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In the colorectal cancer (CRC) niche, the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are hyperactivated in both malignant cells and tumor-infiltrating leukocytes (TILs) and cooperate to maintain cancer cell proliferation/survival and drive protumor inflammation. Through drug repositioning studies, the anthelmintic drug rafoxanide has recently emerged as a potent and selective antitumor molecule for different types of cancer, including CRC. Here, we investigate whether rafoxanide could negatively modulate STAT3/NF-κB and inflammation-associated CRC. The antineoplastic effect of rafoxanide was explored in a murine model of CRC resembling colitis-associated disease. Cell proliferation and/or STAT3/NF-κB activation were evaluated in colon tissues taken from mice with colitis-associated CRC, human CRC cells, and CRC patient-derived explants and organoids after treatment with rafoxanide. The STAT3/NF-κB activation and cytokine production/secretion were assessed in TILs isolated from CRC specimens and treated with rafoxanide. Finally, we investigated the effects of TIL-derived supernatants cultured with or without rafoxanide on CRC cell proliferation and STAT3/NF-κB activation. The results showed that rafoxanide restrains STAT3/NF-κB activation and inflammation-associated colon tumorigenesis in vivo without apparent effects on normal intestinal cells. Rafoxanide markedly reduces STAT3/NF-κB activation in cultured CRC cells, CRC-derived explants/organoids, and TILs. Finally, rafoxanide treatment impairs the ability of TILs to produce protumor cytokines and promote CRC cell proliferation. We report the novel observation that rafoxanide negatively affects STAT3/NF-κB oncogenic activity at multiple levels in the CRC microenvironment. Our data suggest that rafoxanide could potentially be deployed as an anticancer drug in inflammation-associated CRC., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Patients with ulcerative colitis (UC) receiving liver transplantation (LT) due to primary sclerosing cholangitis (PSC) have higher risk of developing colorectal cancers (CRC). Aim of this systematic review was to define the patients' features, immunosuppressive management, and oncological outcomes of LT recipients with UC-PSC developing CRC., Methods: Searches were conducted in PubMed (MEDLINE), Cochrane Library, Web of Science for all English articles published until September 2023. Inclusion criteria were original articles including patients specifying outcomes of interest. Primary endpoints comprised incidence of CRC, disease free survival (DFS), overall survival (OS) and cancer recurrence. Secondary endpoints were patient's and tumor characteristics, graft function, immunosuppressive management and PSC recurrence. PROSPERO CRD42022369190., Results: Fifteen studies included, 88 patients were identified. Patients (mean age: 50 years) had a long history of UC (20 years), mainly with active colitis (79%), and developed tumor within the first 3 years from LT, while receiving a double or triple immunosuppressive therapy. Cumulative incidence of tumor was 5.5%. At one, two and three years, DFS was 92%, 82% and 75%, while OS was 87%, 81% and 79% respectively. Disease progression rate was 15%. After CRC surgery, 94% of patients maintained a good graft functionality, with no reported cases of PSC recurrence., Conclusions: After LT, patients with PSC and UC have an increased risk of CRC, especially in presence of long history of UC and active colitis. Surgical resection guarantees satisfactory mid-term oncological outcomes, but samples are limited, and long-term data are lacking. National and international registry are auspicial to evaluate long-term oncological outcomes and to optimize clinical management., (© 2024. The Author(s).)

