Facing adenocarcinoma of distal esophagus and esophagogastric junction: a CROSS versus FLOT propensity score-matched analysis of oncological outcomes in a high-volume institution.

Multimodality treatments are the gold standard for advanced resectable gastroesophageal cancer. Neoadjuvant CROSS and perioperative FLOT regimens are adopted for distal esophageal and esophagogastric junction adenocarcinoma (DE/EGJ AC). At present, none of the approaches is clearly superior in the context of a curative-intent multimodal treatment. We analyzed consecutive patients treated with CROSS or FLOT and surgery for DE/EGJ AC between August 2017 and October 2021. Propensity score matching was performed to balance baseline characteristics of patients. The primary endpoint was disease-free survival. Secondary endpoints included overall survival, 90-day morbidity/mortality rates, pathological complete response, margin-negative resection, and pattern of recurrence. Of the 111 patients included, 84 were correctly matched after PSM, 42 in each group. The 2-year DFS rate was 54.2% versus 64.1% in the CROSS and FLOT group, respectively (p = 0.182). Patients in the CROSS group showed a lower number of harvested LN when compared to the FLOT group (29.5 versus 39.0 respectively, p = 0.005). A higher rate of distal nodal recurrence was found in the CROSS group (23.8% versus 4.8%, p = 0.026). Although not significant, the CROSS group showed a trend toward higher rate of isolated distant recurrence (33.3% versus 21.4% respectively, p = 0.328), together with a higher rate of early recurrence (23.8% versus 9.5% respectively, p = 0.062). FLOT and CROSS regimens for DE/EGJ AC offer similar DFS and OS, together with comparable morbidity/mortality rates. CROSS regimen was associated with a higher distant nodal recurrence rate. Results of ongoing randomized clinical trials are awaited.

MLH1 Deficiency Down-Regulates TLR4 Expression in Sporadic Colorectal Cancer.

Patients with mismatch repair (MMR)-deficient colorectal cancer (CRC) have a more favorable prognosis than patients with tumors with intact MMR. In order to obtain further insights on the reasons for this different outcome, we investigated the interplay between MMR genes and TLR4/MyD88 signaling. The cancer genome atlas (TCGA) databases were selected to predict the differential expression of TLR4 in colon cancer and its correlation with MMR genes. Moreover, the expression of MMR genes and TLR4 was evaluated by immunohistochemistry in 113 CRC samples and a cohort of 63 patients was used to assess TLR4 mRNA expression and MLH1 epigenetic silencing status. In vitro, the effect of MLH1 knockdown on TLR4 expression was quantified by Real Time PCR. TLR4 expression resulted dependent on MMR status and directly correlated to MLH1 expression. In vitro, MLH1 silencing decreased TLR4 expression. These observations may reflect the better prognosis and the chemoresistance of patients with CRC and MMR defects.

Management of Liver Oligometastatic Esophageal Cancer: Overview and Critical Analysis of the Different Loco-Regional Treatments.

Esophageal cancer (EC) is an aggressive disease that is associated with a poor prognosis. Since metastastic EC is usually considered suitable only for palliative therapy with an estimated 5-year overall survival (OS) less than 5%, the optimal management of patients with liver oligometastatic EC (LOEC) is still undefined. The aim of this review is to provide an overview of the different treatment options for LOEC. A literature search was conducted using PubMed, Embase, and Cochrane to identify articles evaluating different treatment strategies for LOEC. Among 828 records that were identified, 20 articles met the inclusion criteria. These studies included patients who have undergone any type of surgical procedure and/or loco-regional therapy. Liver resection resulted in the best survival for patients with low tumor burden (3 lesions): 5-year OS 30-50% versus 8-12% after only chemotherapy (CHT). The 5-year OS of loco-regional therapies was 23% with a local recurrence risk ranging 0-8% for small lesions (2 to 3 cm). An aggressive multidisciplinary approach for LOEC patients may improve survival. Surgery seems to be the treatment of choice for resectable LOEC. If unfeasible, loco-regional therapies may be considered. In order to better select these patients and offer a chance of cure, prospective trials and a definition of treatment protocols are needed.

Gastric tube cancer after esophagectomy for cancer: a systematic review.

