Decreased expression of the NLRP6 inflammasome is associated with increased intestinal permeability and inflammation in obesity with type 2 diabetes.

BACKGROUND: Obesity-associated dysfunctional intestinal permeability contributes to systemic chronic inflammation leading to the development of metabolic diseases. The inflammasomes constitute essential components in the regulation of intestinal homeostasis. We aimed to determine the impact of the inflammasomes in the regulation of gut barrier dysfunction and metabolic inflammation in the context of obesity and type 2 diabetes (T2D). METHODS: Blood samples obtained from 80 volunteers (n = 20 normal weight, n = 21 OB without T2D, n = 39 OB with T2D) and a subgroup of jejunum samples were used in a case-control study. Circulating levels of intestinal damage markers and expression levels of inflammasomes as well as their main effectors (IL-1ß and IL-18) and key inflammation-related genes were analyzed. The impact of inflammation-related factors, different metabolites and Akkermansia muciniphila in the regulation of inflammasomes and intestinal integrity genes was evaluated. The effect of blocking NLRP6 by using siRNA in inflammation was also studied. RESULTS: Increased circulating levels (P < 0.01) of the intestinal damage markers endotoxin, LBP, and zonulin in patients with obesity decreased (P < 0.05) after weight loss. Patients with obesity and T2D exhibited decreased (P < 0.05) jejunum gene expression levels of NLRP6 and its main effector IL18 together with increased (P < 0.05) mRNA levels of inflammatory markers. We further showed that while NLRP6 was primarily localized in goblet cells, NLRP3 was localized in the intestinal epithelial cells. Additionally, decreased (P < 0.05) mRNA levels of Nlrp1, Nlrp3 and Nlrp6 in the small intestinal tract obtained from rats with diet-induced obesity were found. NLRP6 expression was regulated by taurine, parthenolide and A. muciniphila in the human enterocyte cell line CCL-241. Finally, a significant decrease (P < 0.01) in the expression and release of MUC2 after the knockdown of NLRP6 was observed. CONCLUSIONS: The increased levels of intestinal damage markers together with the downregulation of NLRP6 and IL18 in the jejunum in obesity-associated T2D suggest a defective inflammasome sensing, driving to an impaired epithelial intestinal barrier that may regulate the progression of multiple obesity-associated comorbidities.

Survival and safety after neoadjuvant chemotherapy or upfront surgery for locally advanced colon cancer: meta-analysis.

BACKGROUND: Neoadjuvant chemotherapy is increasingly used to treat locally advanced (T3-4 Nx-2 M0) colon cancer due to its potential advantages over the standard approach of upfront surgery. The primary objective of this systematic review and meta-analysis was to analyse data from comparative studies to assess the impact of neoadjuvant chemotherapy on oncological outcomes. METHODS: A systematic review was conducted by searching the MEDLINE and Scopus databases. The search encompassed RCTs, propensity score-matched studies, and controlled prospective studies published up to 1 April 2023. As a primary objective, overall survival and disease-free survival were compared. As a secondary objective, perioperative morbidity, mortality, and complete resection were compared using the DerSimonian and Laird models. RESULTS: A total of seven studies comprising a total of 2120 patients were included. Neoadjuvant chemotherapy was associated with a reduction in the hazard of recurrence (HR 0.73, 95% c.i. 0.59 to 0.90; P = 0.003) and death (HR 0.67, 95% c.i. 0.54 to 0.83; P < 0.001) compared with upfront surgery. Additionally, neoadjuvant chemotherapy was significantly associated with higher 5-year overall survival (79.9% versus 72.6%; P < 0.001) and disease-free survival (73.1% versus 64.5%; P = 0.028) rates. No significant differences were observed in perioperative mortality (OR 0.97, 95% c.i. 0.28 to 3.33), overall complications (OR 0.95, 95% c.i. 0.77 to 1.16), or anastomotic leakage/intra-abdominal abscess (OR 0.88, 95% c.i. 0.60 to 1.29). However, neoadjuvant chemotherapy was associated with a lower risk of incomplete resection (OR 0.70, 95% c.i. 0.49 to 0.99). CONCLUSION: Neoadjuvant chemotherapy is associated with a reduced hazard of recurrence and death, as well as improved overall survival and disease-free survival rates, compared with upfront surgery in patients with locally advanced colon cancer.