Purpose: Routine use of abdominal drain or prolonged antibiotic prophylaxis is no longer part of current clinical practice in colorectal surgery. Nevertheless, in patients undergoing laparoscopic right hemicolectomy with intracorporeal anastomosis (ICA), it may reduce perioperative abdominal contamination. Furthermore, in cancer patients, prolonged surgery with extensive dissection such as central vascular ligation and complete mesocolon excision with D3 lymphadenectomy (altogether radical right colectomy RRC) is called responsible for affecting postoperative ileus. The aim was to evaluate postoperative resumption of gastrointestinal functions in patients undergoing right hemicolectomy for cancer with ICA and standard D2 dissection or RRC, with or without abdominal drain and prolonged antibiotic prophylaxis., Methods: Monocentric factorial parallel arm randomized pilot trial including all consecutive patients undergoing laparoscopic right hemicolectomy and ICA for cancer, in 20 months. Patients were randomized on a 1:1:1 ratio to receive abdominal drain, prolonged antibiotic prophylaxis or neither (I level), and 1:1 to receive RRC or D2 colectomy (II level). Patients were not blinded. The primary aim was the resumption of gastrointestinal functions (time to first gas and stool, time to tolerated fluids and food). Secondary aims were length of stay and complications' rate., Clinicaltrials: gov no. NCT04977882., Results: Fifty-seven patients were screened; according to sample size, 36 were randomized, 12 for each arm for postoperative management, and 18 for each arm according to surgical techniques. A difference in time to solid diet favored the group without drain or antibiotic independently from standard or RRC. Furthermore, when patients were divided with respect to surgical technique and into matched cohorts, no differences were seen for primary and secondary outcomes., Conclusion: Abdominal drainage and prolonged antibiotic prophylaxis in patients undergoing right hemicolectomy for cancer with ICA seem to negatively affect the resumption of a solid diet after laparoscopic right hemicolectomy with ICA for cancer. RRC does not seem to influence gastrointestinal function recovery., (© 2024. The Author(s).)

BACKGROUND Bariatric surgery (BS) has a lower percentage of complications than other abdominal surgeries. Hemorrhage in one of the most common complications and can be life-threatening. Hereditary factor XI (FXI) deficiency is a coagulation disorder that can result in excessive bleeding requiring intervention to restore hemostasis. Risks over benefits in patients with morbid obesity with BS indication, as well as those with FXI deficiency, should be carefully evaluated. This article reports the case of an obese woman with FXI deficiency -undergoing SG. CASE REPORT A 49-year-old woman with a BMI of 51 kg/m² was diagnosed as having severe FXI deficiency during preoperative exams prior to bariatric surgery. Virus-inactivated homo-group plasma 10 ml/kg infusion was administrated 1 h before surgery, during the entire procedure, and continuing until postoperative day (POD) 4. A very low-calorie ketogenic diet (VLCKD) was proposed to the patient 4 weeks before surgery. Laparoscopic sleeve gastrectomy was performed with staple-line reinforcement by oversewing the seromuscular layer using continuous suture. Subcutaneous enoxaparin 4000 U.I. was administered from POD 1 until POD 25 to prevent any thromboembolic event. The patient was discharged on POD 5 in good clinical condition. CONCLUSIONS Risks of bleeding andor thromboembolic events before or after BS are increased in patient with FXI deficiency. Bariatric surgery in these patients is safe in experienced BS centers, and the risks associated with the obesity seem to exceed those of the coagulopathy and surgery. Careful preoperative counseling, extensive hematological checks, and meticulous surgery are essential to reduce BS risks. Sleeve gastrectomy oversewing the stapler line seems a reasonable choice.

Introduction: The role of robotic lateral pelvic lymph node dissection (LPLND) for lateral pelvic nodal disease (LPND) in rectal cancer has yet to be investigated in the Western hemisphere. This study aims to investigate the safety and feasibility of robotic LPLND by utilising a well-established totally robotic TME protocol., Methods: We conducted a retrospective study on 17 consecutive patients who underwent robotic LPLND for LPND ± TME for rectal cancer between 2015 and 2021. A single docking totally robotic approach from the left hip with full splenic mobilisation was performed using the X/Xi da Vinci platform. All patients underwent a tri-compartmental robotic en bloc excision of LPND with preservation of the obturator nerve and pelvic nerve plexus, leaving a well-skeletonised internal iliac vessel and its branches., Results: The median operative time was 280 min, which was 40 min longer than our standard robotic TME. The median BMI was 26, and there were no conversions. The median inpatient stay was 7 days with no Clavien-Dindo > 3 complications. One patient (6%) developed local recurrence and metastatic disease within 5 months. The proportion of histologically confirmed LPND was 41%, of which 94% were well to moderately differentiated adenocarcinoma. Median pre-operative lateral pelvic node size was significantly higher in positive nodes (14 mm vs. 8 mm ( p = 0.01)). All patients had clear resection margins on histology., Discussion: Robotic LPLND is safe and feasible with good peri-operative and short-term outcomes, with the ergonomic advantages of a robotic TME docking protocol readily transferrable in LPLND.