Gastric conduit used for reconstruction after esophagectomy for cancer has the potential to develop a metachronous neoplasm known as gastric tube cancer (GTC). The aim of this study was to review literature and evaluate outcomes and possible treatment strategies for GTC. A comprehensive systematic literature search was conducted using PubMed, EMBASE, Scopus, and the Cochrane Library Central Register of Controlled Trials. No restriction was set for the type of publication, number, age, or sex of the patients. The search was limited to articles in English. Characteristics of esophageal cancer (EC) and its treatment and GTC and its treatment were analyzed. A total of 28 studies were analyzed, 12 retrospective analyses and 16 case reports, involving 229 patients with 250 GTCs in total. The majority of ECs (88.2%) were squamous cell carcinomas. In 120 patients (52.4%) a posterior mediastinal reconstructive route was used when esophagectomy was performed. The mean interval between esophagectomy and diagnosis of GTC was 55.8 months, with a median interval of 56.8 months (4-236 months). One hundred and twenty-four GTCs (49.6%) were located in the lower part of the gastric tube. One hundred and forty patients were endoscopically treated. Eighty-five patients underwent surgery. Thirty-six total gastrectomies with lymphadenectomy with colon or jejunal interposition were performed. Forty-three subtotal gastrectomies and 6 wedge resections were performed. The main reported postoperative complications were anastomotic leak, vocal cord palsy, and respiratory failure. Twenty-five patients were treated with palliative chemotherapy. Three-year survival rates were 69.3% for endoscopically treated patients, 58.8% for surgically resected patients, and 4% for patients who underwent palliative treatment. The feasibility of endoscopic resections in patients diagnosed with superficial GTC has been reported. Surgical treatment represented the preferred treatment method in operable patients with locally invasive tumor. Patients treated with conservative therapy have a scarce prognosis. The development of GTC should be taken into consideration during the extended follow-up of patients undergoing esophagectomy for cancer. Total gastrectomy plus lymphadenectomy should be considered the preferred treatment modality in operable patients with locally invasive tumor, when endoscopy is contraindicated. Long-term yearly endoscopic follow-up is recommended.

CD80 down-regulation is associated to aberrant DNA methylation in non-inflammatory colon carcinogenesis.

BACKGROUND: The lack of positive costimulatory molecules represents one of the mechanisms by which tumor cells evade immune surveillance. Promoter hypermethylation plays a major role in cancer development through transcriptional silencing of critical genes. The aim of this study was to examine the expression of the costimulatory molecule CD80 in relationship with genomic methylation in non-inflammatory colon carcinogenesis. METHODS: Colonic mucosal samples were collected from healthy subjects (n = 30) and from dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, -3a, -3b and CD80 mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR. CD80 expression was assessed in HT29, HCT-15 and LoVo cell lines after treatment with the DNA-methyltransferase inhibitor 5-Aza-2'-deoxycytidine. RESULTS: CD80 mRNA levels were significantly lower in the non-inflammatory dysplastic colonic mucosa of patients with one or more methylated genes and inversely correlated with patients' methylation scores (τ = -0.41, p = 0.05 and τ = -0.37, p = 0.05, respectively). Treatment with 5-Aza-2'-deoxycytidine significantly increased CD80 expression both in terms of the level of CD80 mRNA (p = 0.007) and of CD80+ cells (p = 0.003). CONCLUSIONS: These results indicate that the failure of immune surveillance mechanisms in non-inflammatory colon carcinogenesis may be linked to genomic methylation directly or indirectly affecting CD80 expression.

Aberrant gene methylation in non-neoplastic mucosa as a predictive marker of ulcerative colitis-associated CRC.