Colon cancer is a common medical condition, the established treatment for which involves surgical resection followed by chemotherapy. However, a contemporary shift has led to the investigation of an alternative treatment sequence known as neoadjuvant chemotherapy, wherein chemotherapy precedes the surgery. This study critically assesses the efficacy of neoadjuvant chemotherapy compared with the standard treatment approach of surgery followed by chemotherapy. A systematic review of medical databases was undertaken to identify pertinent research publications on this subject matter. In total, seven studies encompassing data from 2120 patients were included in the analysis. Employing a meta-analysis methodology to synthesize the collective data from these studies, it was revealed that neoadjuvant chemotherapy was linked to higher rates of 5-year overall survival and disease-free survival, alongside a diminished hazard of both recurrence and death. Furthermore, no discernible differences in surgical complications or perioperative mortality were evident across the compared approaches.

The ELECLA trial: A multicentre randomised control trial on outcomes of neoadjuvant treatment on locally advanced colon cancer.

BACKGROUND: Colon cancer (CC) is a public health concern with increasing incidence in younger populations. Treatment for locally advanced CC (LACC) involves oncological surgery and adjuvant chemotherapy (AC) to reduce recurrence and improve overall survival (OS). Neoadjuvant chemotherapy (NAC) is a novel approach for the treatment of LACC, and research is underway to explore its potential benefit in terms of survival. This trial will assess the efficacy of NAC in LACC. METHODS: This is a multicentre randomised, parallel-group, open label controlled clinical trial. Participants will be selected based on homogenous inclusion criteria and randomly assigned to two treatment groups: NAC, surgery, and AC or surgery followed by AC. The primary aim of this study is to evaluate the 2-year progression-free survival (PFS), with secondary outcomes including 5-year PFS, 2- and 5-year OS, toxicity, radiological and pathological response, morbidity, and mortality. DISCUSSION: The results of this study will determine whether NAC induces a clinical and histological tumour response in patients with CCLA and if this treatment sequence improves survival without increasing morbidity and mortality. REGISTRATION NUMBER: NCT04188158.

Dermatopontin Influences the Development of Obesity-Associated Colon Cancer by Changes in the Expression of Extracellular Matrix Proteins.

Dysfunctional adipose tissue (AT) in the context of obesity leads to chronic inflammation together with an altered extracellular matrix (ECM) remodelling, favouring cancer development and progression. Recently, the influence of dermatopontin (DPT) in AT remodelling and inflammation has been proposed. We aimed to evaluate the role of DPT in the development of obesity-associated colon cancer (CC). Samples obtained from 73 subjects [26 lean (LN) and 47 with obesity (OB)] were used in a case-control study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (42 without CC and 31 with CC). In vitro studies in the adenocarcinoma HT-29 cell line were performed to analyse the impact of pro- and anti-inflammatory mediators on the transcript levels of DPT as well as the effect of DPT on ECM remodelling and inflammation. Although obesity increased (p < 0.05) the circulating levels of DPT, its concentrations were significantly decreased (p < 0.05) in patients with CC. Gene expression levels of DPT in the colon from patients with CC were downregulated and, oppositely, a tendency towards increased mRNA levels in visceral AT was found. We further showed that DPT expression levels in HT-29 cells were enhanced (p < 0.05) by inflammatory factors (LPS, TNF-α and TGF-ß), whereas the anti-inflammatory IL-4 decreased (p < 0.05) its expression levels. We also demonstrated that DPT upregulated (p < 0.05) the mRNA of key molecules involved in ECM remodelling (COL1A1, COL5A3, TNC and VEGFA) whereas decorin (DCN) expression was downregulated (p < 0.05) in HT-29 cells. Finally, we revealed that the adipocyte-conditioned medium obtained from volunteers with OB enhanced (p < 0.01) the expression of DPT in HT-29 and Caco-2 cells. The decreased circulating and expression levels of DPT in the colon together with the tendency towards increased levels in visceral AT in patients with CC and its influence on the expression of ECM proteins suggest a possible role of DPT in the OB-associated CC.

Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling.

OBJECTIVE: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). METHODS: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. RESULTS: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.

The impact of SARS-CoV-2 infection on the surgical management of colorectal cancer: lessons learned from a multicenter study in Spain.