A higher frequency of mucinous and signet-ring cell colonic adenocarcinoma has been reported in inflammatory bowel disease (IBD). The primary aim was to investigate the frequency of mucinous and signet-ring cell colorectal adenocarcinoma in patients with IBD (Cases) versus age-matched non-IBD Controls. The secondary aims were to compare the characteristics of these two histotypes of colorectal cancer (CRC) in IBD patients vs. Controls and to search for specific risk factors in IBD. In a case-control study, all IBD patients with CRC diagnosed from 2000 to 2022 were enrolled and matched for age (1:2) with non-IBD Controls with CRC. The study population included 120 CRC patients (40 IBD, 80 Controls). In IBD, CRC included standard adenocarcinoma in 23 (57.5%) patients mucinous/signet-ring cell adenocarcinoma in 17 (42.5%) patients. The proportion of mucinous/signet-ring cell adenocarcinoma was higher in IBD than in Controls (17 [42.5%] vs. 18 [22.5%]; p = 0.03). In rectal CRC, the proportion of mucinous/signet-ring cell adenocarcinoma was higher than standard adenocarcinoma in IBD (8 [47.1%] vs. 4 [17.4%]; p = 0.04) but not in Controls (4 [22.2%] vs. 20 [32.2%]; p = 0.59). In rectal CRC, the proportion of these two histotypes was higher in Cases than in Controls (8/12 [66.6%] vs. 4/24 [16.6%]; p = 0.008), with no risk factors identified in IBD. CRC was more frequently represented by mucinous/signet-ring cell adenocarcinoma in IBD than in age-matched non-IBD Controls. In IBD, these two CRC histotypes were more frequent in the rectum.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

The aim of the study was to investigate whether the COVID-19 pandemic and related measures had an influence on colorectal cancer (CRC) presentation, management, and outcomes; it was a retrospective monocentric study. CRC patients undergoing surgery during the COVID-19 pandemic (1 March 2020-28 February 2022) (group B) were compared with patients operated on in the previous two years (1 March 2018-29 February 2020) in the same unit (group A). The primary outcome was to investigate whether there were differences in concern regarding the stage at presentation, as a whole and after dividing groups based on cancer location (right colon cancer, left colon cancer, rectal cancer). Secondary outcomes included differences in the number of patients admitted from emergency departments and emergency surgeries between periods, and differences in the postoperative outcomes. A subanalysis within the pandemic group was conducted on the same outcomes, dividing the aforementioned group based on pandemic trends. Two hundred and eighty (280) were operated on during the study period: 147 in group A and 133 in group B. Stage at presentation was similar between groups; however, the subgroups analysis showed that in the pandemic group, the number of early-stage left colon cancer occurrences almost halves, yet not significantly. Emergency department referral was more common in group B ( p -value: 0.003); in group B, they also had longer operations and there was a more frequent use of ostomy. No differences in the number of postoperative complications nor in the postoperative outcomes were found. Patients with CRC were more frequently referred through the emergency department during the COVID-19 pandemic and left-sided cancers appear to be generally diagnosed at a more advanced stage. Postoperative outcomes showed that high specialized colorectal units can deliver standard high-level treatment under high-pressure external conditions.

