the TRG score, which agreed with the state-of-the-art results. Background: Rectal cancer is a malignant neoplasm of the large intestine resulting from the uncontrolled proliferation of the rectal tract. Predicting the pathologic response of neoadjuvant chemoradiotherapy at an MRI primary staging scan in patients affected by locally advanced rectal cancer (LARC) could lead to significant improvement in the survival and quality of life of the patients. In this study, the possibility of automatizing this estimation from a primary staging MRI scan, using a fully automated artificial intelligence-based model for the segmentation and consequent characterization of the tumor areas using radiomic features was evaluated. The TRG score was used to evaluate the clinical outcome. Methods: Forty-three patients under treatment in the IRCCS Sant'Orsola-Malpighi Polyclinic were retrospectively selected for the study; a U-Net model was trained for the automated segmentation of the tumor areas; the radiomic features were collected and used to predict the tumor regression grade (TRG) score. Results: The segmentation of tumor areas outperformed the state-of-the-art results in terms of the Dice score coefficient or was comparable to them but with the advantage of considering mucinous cases. Analysis of the radiomic features extracted from the lesion areas allowed us to predict the TRG score, with the results agreeing with the state-of-the-art results. Conclusions: The results obtained regarding TRG prediction using the proposed fully automated pipeline prove its possible usage as a viable decision support system for radiologists in clinical practice. [ABSTRACT FROM AUTHOR]

Pre-operative chemoradiotherapy (CRT) followed by surgical resection is still the standard treatment for locally advanced low rectal cancer. Nowadays new strategies are emerging to treat patients with a complete response to pre-operative treatment, rendering the optimal management still controversial and under debate. The primary aim of this study was to obtain a snapshot of tumor regression grade (TRG) distribution after standard CRT. Second, we aimed to identify a correlation between clinical tumor stage (cT) and TRG, and to define the accuracy of magnetic resonance imaging (MRI) in the restaging setting. Between January 2017 and June 2019, a cross sectional multicentric study was performed in 22 referral centers of colon-rectal surgery including all patients with cT3-4Nx/cTxN1-2 rectal cancer who underwent pre-operative CRT. Shapiro–Wilk test was used for continuous data. Categorical variables were compared with Chi-squared test or Fisher's exact test, where appropriate. Accuracy of restaging MRI in the identification of pathologic complete response (pCR) was determined evaluating the correspondence with the histopathological examination of surgical specimens. In the present study, 689 patients were enrolled. Complete tumor regression rate was 16.9%. The "watch and wait" strategy was applied in 4.3% of TRG4 patients. A clinical correlation between more advanced tumors and moderate to absent tumor regression was found (p = 0.03). Post-neoadjuvant MRI had low sensibility (55%) and high specificity (83%) with accuracy of 82.8% in identifying TRG4 and pCR. Our data provided a contemporary description of the effects of pre-operative CRT on a large pool of locally advanced low rectal cancer patients treated in different colon-rectal surgical centers. [ABSTRACT FROM AUTHOR]

Purpose: The objective was to collect the data available regarding the presence of laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gastrointestinal system and to evaluate whether the digestive system could contribute to viral transmission. Methods: Bibliographic databases were searched to identify all studies documenting, in adult patients with a confirmed diagnosis of coronavirus disease 2019 (COVID-19): (1) the presence of SARS-CoV-2 ribonucleic acid in the feces; (2) the presence of SARS-CoV-2 ribonucleic acid in the intestinal cells; (3) live SARS-CoV-2 in the feces. Results: Twenty seven met the inclusion criteria. In 26 studies, the presence or absence of SARS-CoV-2 ribonucleic acid in the feces of COVID-19 patients had been reported. Out of the 671 patients, 312 (46.5%) had a positive stool sample for viral nucleic acid. Of these patients, 63.9% remained positive for viral nucleic acid in the feces after pharyngeal swabs became negative; Three studies also evaluated the viral ribonucleic acid in the gastrointestinal tissues and the presence of SARS-CoV-2 nucleic acid was found in samples of 3 patients out of 8 examined (37.5%). The presence of the live virus in stool samples was confirmed in two studies but no in in a recent study from Germany. These results suggested that SARS-CoV-2 could infect gastrointestinal epithelial cells and it may be transmitted through the digestive tract. Conclusion: In order to control the pandemic, every effort should be made to understand all the possible routes of transmission of the infections, even the less important ones. [ABSTRACT FROM AUTHOR]

Purpose: In patients with colorectal cancer (CRC) and synchronous colorectal liver metastases (CRLM) potentially candidates to combined liver (LR) and colorectal resection (CRR), the extent of LR and the need of hepatic pedicle clamping (HPC) in selected cases are considered risk factors for the outcome of the intestinal anastomosis. This study aimed to determine whether intermittent HPC is predictive of anastomotic leakage (AL) and has an adverse effect on the clinical outcome in patients undergoing combined restorative CRR and LR. Methods: One hundred six LR have been performed for CRLM in our unit from July 2005. Patients who received CRR with anastomosis and simultaneous intraoperative ultrasonography (IOUS)-guided LR/ablation for resectable CRLM were included in this study. CRR was performed first. Intermittent HPC was decided at the discretion of the liver surgeon. The perioperative outcome was evaluated according to occurrence of AL and overall postoperative morbidity and mortality. Results: Thirty-eight patients underwent simultaneous IOUS-guided LR/ablation and CRR with intestinal anastomosis; 19 underwent intermittent HPC (group ICHPY) while 19 did not (group ICHPN); the mean ± SD (range) duration of clamping in group ICHPY was 58.6 ± 32.2 (10.0-125.0) min. Postoperative results were similar between groups. One asymptomatic AL occurred in group ICHPY (5.2 %). Major postoperative complications were none in group ICHPY and one (5.2 %) in group ICHPN, respectively. One patient in group ICHPY died postoperatively (5.2 %). Conclusions: This study suggests that intermittent HPC during LR is not predictive of AL and has no adverse effect on the overall clinical outcome in patients undergoing combined restorative colorectal surgery and hepatectomy for advanced CRC. [ABSTRACT FROM AUTHOR]

Background: Twenty percent of rectal cancer patients have synchronous distant metastasis at diagnosis. At present, the treatment strategy in this patient setting is not well defined. This study in one institution evaluates the treatment strategy of three different patient groups. Patients and Methods: Between January 2000 and July 2011, 65 patients with M1 rectal cancer were evaluated. Three different groups were defined: rectal cancer with resectable metastatic disease (group A); rectal cancer with potentially resectable metastatic disease (group B), and rectal cancer with unresectable metastatic disease (group C). Results: Group A included 11 patients (16.9%), group B 28 patients (43.1%) and group C 26 patients (40%). Forty-three (66.2%) patients underwent surgery for primary rectal cancer, and 30 (46.2%) patients for metastasis resection (23 liver, 4 lung and 3 ovary). Median overall survival (OS) by group was: 51 (5-86; group A), 32 (24-40; group B) and 16 (7-26; group C) months. Patients undergoing metastasis resection have higher median OS than unresected patients (44 vs. 15 months; p < 0.001). Conclusions: The treatment strategy in synchronous metastatic rectal cancer must consider the possibility of distant metastasis resection. Long-term survival can be achieved using an integrated approach. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Our study aimed to investigate whether radiomics on MRI sequences can differentiate responder (R) and non-responder (NR) patients based on the tumour regression grade (TRG) assigned after surgical resection in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT). Eighty-five patients undergoing primary staging with MRI were retrospectively evaluated, and 40 patients were finally selected. The ROIs were manually outlined in the tumour site on T2w sequences in the oblique-axial plane. Based on the TRG, patients were grouped as having either a complete or a partial response (TRG = (0,1), n = 15). NR patients had a minimal or poor nCRT response (TRG = (2,3), n = 25). Eighty-four local first-order radiomic features (RFs) were extracted from tumour ROIs. Only single RFs were investigated. Each feature was selected using univariate analysis guided by a one-tailed Wilcoxon rank-sum. ROC curve analysis was performed, using AUC computation and the Youden index (YI) for sensitivity and specificity. The RF measuring the heterogeneity of local skewness of T2w values from tumour ROIs differentiated Rs and NRs with a p-value ≈ 10−5; AUC = 0.90 (95%CI, 0.73–0.96); and YI = 0.68, corresponding to 80% sensitivity and 88% specificity. In conclusion, higher heterogeneity in skewness maps of the baseline tumour correlated with a greater benefit from nCRT. [ABSTRACT FROM AUTHOR]

Background Preoperative chemoradiotherapy (CRT) has been widely adopted as the standard of care for locally advanced rectal cancer in most western countries. However there has been a general exclusion of the elderly patients from neoadjuvant trials often due to concerns over their tolerance of surgery and/or (chemo)radiotherapy. Our aim was to compare the compliance to preoperative CRT of rectal cancer patients aged ≥75 years and younger. Materials and methods From March 2002 to October 2008, 132 patients underwent preoperative long-course radiotherapy (5040 cGy in 28 fractions) with concurrent fluorouracil (FU)-based chemotherapy for locally advanced (T3-4 and/or N+) or metastatic (resectable synchronous liver only or lung only metastases) rectal cancer at Bologna University Hospital. Chemotherapy was delivered according to one of the following regimens: 1) continuous infusion i.v. of 5-FU alone (225 mg/m²/day); 2) continuous infusion i.v. of 5-FU (225 mg/m²/day) plus a weekly bolus of oxaliplatin 60 mg/m2 for 6 times and 3) oral capecitabine (1300 mg/ m2/day). Out of 132 patients, 17 were characterised by aged 75 or older, Karnofsky performance scale ≥70, absence of significant comorbidities and comprise the elderly group. The Fisher's exact test was used to compare proportions and the Mann-Whitney U test to compare continuous variables. Results Planned radiation therapy was completely delivered in 15 of 17 patients (88 percent) of the older age group and in 106 of 115 (92 percent) of the younger age group (p > 0.05). In only one patient (aged 74 years) radiotherapy was early (1800 cGy) interrupted because of bowel obstruction. The full protocol dose of chemotherapy was delivered in 10 (59%) and 94 (82%) patients of older and younger age group respectively (p = 0.0514). The main causes of chemotherapeutic schedule violation in the older age group were GR3/4 diarrhoea (2 patients), GR3 neutropenia (2 patients), acute neurotoxicity (1 patient), heart complication (1 patients) and Jacksonian epilepsy (1 patient). However none of these seven patients received less than eighty percent of total dose planned. All older patients underwent surgical treatment seven to eight weeks after CRT as follow: low anterior resection (10 patients), abdominoperineal resection (5 patients) and transanal excision (2 patients). Conclusion Our results are consistent with the concept that age should not be the only deciding factor in the treatment of advanced rectal cancer. As International Society of Geriatric Oncology recommendations, patients should receive the most intensive and appropriate treatment thought to be safe and effective according to their biological age and comorbidities. [ABSTRACT FROM AUTHOR]