OBJECTIVE: the aim of the study was to analyze the management of colorectal cancer (CRC) patients diagnosed with CRC or undergoing elective surgery during the period of the SARS-CoV-2 pandemic. MATERIAL AND METHODS: a multicenter ambispective analysis was performed in nine centers in Spain during a four-month period. Data were collected from every patient, including changes in treatments, referrals or delays in surgeries, changes in surgical approaches, postoperative outcomes and perioperative SARS-CoV-2 status. The hospital's response to the outbreak and available resources were categorized, and outcomes were divided into periods based on the timeline of the pandemic. RESULTS: a total of 301 patients were included by the study centers and 259 (86 %) underwent surgery. Five hospitals went into phase III during the peak of incidence period, one remained in phase II and three in phase I. More than 60 % of patients suffered some form of change: 48 % referrals, 39 % delays, 4 % of rectal cancer patients had a prolonged interval to surgery and 5 % underwent neoadjuvant treatment. At the time of study closure, 3 % did not undergo surgery. More than 85 % of the patients were tested preoperatively for SARS-CoV-2. A total of nine patients (3 %) developed postoperative pneumonia; three of them had confirmed SARS-CoV-2. The observed surgical complications and mortality rates were similar as expected in a usual situation. CONCLUSIONS: the present multicenter study shows different patterns of response to the SARS-CoV-2 pandemic and collateral effects in managing CRC patients. Knowing these patterns could be useful for planning future changes in surgical departments in preparation for new outbreaks.

Prognostic significance of lymph node count in high-risk node-negative colon carcinoma.

BACKGROUND: the prognostic value of the number of lymph nodes isolated (< 12 versus ≥ 12) in the surgical specimen continues to be controversial. In this study, the impact of isolating fewer or more than 12 lymph nodes in stage II colon cancer with a high-risk biologic phenotype was analyzed, such as the presence of perineural invasion. METHODS: all cases of stage II disease (T3-4N0M0) with perineural invasion (PNI+) were retrospectively identified from a prospective database of patients undergoing surgery for colon cancer. The cohort was divided into two groups depending on the number of lymph nodes isolated (< 12 vs ≥ 12). Apart from clinical and surgical data, the patterns of recurrence, overall (OS) and disease-free survival (DFS) at five and ten years were analyzed. RESULTS: sixty patients met the inclusion criteria, 31.7 % had < 12 lymph nodes isolated and 68.3 % had more than 12 isolated. There were no clinical or surgical differences between the two groups. OS at five and ten years was significantly lower in the patients with < 12 lymph nodes isolated (84.2 %, 62.7 % vs 94.6 % and 91.6 %, p = 0.01). DFS at five and ten years was 51 % vs 86.5 %, respectively (p = 0.005). CONCLUSION: the number of lymph nodes isolated (with a cutoff of 12) in stage II colon cancer with PNI+ has prognostic value and should therefore be borne in mind when planning adjuvant chemotherapy.

Neoadjuvant chemotherapy without radiotherapy for patients with locally advanced rectal cancer. Oncologic outcomes.

BACKGROUND: the standard treatment for locally advanced rectal cancer is neoadjuvant chemo-radiotherapy, surgery and adjuvant chemotherapy. Only 50% of patients receive the adjuvant treatment due to the surgical complications and toxicity of radiotherapy. Recently, neoadjuvant chemotherapy has been investigated in the locally advanced rectal cancer setting, with the aim of guaranteeing an uninterrupted systemic treatment. The objective of the present study was to assess the safety and efficacy of neoadjuvant chemotherapy in locally advanced rectal cancer. METHODS AND PATIENTS: patients treated with neoadjuvant chemotherapy and surgery were identified from a prospective database of patients with rectal cancer (cII-III). The primary outcomes were the assessment of the number of R0 resections, the degree of pathologic response, patterns of recurrence and overall and disease-free survival. Treatment schedule: patients received 6-8 cycles of oxaliplatin and fluoropyrimides based chemotherapy. RESULTS: twenty-seven patients who received neoadjuvant chemotherapy were identified. Twenty-six anterior resections and one Hartmann intervention were performed. An R0 resection was performed in 27 (100%) patients and no involvement of the circumferential margin was observed. Complete pathologic response (ypT0N0) was confirmed in four (14.8%) patients. The median follow-up was 35 months (range: 10-81) and four distant recurrences were recorded. Overall and disease-free survival at five years was 85% and 84.7%, respectively. Twenty-seven (100%) patients received all the cycles of chemotherapy, with a mean of six cycles (range 5-8) per patient. CONCLUSIONS: neoadjuvant chemotherapy is a promising alternative in the locally advanced rectal cancer setting and further phase III clinical trials are clearly warranted.

Clinico-pathological and oncological differences between right and left-sided colon cancer (stages I-III): analysis of 950 cases.