Colorectal cancer (CRC) remains a leading causes of cancer-related death in the world, mainly due to the lack of effective treatment of advanced disease. TNF-related apoptosis-inducing ligand (TRAIL)-driven cell death, a crucial event in the control of tumor growth, selectively targets malignant rather than non-transformed cells. However, the fact that cancer cells, including CRC cells, are either intrinsically resistant or acquire resistance to TRAIL, represents a major hurdle to the use of TRAIL-based strategies in the clinic. Agents able to overcome CRC cell resistance to TRAIL have thus great therapeutic potential and many researchers are making efforts to identify TRAIL sensitizers. The anthelmintic drug rafoxanide has recently emerged as a potent anti-tumor molecule for different cancer types and we recently reported that rafoxanide restrained the proliferation of CRC cells, but not of normal colonic epithelial cells, both in vitro and in a preclinical model mimicking sporadic CRC. As these findings were linked with the induction of endoplasmic reticulum stress, a phenomenon involved in the regulation of various components of the TRAIL-driven apoptotic pathway, we sought to determine whether rafoxanide could restore the sensitivity of CRC cells to TRAIL. Our data show that rafoxanide acts as a selective TRAIL sensitizer in vitro and in a syngeneic experimental model of CRC, by decreasing the levels of c-FLIP and survivin, two key molecules conferring TRAIL resistance. Collectively, our data suggest that rafoxanide could potentially be deployed as an anti-cancer drug in the combinatorial approaches aimed at overcoming CRC cell resistance to TRAIL-based therapies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Giovanni Monteleone reports a relationship with AbbVie Inc that includes: consulting or advisory., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Colorectal carcinoma is the second leading cause of cancer-related deaths, and indeed, rectal cancer accounting for approximately one third of newly diagnosed patients. Gold standard in the treatment of rectal cancer is a multimodality approach, aiming at a good control of the local disease. Distant recurrences are the major cause of mortality. Currently, Locally Advanced Rectal Cancer (LARC) patients undergo a combined treatment of chemotherapy and radiotherapy, followed by surgery. Eventually, more chemotherapy, namely adjuvant chemotherapy (aCT), may be necessary. Total Neoadjuvant Therapy (TNT) is an emerging approach aimed to reduce distant metastases and improve local control. Several ongoing studies are analyzing whether this new approach could improve oncological outcomes. Published results were encouraging, but the heterogeneity of protocols in use, makes the comparison and interpretation of data rather complex. One of the major concerns regarding TNT administration is related to its effect on larger and more advanced cancers that might not undergo similar down-staging as smaller, early-stage tumors. This minireview, based on a systematic literature search of randomized clinical trials and meta-analysis, summarizes current knowledge on TNT. The aim was to confirm or refute whether or not current practice of TNT is based on relevant evidence, to establish the quality of that evidence, and to address any uncertainty or variation in practice that may be occurring. A tentative grouping of general study characteristics, clinical features and treatments characteristics has been undertaken to evaluate if the reported studies are sufficiently homogeneous in terms of subjects involved, interventions, and outcomes to provide a meaningful idea of which patients are more likely to gain from this treatment., (© 2022. The Author(s).)

Mesenteric closure following right colectomy remains controversial and, following the advent of laparoscopic surgery, many surgeons do not routinely close the mesentery after colorectal resection. Nevertheless, especially after the introduction of operations such as right colectomy with complete mesocolic excision and ileocolic resections with extensive mesentery removal for Crohn's disease, the wide mesenteric defect resulting from the dissections can certainly expose the patients to complications such as internal hernias or volvuli. In general, mesenteric closure requires intracorporeal suturing. We describe a simple technique for the closure of the mesentery after surgical resection using polymer-ligating clips. This novel technique seems to minimize the time, effort and risk inherent to the procedure, even after large mesenteric excisions., (© 2021. Springer Nature Switzerland AG.)

Background: Programs of Enhanced Recovery After Surgery reduces morbidity and shorten recovery in patients undergoing colorectal resections for cancer. Patients presenting with more advanced disease such as T4 cancers are frequently excluded from undergoing ERAS programs due to the difficulty in applying established protocols. The primary aim of this investigation was to evaluate the possibility of applying a validated ERAS protocol in patients undergoing colorectal resection for T4 colon and rectal cancer and to evaluate the short-term outcome., Methods: Single-center, retrospective cohort study. All patients with a clinical diagnosis of stage T4 colorectal cancer undergoing surgery between November 2016 and January 2020 were treated following the institutional fast track protocol without exclusion. Short-term postoperative outcomes were compared to those of a control group treated with conventional care and that underwent surgical resection for T4 colorectal cancer at the same institution from January 2010 to October 2016. Data from both groups were collected retrospectively from a prospectively maintained database., Results: Eighty-two patients were diagnosed with T4 cancer, 49 patients were included in the ERAS cohort and 33 in the historical conventional care cohort. Both, the mean time of tolerance to solid food diet and postoperative length of stay were significantly shorter in the ERAS group than in the control group (3.14 ± 1.76 vs 4.8 ± 1.52; p < 0.0001 and 6.93 ± 3.76 vs 9.50 ± 4.83; p = 0.0084 respectively). No differences in perioperative complications were observed., Conclusions: Results from this cohort study from a single-center registry support the thesis that the adoption of the ERAS protocol is effective and applicable in patients with colorectal cancer clinically staged T4, reducing significantly their length of stay and time of tolerance to solid food diet, without affecting surgical postoperative outcomes.