UNLABELLED: BACKGROUND PROMOTER: hypermethylation plays a major role in cancer through transcriptional silencing of critical genes. The aim of our study is to evaluate the methylation status of these genes in the colonic mucosa without dysplasia or adenocarcinoma at the different steps of sporadic and UC-related carcinogenesis and to investigate the possible role of genomic methylation as a marker of CRC. RESULTS: The expression of Dnmts 1 and 3A was significantly increased in UC-related carcinogenesis compared to non inflammatory colorectal carcinogenesis. In non-neoplastic colonic mucosa, the number of methylated genes resulted significantly higher in patients with CRC and in those with UC-related CRC compared to the HC and UC patients and patients with dysplastic lesion of the colon. The number of methylated genes in non-neoplastic colonic mucosa predicted the presence of CRC with good accuracy either in non inflammatory and inflammatory related CRC. METHODS: Colonic mucosal samples were collected from healthy subjects (HC) (n = 30) and from patients with ulcerative colitis (UC) (n = 29), UC and dysplasia (n = 14), UC and cancer (n = 10), dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, -3a, -3b, mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR. CONCLUSIONS: Methylation status of APC, CDH13, MGMT, MLH1 and RUNX3 in the non-neoplastic mucosa may be used as a marker of CRC: these preliminary results could allow for the adjustment of a patient's surveillance interval and to select UC patients who should undergo intensive surveillance.

Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance.

BACKGROUND: There is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC. PATIENTS AND METHODS: A group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used. RESULTS: Patients with MMR-D showed a higher T-bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively). CONCLUSIONS: CRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D.

Obesity is a risk factor for multifocal disease and recurrence after colorectal cancer surgery: a case-control study.

BACKGROUND: Several studies have demonstrated that obesity is a risk factor for colorectal cancer (CRC), but few data are available regarding its role in multifocal disease and postoperative recurrence. The present study aimed to assess the role of obesity as a risk factor for multifocal disease and postoperative recurrence in patients with CRC. PATIENTS AND METHODS: The records of 940 consecutive patients with CRC admitted to three surgical centres between January 2006 and January 2011 were retrospectively analysed. The 595 individuals whose preoperative body mass index (BMI) values were available were included in the study. Following WHO guidelines, the patients were stratified into four groups depending on their BMI values. Age at disease onset, clinical presentation, tumor invasiveness, the presence of multiple foci, and the colon cancer recurrence rate in the four groups were assessed and compared. RESULTS: At multivariate analysis, diagnosis of familial adenomatous polyposis (FAP) and a BMI>30 were found to be independent predictors of synchronous polyps (Odd Ratio [OR]=10.7, 95% Confidence interval (CI)=2-75, p=0.005; and OR=2.2, 95% CI=1.3-3.9, p=0.003, respectively). The cancer recurrence rate in the patients with stage 2 CRC was significantly higher in the obese with respect to the non-obese (p=0.05). At multivariate analysis, BMI>30, FAP, and positivity by the Bethesda criteria were found to be independent predictors of recurrence after CRC surgery. CONCLUSION: Obese patients diagnosed with CRC require thorough colonic exploration prior to surgery and necessitate more frequent postoperative endoscopic examinations with respect to patients without any risk factors.

A critical appraisal of laparoscopic pancreatic enucleations: right-sided procedures (Pancreatic Head, Uncus) are not mini-invasive surgery.

Laparoscopic pancreatic enucleation is increasingly performed worldwide. Few small-sized series show encouraging results, especially after enucleations performed for lesions located in the left part of the pancreas. The outcome of laparoscopic pancreatic enucleations was retrospectively evaluated by the analysis of prospectively collected parameters. Results of right-sided (head/uncus) and left-sided (neck/body/tail) enucleations were compared. From 1997 to 2010, 25 patients underwent laparoscopic pancreatic enucleation. The conversion rate was 12%, mean operating time was 158 minutes, and mean blood loss was 106 mL. Morbidity was 56% and the rate of pancreatic fistula 32%. Outcome differed between patients undergoing right-sided and left-sided enucleations, the operative time being 178 versus 132 minutes, morbidity 64% versus 45%, and median hospital stay 26 versus 9 days, respectively. Pancreatic enucleation is feasible by laparoscopy, with a high success rate and no mortality but significant morbidity. Laparoscopy seems to be of no use in right-sided procedures. Pancreatic fistula is still the main cause of long-lasting morbidity.

Laparoscopic minor pancreatic resections (enucleations/atypical resections). A long-term appraisal of a supposed mini-invasive approach.