PURPOSE: The objective of the study was to analyze the clinico-pathological differences and the oncologic outcomes between right and left-sided colon cancer. PATIENTS AND METHODS: The patients cohort was identified from a prospective register of colon cancer, 950 patients underwent surgery (stages I, II and III), of which 431 had right-sided colon cancer and 519 had left-sided colon cancer. RESULTS: More laparoscopic resections were performed (101 vs 191; p < 0.001) and operating times were longer (146 min vs 165 min; p < 0.001) in the left-sided colon group. Patients with right-sided colon cancer more frequently received transfusions (18.8% vs 11.3%; p < 0.001) and experienced a greater number of complications (28.5% vs 20.9%, p = 0.004), although severity and operative mortality were similar in both groups (1.2% vs 0.2%). Mucinous adenocarcinomas and undifferentiated tumors were more frequent in the right-sided group (12% vs 6.5%; p < 0.001). Early stage was predominant in the left-sided colon tumors (28.2% vs 34.5%, p = 0.02). There were no differences in disease-free survival (DFS) in stages I and II after a median follow-up of 103 months. However, a greater survival at five and ten years in left-sided, stage III tumors was observed, with a trend towards statistical significance (p = 0.06). No differences were found with regard to the patterns of recurrence. CONCLUSIONS: Right-sided colon cancer exhibits phenotypical differences with regard to left-sided colon cancer. In stage III disease, left-sided colon cancer has a greater survival with a trend towards statistical significance. Overall, tumor location is a variable that should be taken into consideration in clinical studies of colon cancer.

Screening-detected colorectal cancers show better long-term survival compared with stage-matched symptomatic cancers.

PURPOSE: the aim of this study was to compare overall and disease-free survival among patients with colorectal cancer detected via a screening program as compared to those with symptomatic cancer. MATERIAL AND METHODS: patients diagnosed via colonoscopy (screening group) and those with clinical symptoms (non-screening) were identified from 1995 to 2014. Demographic, clinical, surgical and pathologic variables were recorded. Stage I, II and III cancers were included. Overall and disease-free survival were calculated at five and ten years after tumor resection and survival was calculated by matching both groups for cancers at stage I, II and III. RESULTS: two hundred and fifty patients were identified as a result of screening procedures and 1,330 patients presented with symptomatic cancers. There were no significant differences in the baseline characteristics between the two groups. Pathologic stage, degree of differentiation, perineural invasion and lymphovascular invasion were lower in the screening group (p < 0.01). Overall and disease-free survival at five and ten years were higher in the screening group (p < 0.01). However, when the subjects were matched for pathologic stage, significant differences were found between the two groups with regard to stage I and III tumors. Disease-free survival in stage III at five years (79.1 vs 61.7%; p < 0.001) and ten years (79.1% vs 58.5%; p < 0.001) were significantly higher in the screening group. CONCLUSIONS: patients with stage I and III tumors that were diagnosed via a screening program have a higher overall and disease-free survival at five and ten years.

Short-term outcome of patients with colon cancer diagnosed by symptoms and screening.

Colon cancer diagnosed as part of a screening program, showed better short-term outcomes following surgery. These advantages seem to have impact on long-term outcomes as well.

Long-term oncologic results in cancer of the rectum treated by preoperative chemoradiotherapy and surgery: An analysis of 500 cases.

BACKGROUND: The standard treatment for locally advanced cancer of the rectum (LACR) and selective cases of stage IV disease is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Despite reductions in local recurrence, disease-free survival (DSF) has remained stable in recent years. OBJECTIVE: The objective of this study is to analyze patterns of recurrence, long-term survival and prognostic factors in a program of neoadjuvant CRT and surgery in LACR. METHODS: Between January 1992 and December 2011, 446 patients with LACR and 54 patients (with single metastases) were treated with pre-operative long course CRT and surgery. Three hundred forty four (66.8%) anterior resections of the rectum and 123 (24.6%) abdomino-perineal resections were performed. RESULTS: With a mean follow-up of 70.06 months, local recurrence was 4.8% and distant recurrence 25.5%. No differences were found in the histopathologic prognostic factors across the three groups studied depending on distance (cm) from the analmargin. Involvement of the circumferential resection margin (CRM+) was significantly greater in tumors in the distal third of the rectum (8.5%; p = 0.04). 67 patients (13.4%) showed a complete pathologic response. DSF at 5 and 10 years was significantly lower in patients with tumors affecting the distal third as compared to the middle third of the rectum (61.9% vs. 57.7%; p = 0.04). Tumors at this distal location resulted in a significantly higher incidence of lung metastases (p = 0.016).

Liver regeneration--the best kept secret. A model of tissue injury response.

Liver regeneration (LR) is one of the most amazing tissue injury response. Given its therapeutic significance has been deeply studied in the last decades.LR is an extraordinary complex process, strictly regulated, which accomplishes the characteristics of the most evolutionary biologic systems (robustness) and explains the difficulties of reshaping it with therapeutic goals.TH reproduces the physiological tissue damage response pattern, with a first phase of priming of the hepatocytes-cell-cycle transition G0-G1­, and a second phase of proliferation ­cell-cycleS/M phases­ which ends with the liver mass recovering. This process has been related with the tissue injury response regulators as: complement system, platelets, inflammatory cytokines(TNF-a, IL-1b, IL-6), growth factors (HGF, EGF, VGF) and anti-inflammatory factors (IL-10, TGF-b).Given its complexity and strict regulation, illustrates the unique alternative to liver failure is liver transplantation.The recent induced pluripotential cells (iPS) description and the mesenchymal stem cell (CD133+) plastic capability have aroused new prospects in the cellular therapy field. Those works have assured the cooperation between mesenchymal and epithelial cells. Herein, we review the physiologic mechanisms of liver regeneration.

Prognosis factors for recurrence in patients with locally advanced rectal cancer preoperatively treated with chemoradiotherapy and adjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by total mesorectal excision has improved the outcome of locally advanced rectal carcinoma. OBJECTIVE: The aim of this study was to identify independent prognosis factors of disease recurrence in a group of patients treated with this approach. DESIGN AND PATIENTS: This study was retrospective in design. Data from patients with locally advanced rectal cancer who had completed treatment from 2000 to 2010 were reviewed. SETTINGS: The analysis was performed in a tertiary referral center. MAIN OUTCOME MEASURES: The primary outcomes measured were the recurrence risk factors. RESULTS: The cohort consisted of 228 patients; 69.3% of them were men, and median age was 59 years. Stage III rectal cancer was found in 64.9% of patients. The most frequently administered therapy was concurrent capecitabine, oxaliplatin, and 7-field radiotherapy, followed by 3-field radiotherapy and fluoropyrimidines. After a median follow-up of 49 months, 23.7% of the patients experienced disease recurrence: 2.6% had local recurrence, 21.1% had distant metastases, and 0.5% had both. Factors significantly correlated with recurrence risk in multivariate logistic regression were y-pathological stage (III vs I/II: OR = 2.51), tumor regression grade (1/2 vs 3+/4: OR = 3.34; 3 vs 3+/4: OR = 1.20), and low rectal location (OR = 2.36). The only independent prognosis factor for liver metastases was tumor regression grade (1/2 vs 3+/4: OR = 4.67; 3 vs 3+/4: OR = 1.41), whereas tumor regression grade (1-2 vs 3+/4: OR = 5.5; 3 vs 3+/4: OR = 1.84), low rectal location (OR = 3.23), and previous liver metastasis (OR = 7.73) predicted lung recurrence. LIMITATIONS: This is a single institutional experience, neoadjuvant combined therapy is not homogeneous, and the analysis has been performed in a retrospective manner. CONCLUSIONS: Patients with low third locally advanced rectal cancer with a poor response to neoadjuvant chemoradiotherapy (high y-pathological stage or low tumor regression grade) are at high risk of recurrence. Intense surveillance and the design of alternative therapeutic approaches aimed to lower the distant failure rate seem warranted.

Surgical training on rectal cancer surgery: do supervised senior residents differ from consultants in outcomes?

INTRODUCTION: The present work is a comparative study to investigate the independent effect of tutored senior residents on rectal cancer surgery in an academic university hospital. The variable "surgeon" is held to be a major determinant of outcome following total mesorectal excision (TME) for rectal cancer. OBJECTIVE: We hypothesized that TME can be tutored to senior surgical residents without compromising surgical and oncological outcomes. METHODS: Demographics, preoperative characteristics, and surgical data from consecutive patients undergoing elective TME in an academic center over the last decade were retrospectively reviewed from a prospectively collected database. Outcomes were compared in the two cohorts by a principal surgeon (senior resident or staff) and supervised in all cases by a senior colorectal consultant. Association of outcome variables with the type of surgeon was determined by univariate and multivariate analyses and results were corrected by tumor's height. RESULTS: A total of 230 patients were treated over the study period; 136 (59 %) surgeries were performed by staff surgeons (group S) and 94 (41 %) by residents (group R). Both groups were comparable except for distance to anal verge; staff surgeons operated on lower tumors and performed a high percentage of coloanal anastomosis. There were no statistical differences between groups in terms of surgical and oncological outcomes when tumors were located over 7 cm from the anal verge. CONCLUSIONS: Rectal surgery can be performed by senior residents with equal results to staff surgeons when there is direct supervision by a senior consultant and when the tumor is located in the mid-upper rectum (>7 cm from the anal verge). For lower tumors, a careful selection must be made as the operation may require a higher level of training.