INTRODUCTION: A few retrospective, small, often multicentric studies show encouraging results of laparoscopic minor pancreatic surgery, but do not allow for an evaluation of feasibility and effectiveness. AIM: Evaluation of the results of laparoscopic minor pancreatic resections (LMPR), including atypical resections and enucleations. MATERIAL AND METHODS: The outcome of all consecutive patients undergoing LMPR in a tertiary care university hospital specializing in the laparoscopic approach to solid organs (I.M.M., Paris - France) was retrospectively evaluated by the analysis of operating time, blood loss, conversion, morbidity, stay and late outcome. RESULTS: Thirty-three patients underwent LMPR (29 enucleations and 4 atypical resections) for various diseases. The conversion rate was 21%, mean operating time 189 min, and mean blood loss 133 ml. Morbidity was 60%; 10 patients (30%) presented a pancreatic fistula. Pancreatic fistula was independent of type of resection, technique of pancreas section, management of enucleated surface and somatostatin administration. Median stay for enucleations was 18 days. Mean follow-up was 61 months. CONCLUSIONS: Laparoscopic pancreatic enucleation is feasible and safe, with no mortality, no lengthening of operating time and a high success rate. Conversely, it does not imply a reduction in complications or hospital stay at the present state of the art.

Lipid and phospholipid profile after bowel resection for Crohn's disease.

BACKGROUND AND AIM: Chronic inflammation, impaired intestinal adsorption, and bowel resection may have an impact on lipid metabolism before and after intestinal surgery for Crohn's disease (CD). The aim of this prospective study was to define the impact of intestinal surgery for CD on plasma phospholipid fatty acid (FA) composition and of serum plasma lipoprotein concentrations and to investigate the role of CD recurrence on lipid parameters. MATERIALS AND METHODS: Twenty-four consecutive patients who had intestinal surgery for CD since December 2004 to March 2006 were enrolled in this prospective study. The total amount of calorie intake and the quality of the aliments, systemic inflammatory activity, and plasma lipoproteins and phospholipid fatty acid composition were determined at operation and at follow-up. Statistical analysis was performed with pair-matched tests. RESULTS: The median follow-up was 6 (4-20) months. During the follow-up, no significant modification of body mass index was observed. An increase of high-density lipoprotein (HDL) cholesterol (p=0.02) without other modifications in the plasma phospholipid FA composition were evidenced after surgery. The comparison between colectomy and ileo-colonic or ileal resection groups did not show any significant difference in the lipoprotein concentration and phospholipid FA profile. The length of resected bowel did not show any significant correlation with any relevant difference in lipid, phospholipid profile, or in inflammatory parameters. Patients who experienced a recurrence of CD reported significantly higher levels of total (p<0.01), HDL (p=0.01), and low-density lipoprotein cholesterol (p=0.01) were observed in patients in remission than in those with recurrent active disease. CONCLUSIONS: Patients who are submitted to intestinal resection for CD improve their inflammatory status as well as their lipid metabolism, and CD recurrence, but not the extent of bowel resection, is the main predictor of alteration of serum lipid concentration.

Restorative proctocolectomy for ulcerative colitis: impact on lipid metabolism and adipose tissue and serum fatty acids.

The aim of this prospective study was to evaluate the changes of the metabolism of circulating and storage lipids in patients with ulcerative colitis after restorative proctocolectomy. Fifteen consecutive patients and 15 sex- and age-matched healthy controls were enrolled. Disease activity, diet, inflammatory parameters, plasma lipoprotein concentrations, and fatty acids (FA) of serum phospholipids and of the subcutaneous adipose tissue were assessed at colectomy and at ileostomy closure. In ulcerative colitis patients, total cholesterol and docosahexaenoic acid were lower than in healthy subjects (p < 0.01 and p < 0.05). The median interval between colectomy and ileostomy closure was 6 (range 2-9) months. During that interval, the inflammatory parameters improved, high-density lipoproteins (HDL) cholesterol increased (p < 0.01), and low-density (LDL) cholesterol decreased (p = 0.01). At ileostomy closure, serum arachidonic acid levels were increased (p = 0.04), whereas serum oleic acid level was decreased (p = 0.02). In this interval, no significant alteration, either in serum n-3 FA precursors or in the FA of subcutaneous adipose tissue, was observed. The increase of serum arachidonic acid after colectomy might suggest a lower utilization for inflammatory process. The reduction of LDL cholesterol is an index of malabsorption probably due to the accelerated transit and to the exclusion of the terminal ileum caused by the covering ileostomy.