The role of transanal compared to laparoscopic total mesorectal excision (taTME vs. lapTME) for the treatment of mid-low rectal cancer in obese patients: outcomes of a multicenter propensity-matched analysis.

To compare the rate of sphincter-saving interventions between transanal and laparoscopic Total Mesorectal Excision in this particular group of patients. A multicentre observational study was conducted using a prospective database, including patients diagnosed with rectal cancer below the peritoneal reflection and BMI ≥ 30 kg/m2, who underwent minimally invasive elective surgery over a 5-year period. Exclusion criteria were (1) sphincter and/or puborectalis invasion; (2) multi-visceral resections; (3) palliative surgeries. The study population was divided into two groups according to the intervention: transanal or laparoscopic total mesorectal excision. The primary outcome was the rate of sphincter-saving surgery. Secondary outcomes included conversion, postoperative complications, quality of the specimen, and survival. A total of 93 patients were included; 40 (43%) transanal total mesorectal excision were compared to 53 (57%) laparoscopic. In addition, 35 cases of transanal approach were case-matched with an equal number of laparoscopic approaches, based on gender, tumor's height, and neoadjuvant therapy. In both groups, 43% of the patients had low rectal cancer; however, the rate of sphincter-saving surgery was significantly higher in the transanal group (97% vs. 71%, p = 0.003). There were no conversions to open surgery in the transanal group, compared to 2 cases in the laparoscopic group (6%) (p = 0.246). The percentage of major complications was similar, including the rate of anastomotic leakage (10% transanal vs. 19% laparoscopic, p = 0.835). In our experience, higher percentages of sphincter-saving procedures and lower conversion rates are potential benefits of using the transanal approach in a complex surgical setting population of obese patients with mid-low rectal tumors when compared to laparoscopic.

Impact of perineural invasion on the outcome of patients with synchronous colorectal liver metastases treated with neoadjuvant chemotherapy and surgery.

PURPOSE: To analyze the prognostic value of variables of the primary tumor in patients with synchronous liver metastases in colorectal cancer (CLRMs) treated with neoadjuvant chemotherapy and surgery. METHODS/PATIENTS: From a prospective database, we retrospectively identified all patients with synchronous CLRMs who were treated with neoadjuvant chemotherapy and liver resection. Using univariate and multivariate analyses, we identified the variables associated with tumor recurrence. Overall survival and disease-free survival were calculated using the Kaplan-Meier method with differences determined by the Cox multiple hazards model. Results were compared using the log-rank test. RESULTS: Ninety-eight patients with synchronous CLRMs were identified. With a median follow-up of 39.8 months, overall survival and disease-free survival at 5 and 10 years were 53%, 41.7%, 29% and 29%, respectively. Univariate analysis identified three variables associated with tumor recurrence: location in the colon (p = 0.025), lymphovascular invasion (p = 0.011) and perineural invasion (p = 0.005). Multivariate analysis identified two variables associated with worse overall survival: perineural invasion (HR 2.36, 95% CI 1.162-4.818, p = 0.018) and performing frontline colectomy (HR 3.286, 95% CI 1.256-8.597, p = 0.015). Perineural invasion remained as the only variable associated with lower disease-free survival (HR 1.867, 95% CI 1.013-3.441, p = 0.045). Overall survival at 5 and 10 years in patients with and without perineural invasion was 68.2%, 54.4% and 29.9% and 21.3%, respectively (HR 5.920, 95% CI 2.241-15.630, p < 0.001). CONCLUSIONS: Perineural invasion in the primary tumor is the variable with most impact on survival in patients with synchronous CLRMs treated with neoadjuvant chemotherapy and surgery.

Increased Expression Levels of Netrin-1 in Visceral Adipose Tissue during Obesity Favour Colon Cancer Cell Migration.

Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells.