Innate Immunity Activation in Newly Diagnosed Ileocolonic Crohn's Disease: A Cohort Study.

BACKGROUND: Recent studies showed that early surgery for Crohn's disease leads to a lower recurrence rate. However, the underlying mechanism is unknown. OBJECTIVE: The study aims to analyze the innate immunity microenvironment in ileal mucosa according to the duration of Crohn's disease. DESIGN: A prospective cohort study. SETTINGS: Tertiary referral center for IBD surgery. PATIENTS: A total of 88 consecutive patients with Crohn's disease undergoing ileocolonic resection were prospectively enrolled. Mucosal samples were obtained from both healthy and inflamed ileum. Data from a public data set were analyzed as an external validation cohort. MAIN OUTCOME MEASURES: Neutrophil infiltration was evaluated by histological asessment and macrophage subpopulation was assessed by immunohistochemistry. Expressions of TLR2 , TLR4 , TLR5 , DEFB1 , DEFB4A , DEFB103 , DEFA5 , and DEFA6 were quantified by real-time quantitative polymerase chain reaction. Concentrations of BDNF, CCL-11, ICAM-1, IL-1A, IL-1ß, IL-1RN, IL-12p40, IL-12p70, IL-15, IL-17A, IL-23A, MMP-3, CCL-3, KITLG, and VEGFA were determined with an immunometric assay. RESULTS: Neutrophil infiltration is inversely correlated with disease duration. DEFB4A mRNA expression tended to be higher in late-stage Crohn's disease ( p = 0.07). A higher number of macrophages expressed CD163 at low intensity in late-stage Crohn's disease ( p = 0.04). The concentration of IL-15 ( p = 0.02) and IL-23A ( p = 0.05) was higher in healthy ileal mucosa of early-stage patients. In the external cohort, expressions of DEFB1 ( p = 0.03), DEFB4A ( p = 0.01), IL-2 ( p = 0.04), and IL-3 ( p = 0.03) increased in patients with late-stage Crohn's disease. LIMITATIONS: A relatively small number of patients, especially in the newly diagnosed group. CONCLUSIONS: In newly diagnosed Crohn's disease, high levels of IL-15 and IL-23 in healthy mucosa suggest that innate immunity is the starter of acute inflammation. Moreover, M2 macrophages increase in the healthy mucosa of patients with late-stage Crohn's disease, suggesting that reparative and profibrotic processes are predominant in the long term, and in this phase, anti-inflammatory therapy may be less efficient. See Video Abstract . ACTIVACIN DE LA INMUNIDAD INNATA EN LA RECIENTEMENTE DIAGNOSTICADA ENFERMEDAD DE CROHN ILEOCLICA UN ESTUDIO DE COHORTE: ANTECEDENTES:Estudios recientes demostraron que la cirugía temprana para la enfermedad de Crohn (EC) conduce a una menor tasa de recurrencia. Sin embargo, se desconoce el mecanismo subyacente.OBJETIVO:El estudio tiene como objetivo analizar el microambiente de la inmunidad innata en la mucosa ileal según la duración de la EC.DISEÑO:Un estudio de cohorte prospectivo.AJUSTES:Centro terciario de referencia para cirugía de EII.PACIENTES:Fueron registrados de manera prospectiva y consecutiva 88 pacientes con EC sometidos a resección ileocolónica. Se obtuvieron muestras de mucosa ileal, tanto del íleon sano como del íleon inflamado. Los datos se analizaron como una cohorte de validación externa.PRINCIPALES MEDIDAS DE RESULTADO:Fueron evaluados la infiltración de neutrófilos por histología y la subpoblación de macrófagos por inmunohistoquímica. La expresión de TLR2, TLR4, TLR5, DEFB1, DEFB4A, DEFB103, DEFA5 y DEFA6 fueron cuantificados mediante qPCR en tiempo real. Las concentraciones de BDNF, CCL-11, ICAM-1, IL-1A, IL-1B, IL-1RN, IL-12 p40, IL-12 p70, IL-15, IL-17A, IL-23A, MMP-3, CCL-3, KITLG, VEGFA se determinaron con ensayo inmunométrico.RESULTADOS:La infiltración de neutrófilos se correlaciona inversamente con la duración de la enfermedad. La expresión del ARNm de DEFB4A mostro una tendencia a ser mayor en la EC en etapa tardía ( p = 0,07). Un mayor número de macrófagos expresaron CD163 a baja intensidad en la etapa tardía ( p = 0,04). La concentración de IL15 ( p = 0,02) e IL23A ( p = 0,05) fue mayor en la mucosa ileal sana de pacientes en estadio temprano. En la cohorte externa, la expresión de DEFB1 ( p = 0,03) y DEFB4A ( p = 0,01), IL2 ( p = 0,04) e IL3 ( p = 0,03) aumentó en pacientes en etapa tardía.LIMITACIONES:Un número relativamente pequeño de pacientes, especialmente en el grupo recién diagnosticado.CONCLUSIONES:En la EC recién diagnosticada, los altos niveles de IL-15 e IL-23 en la mucosa sana sugieren que la inmunidad innata es el promotor de la inflamación aguda. Además, los macrófagos M2 aumentan en la mucosa sana de pacientes con EC en etapa tardía, lo que sugiere que los procesos reparadores y profibróticos son predominantes a largo plazo y en esta fase, la terapia antiinflamatoria puede ser menos eficiente. (Traducción-Dr. Osvaldo Gauto ).

Collagen VI promotes recovery from colitis by inducing lymphangiogenesis and drainage of inflammatory cells.

Despite a number of studies providing evidence that the extracellular matrix (ECM) is an active player in the pathogenesis of intestinal inflammation, knowledge on the actual contribution of specific ECM molecules in the progression of inflammatory bowel disease (IBD) remains scant. Here, we investigated the role of a major ECM protein, collagen VI (ColVI), in gut homeostasis and elucidated the impact of its deregulation on the pathophysiology of IBD. To this end, we combined in vivo and ex vivo studies on wild type and ColVI-deficient (Col6a1-/- ) mice both under physiological conditions and during experimentally induced acute colitis and its subsequent recovery, by means of gut histology and immunostaining, gene expression, bone marrow transplantation, flow cytometry of immune cell subpopulations, and lymph flow assessment. We found that ColVI displayed dynamic expression and ECM deposition during the acute inflammatory and recovery phases of experimentally induced colitis, whereas the genetic ablation of ColVI in Col6a1 null mice impaired the functionality of lymphatic vessels, which in turn affected the resolution of inflammation during colitis. Based on these findings, we investigated ColVI expression and deposition in ileal specimens from two cohorts of patients affected by Crohn's disease (CD) and correlated ColVI abundance to clinical outcome. Our results show that high ColVI immunoreactivity in ileal biopsies of CD patients at diagnosis correlates with increased risk of surgery and that ColVI expression in biopsies taken at the resection margin during surgery, and showing inactive disease, predict disease recurrence. Our data unveil a key role for ColVI in the intestinal microenvironment, where it is involved in lymphangiogenesis and intestinal inflammation. Altogether, these findings point at the dysregulation of ColVI expression as a novel factor contributing to the onset and maintenance of inflammation in CD via mechanisms impinging on the modulation of inflammatory cell recruitment and function. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Molecular Determinants of Peritoneal Dissemination in Gastric Adenocarcinoma.

BACKGROUND: Peritoneal dissemination represents a poor prognostic indicator in gastric cancer. Despite a comprehensive molecular characterization of this disease, no peritoneal dissemination-specific signature has been identified, limiting the tailoring of the surgical and oncological treatments. In this review, we outline the available literature focusing on the role of the different molecular pathways involved in the acquisition of peritoneal metastatic dissemination. SUMMARY: According to our results, several molecular determinants are associated with peritoneal carcinomatosis and are involved in several cellular and molecular carcinogenetic processes. However, a comprehensive understanding of the complex molecular landscape of gastric carcinosis is still lacking. KEY MESSAGES: More efforts should be made toward the integration of molecular and histologic data to perform a risk prediction assessment of peritoneal dissemination based on molecular profiling and histological evaluation.

Predictors of urinary tract infection after lower gastrointestinal surgery.

BACKGROUND: Urinary tract infections (UTIs) cause postoperative morbidity in patients undergoing lower gastrointestinal (GI) surgery that can prolong postoperative hospital stays. In patients with a fever of unknown origin (FUO), clinicians ignore what to do while waiting for the results of the urine culture test. This study aimed to develop a nomogram predicting UTI in the case of postoperative FUO. METHODS: This observational, retrospective study included all consecutive patients from 1 November 2020 to 1 November 2021 undergoing lower-GI surgery at the Chirurgia Generale 3, University Hospital of Padua, Italy. A nomogram was created and externally validated in 90 consecutive patients undergoing urine culture tests for FUO at the Chirurgia Oncologica Unit, Veneto Institute of Oncology. RESULTS: In the development cohort, 109 (N = 109) patients performed a urine culture test for FUO, and 39 were diagnosed with UTI. In a multivariate analysis of patients who underwent urine culture tests for FUO, UTI was associated with female sex, older age, and duration of catheterization at the date of the urine culture test. We developed a nomogram to predict UTI in surgical patients with a C-index of 0.76. In the validation cohort, 90 consecutive patients, who had lower-GI surgery, underwent a urine culture test for FUO and were tested with this nomogram. In the validation cohort, the C-index of the nomogram for predicting a positive urine culture test was 0.71. CONCLUSIONS AND RELEVANCE: UTIs are a common problem in patients undergoing lower-GI surgery. A nomogram including the major risk factors may help to reduce the inappropriate use of antibiotics during the period awaiting the result of the urine culture test.

Leaving behind a diseased small bowel during surgery for Crohn's disease: Long-term outcomes.

PURPOSES: Stricture is a common complication of Crohn's disease (CD) and may be treated with bowel-sparing procedures. Our study analyzed what happens in terms of intestinal and systemic inflammation when the diseased bowel is left behind following surgery. METHODS: In this retrospective study, we enrolled 42 consecutive patients who underwent strictureplasty (alone or with resection) for stricturing CD. Control patients who underwent complete diseased bowel resection were identified and propensity score-matched for the sex, age, and history of abdominal surgery. Biohumoral values were collected at follow-up examinations at 1, 6, and 12 months after surgery. Magnetic resonance imaging (MRI) was performed before and after strictureplasty in 19 patients. RESULTS: In the strictureplasty group, fecal calprotectin levels were decreased at 12 months (p = 0.03), whereas in the resectiongroup, they were decreased at 6 months (p = 0.02). On MRI, the ADC [apparent diffusion coefficient] (p < 0.001), wall thickness (p = 0.046) and Magnetic Resonance Index of Activity (MaRIA) (p < 0.001) and Clermont (p < 0.001) scores were improved after strictureplasty. Surgical recurrence was more frequent in the strictureplasty group than in the resection group (p = 0.003). CONCLUSIONS: Our retrospective study showed that even if the diseased bowel was left behind after surgery, the intestinal inflammatory activity still decreased. However, the permanence of the diseased bowel still increased the risk of reoperation, probably because of the fibrotic nature of the stenosis and the multifocality of CD.

Discrimination Toward Women in Surgery: A Systematic Scoping Review.

BACKGROUND: Over the past twenty years explicit gender bias toward women in surgery has been replaced by more subtle barriers, which represent indirect forms of discrimination and prevents equality. OBJECTIVE: The aim of our scoping review is to summarize the different forms of discrimination toward women in surgery. METHODS: The database search consisted of original studies regarding discrimination toward female surgeons. RESULTS: Of 3615 studies meeting research criteria, 63 were included. Of these articles, 11 (18%) were focused on gender-based discrimination, 14 (22%) on discrimination in authorship, research productivity, and research funding, 21 (33%) on discrimination in academic surgery, 7 (11%) on discrimination in surgical leadership positions and 10 (16%) on discrimination during conferences and in surgical societies. The majority (n = 53, 84%) of the included studies were conducted in the U.S.A. According to our analysis, female surgeons experience discrimination from male colleagues, healthcare workers, but also from patients and trainees. Possible solutions may include acknowledgment of the problem, increased education of diversity and integration for the younger generations, mentorship, coaching, and more active engagement by male and female partners to support women in the surgical field. CONCLUSIONS: Gender-based discrimination toward women in the field of surgery has evolved over the past twenty years, from an explicit to a more subtle attitude. A work-environment where diversity and flexibility are valued would allow female surgeons to better realize their full potential.

Lasting Symptoms After Esophageal Resection (LASER): European Multicenter Cross-sectional Study.

OBJECTIVE: To identify the most prevalent symptoms and those with greatest impact upon health-related quality of life (HRQOL) among esophageal cancer survivors. BACKGROUND: Long-term symptom burden after esophagectomy, and associations with HRQOL, are poorly understood. PATIENTS AND METHODS: Between 2010 and 2016, patients from 20 European Centers who underwent esophageal cancer surgery, and were disease-free at least 1 year postoperatively were asked to complete LASER, EORTC-QLQ-C30, and QLQ-OG25 questionnaires. Specific symptom questionnaire items that were associated with poor HRQOL as identified by EORTC QLQ-C30 and QLQ-OG25 were identified by multivariable regression analysis and combined to form a tool. RESULTS: A total of 876 of 1081 invited patients responded to the questionnaire, giving a response rate of 81%. Of these, 66.9% stated in the last 6 months they had symptoms associated with their esophagectomy. Ongoing weight loss was reported by 10.4% of patients, and only 13.8% returned to work with the same activities.Three LASER symptoms were correlated with poor HRQOL on multivariable analysis; pain on scars on chest (odds ratio (OR) 1.27; 95% CI 0.97-1.65), low mood (OR 1.42; 95% CI 1.15-1.77) and reduced energy or activity tolerance (OR 1.37; 95% CI 1.18-1.59). The areas under the curves for the development and validation datasets were 0.81 ±â€Š0.02 and 0.82 ±â€Š0.09 respectively. CONCLUSION: Two-thirds of patients experience significant symptoms more than 1 year after surgery. The 3 key symptoms associated with poor HRQOL identified in this study should be further validated, and could be used in clinical practice to identify patients who require increased support.

Chemoradiation vs. local excision in the management of early squamous cell carcinoma of the anus: a systematic review.

PURPOSE: Squamous cell carcinoma of the anus (SCCA) suffers a constant increase each year in the last decades. Recent studies suggested the possibility of local excision (LE) as an option for early-stage SCAC patients. This systematic review aims to summarize the available evidence on the comparison of LE vs. chemoradiotherapy (CRT) in the treatment of early SCCA patients. METHODS: We conducted a literature review including MEDLINE/PubMed, EMBASE, SCOPUS, clinicaltrials.gov, and the Cochrane Database of Systematic Reviews through June 2022. MOOSE guidelines were followed. We used the methodological index for non-randomized studies (MINORS) tool to assess quality. Data on survival and procedure-associated costs were extracted. RESULTS: Four retrospective studies including 3323 patients were included. They were all comparative retrospective cohort studies (three were registry-based studies, either NCDB or SEER) with a MINORS score of 16-19 points. Overall survival (OS) was comparable between LE and CRT patients in three studies, with a 5-year OS of 85.3-100% in LE patients and 85-91.6% in CRT patients. One study investigated cancer-specific survival (CSS) and reported similar 5-year CSS in LE (98%) and CRT patients (96%). One investigated progression-free survival (PFS) and did not report any statistically significant difference in 5-year PFS between LE (91%) and CRT patients (83%). Only one study considered the mean costs associated with the two approaches (29,210 USD with LE and 46,350 USD with CRT). CONCLUSIONS: LE may potentially be considered a valid alternative to CRT for patients with early-stage SCAA. Results of prospective randomized long-term trials comparing LE with CRT are warranted to draw definitive conclusions and consider LE as a true cost-effective strategy for T1N0 SCCA with similar oncologic results offered by CRT, which-to date-remains the "gold standard." PROSPERO REGISTRATION: CRD42022338750.

How a modified Nissen procedure works: a mechanistic study using intraoperative esophageal high-resolution manometry.

OBJECTIVE: We aimed at demonstrating how a modified Nissen procedure works by analyzing intraoperatively the variations of the low esophageal sphincter pressure values using high resolution manometry. METHODS: This study included 15 patients with documented gastroesophageal reflux disease who underwent a laparoscopic modified Nissen procedure. Data regarding the changes in the pressure values were recorded at each step of the procedures using high resolution manometry and after the progressive insufflation of air in the stomach. Categorical data were compared between the preoperative and postoperative periods using Fisher's test, and continuous data were compared using Mann-Whitney U non-parametric test. Preoperative versus postoperative variations in continuous data were assessed using Wilcoxon's non-parametric test for paired data. RESULTS: Intraoperative manometric data showed a rise of basal LES pressure until the creation of the wrap. An evident increase of pressure values was recorded after gastric air insufflation, as consequence of the increase of intragastric pressure. No intraoperative and postoperative complications were observed. All patients experienced a significant reduction in terms of intensity and frequency of gastroesophageal reflux symptoms and no patients complained of dysphagia. CONCLUSIONS: Intraoperative high resolution manometry was feasible in all patients and demonstrated that the modified Nissen procedure works by increasing the LES pressure in response to gastric distension, without impeding the progression of the bolus into the stomach.

Crohn's Disease-Related Stoma Complications and Their Impact on Postsurgical Course.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. The diversion through a colostomy or an ileostomy is sometimes required for disease control. In these patients, common stoma-related complications sum up with CD-related complications and often require revisional surgery. METHODS: The aim of the study was to assess stoma morbidity after surgery for CD and to identify the burden of CD-related or CD-associated complications. Thus, details of past medical history, surgery, and follow-up of 54 consecutive patients operated on for CD with any sort of stoma were retrieved from the stoma therapist prospectively maintained database. RESULTS: In our series, 23 patients had a colostomy, and 31 patients had an ileostomy. Complications occurred after stoma creation in 38 patients (70%) at a median of 1.3 months (interquartile range 0.6-7.2). CD-related complications arose in 8 patients (including pyoderma gangrenosum in 3 patients, peristomal fistulae in 2, granulomas in 2, and peristomal abscess in 1). Patients with CD-related complications tended to have a shorter disease duration (p = 0.07) and higher occurrence of CD-related complications was associated with end-stoma (p = 0.006). In this cohort, 11 cases had to be surgically treated for peristomal fistulae or abscess, parastomal hernia, prolapse, pyoderma gangrenosum, and recurrent CD. DISCUSSION/CONCLUSIONS: In patients with CD, stoma creation is burdened by a high rate of postoperative complication and a relevant rate is specifically related to CD. Often these patients are required to be reoperated on to redo the stoma. Moreover, end-stoma configuration and aggressive CD phenotype are associated to a higher rate of complications.

Prognostic significance of additional histologic features for subclassification of pathological T3 colon cancer.

BACKGROUND: Additional histologic features of T3 colon cancer, such as tumour depth invasion beyond muscularis propria and elastic lamina invasion (ELI), have taken interest for a more accurate staging. METHODS: Patients with pT3 and pT4a (control group) colon adenocarcinoma were retrospectively collected from our institutional database. The study group was divided according to depth of tumour invasion < 5 mm and ≥ 5 mm, and into ELI - and ELI + . Chi-square test was used to compare the clinicopathological characteristics. OS and DFS were estimated using Kaplan-Meier method and compared with the log-rank test. Univariable and multivariable Cox proportional hazard models were employed to assess the effect on OS and DFS. RESULTS: Out of 290 pT3 tumours, 168 (58%) had a depth of tumour invasion < 5 mm and 122 (42%) ≥ 5 mm. The 5-year OS and DFS were 85.2, 68.7 and 60.9%, and 81.4, 73.9 and 60.1% in pT3 < 5 mm, pT3 ≥ 5 mm, and pT4a respectively (p = 0.001, p = 0.072). Considering ELI - (n = 157, 54%) and ELI + (n = 133, 46%), the 5-year OS and DFS were 78.9, 76.7, and 60.9%, and 75.5, 81.5, and 60.1% in ELI - , ELI + and pT4a respectively (p = 0.955, p = 0.462). At multivariable analysis, the depth of invasion was found to be an independent predictive factor for OS (HR 2.04, 95%CI 1.28-3.24, p = 0.003) and DFS (HR 1.98, 95%CI 1.24-3.18, p = 0.004), while ELI did not result a prognostic factor for OS nor DFS. CONCLUSION: In pT3 colon cancer, depth of tumour invasion ≥ 5 mm is an independent risk factor for OS and DFS, whereas ELI did not result a prognostic factor affecting OS nor DFS.

QOLEC2: a randomized controlled trial on nutritional and respiratory counseling after esophagectomy for cancer.

BACKGROUND: Esophagectomy for cancer strongly impairs quality of life. The aim of this trial was to evaluate the effect of the nutritional and respiratory counseling on postoperative quality of life. METHODS: At hospital discharge, patients were randomized into four groups receiving respectively: nutritional and respiratory counseling, nutritional counseling alone, respiratory counseling alone, or standard care. The main endpoint was the impairment in quality of life in the first month after surgery. Linear mixed effect models were estimated to assess mean score differences (MDs) in quality of life scores. RESULTS: Patients receiving nutritional counseling reported less appetite loss (MD - 17.7, 95% CI - 32.2 to -3.3) than those not receiving nutritional counseling at 1 month after surgery. Dyspnea was similar between patients receiving vs. those not receiving respiratory counseling (MD - 3.1, 95% CI - 10.8 to 4.6). Global quality of life was clinically similar between patients receiving vs. those not receiving nutritional counseling over time (MD 0.9, 95% CI - 5.5 to 7.3), as well as in patients receiving vs. those not receiving respiratory counseling over time (MD 0.7, 95% CI - 5.9 to 7.2). CONCLUSIONS: Intensive postoperative care does not affect global quality of life even if nutritional counseling reduced appetite loss.

Can Vascular Endothelial Growth Factors and CD34 Expression Implement NICE (Narrow-Band Imaging International Colorectal Endoscopic) Classification in Colorectal Polypoid Lesion Diagnosis?

BACKGROUND: Vascular endothelial growth factor (VEGF) is a subfamily of growth factors involved in angiogenesis; CD34+ cells are normally found in endothelial progenitor cells and endothelial cells of blood vessels. Colonic adenomatous polyps may not always be completely removable endoscopically, and a preoperative diagnosis might still be necessary. The aim of the study was to evaluate whether VEGF-A, VEGF-C and CD34 mRNA expression along colorectal carcinogenesis steps can implement NICE (Narrow-Band Imaging International Colorectal Endoscopic) classification in the diagnosis of malignancy in colorectal polypoid lesions. METHODS: Seventy-one subjects with colonic adenoma or cancer who underwent screening narrow-band imaging (NBI) colonoscopy were prospectively enrolled in the MICCE1 project (Treviso center). Polyps were classified according to the NICE classification. Real-time RT-PCR for VEGF-A, VEGF-C and CD34 mRNA expression was performed. Nonparametric statistics, receiver-operating characteristic curve analysis and logistic multiple regression analysis were used. RESULTS: VEGF-A and CD34 mRNA expression was significantly higher in sessile adenomas than in polypoid ones (p < 0.001 and p = 0.01, respectively). VEGF-A, VEGF-C and CD34 mRNA expression was significantly higher in adenocarcinoma than in adenoma (p = 0.01, p = 0.01 and p = 0.01, respectively). The accuracy of VEGF-A, VEGF-C and CD34 mRNA expression for prediction of malignancy was 0.79 (95% CI 0.65-0.90), 0.81 (95% CI 0.66-0.91) and 0.80 (95% CI 0.65-0.90), respectively, while the accuracy of the NICE classification was 0.85 (95% CI 0.72-0.94). The determination coefficient R2, which indicates the amount of the variability explained by a regression model, for NICE classification alone was 0.24 (p < 0.001). A regression model that included NICE classification and VEGF-C mRNA expression showed an R2 = 0.39 as well as a model including NICE classification and CD34 mRNA levels. CONCLUSIONS: This study demonstrated that VEGF-C and CD34 mRNA levels might be useful to stratify colorectal polyps in different risk of progression classes by implementing the accuracy of the NICE classification. Studies on in vivo detection of these markers are warranted.

Cholecystectomy during esophagectomy is safe but unnecessary.

Background: Prophylactic cholecystectomy has been proposed as a concomitant procedure during upper gastrointestinal surgery. This study evaluates the safety and the need of concurrent cholecystectomy during esophagectomy for cancer.Methods: All consecutive esophagectomies for esophageal cancer at the Center for Esophageal Diseases in Padova (Italy) between 1992 and 2011 were included. The safety of concurrent cholecystectomy was evaluated by surgical outcomes (length of stay, postoperative mortality and perioperative complications). The need for concurrent cholecystectomy was evaluated by occurrence of biliary duct stones and of cholelithiasis/cholecystitis after esophagectomy.Results: Cholecystectomy was performed during 67 out of 1087 esophagectomies (6.2%). Cirrhosis or chronic liver disease was associated with receiving cholecystectomy during esophagectomy (OR: 1.99, 95%C.I. 1.10-3.56). Patients receiving and those not receiving cholecystectomy showed similar length of stay (median 14 days, p = .87), postoperative mortality (3.0% vs. 2.5%, p = .68), intraoperative complication (4.5% vs. 7.1%, p = .62), early complications (52.2% vs. 44.6%, p = .25) and late complications (20.9% vs. 24.8%, p = .56). Cholelithiasis/cholecystitis after esophagectomy occurred in 61 (6.1%) patients, with only four requiring cholecystectomy during follow-up. The biliary stone occurrence was nil. Only pathologic stage III-IV (OR: 2.17, 95%C.I. 1.19-3.96) was associated with cholelithiasis/cholecystitis after esophagectomy.Conclusion: Routine prophylactic cholecystectomy during esophagectomy could be safe but unnecessary.

Squamous cell carcinoma antigen 1 is associated to poor prognosis in esophageal cancer through immune surveillance impairment and reduced chemosensitivity.

Squamous cell carcinoma antigen-1 (SCCA1) overexpression is associated with poor prognosis and chemoresistance in several tumor types, however, the underlying mechanisms remain elusive. Here, we report SCCA1 in relation to the immune and peritumoral adipose tissue microenvironment in early and advanced esophageal adenocarcinoma (EAC). In our series of patients with EAC, free SCCA1 serum levels were associated with significantly worse overall survival, and SCCA1-IgM serum levels showed a trend to a worse overall survival. Serum SCCA1 and intratumoral SCCA1 were inversely correlated with immune activation markers. In agreement with these findings, SCCA1 induced the expression of the immune checkpoint molecule programmed death ligand-1 on monocytes and a direct correlation of these 2 molecules was observed in sequential tumor sections. Furthermore, SCCA1 mRNA expression within the tumor was inversely correlated with stem cell marker expression both within the tumor and in the peritumoral adipose tissue. In vitro, in EAC cell lines treated with different chemotherapeutic drugs, cell viability was significantly modified by SCCA1 presence, as cells overexpressing SCCA1 were significantly more resistant to cell death. In conclusion, poor prognosis in EAC overexpressing SCCA1 is due to reduced tumor chemosensitivity as well as intratumoral immunity impairment, likely induced by this molecule.

Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases.

BACKGROUND: Claudin-18 (CLDN18) is a highly specific tight junction protein of the gastric mucosa. An isoform of CLDN18, the Claudin 18.2, has recently emerged as an innovative drug target for metastatic gastric cancer. METHODS: We investigated the immunohistochemical profile of CLDN18, p53, p16, E-cadherin, MSH2, MSH6, MLH1, PSM2, HER2, and PDL-1 in a large series of 523 primary gastric carcinomas (GCs; n = 408) and gastro-oesophageal carcinomas (GECs; n = 115) and 135 matched and synchronous nodal metastases. The status of HER2 and EBER by means of chromogenic in situ hybridisation (CISH) was also evaluated. RESULTS: High membranous CLDN18 expression was present in 150/510 (29.4%) primary cases and in 45/132 (34.1%) metastases. An abnormal expression (i.e. nuclear and/or cytoplasmic) was observed in 115 (22.5%) primary cases and in 33 (25.0%) metastases. A 38.8% of the cases showed significant CLDN18 intratumoural variability among the different tissue microarray cores obtained from the same tumour. Positive membrane CLDN18 expression was statistically associated with non-antral GCs (p = 0.016), Lauren diffuse type (p = 0.009), and with EBV-associated cancers (p < 0.001). CONCLUSIONS: CLDN18 is frequently expressed in gastric and gastro-oesophageal cancers; further studies should investigate the prognostic significance of CLDN18 heterogeneity in order to implement its test into clinical practice.

Correction to: Assessment of intratumor immune-microenvironment in colorectal cancers with extranodal extension of nodal metastases.

[This corrects the article DOI: 10.1186/s12935-018-0634-8.].

Prognostic role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with midgut neuroendocrine tumors undergoing resective surgery.

AIM: Several studies demonstrated the prognostic value of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and platelet-to-white blood cells ratio (PWR) in different types of tumors. However, there is no information about a possible role of NLR, PLR and PWR as predictor of presence of metastasis or multifocal disease in patients undergoing surgery with curative intent for midgut NET. The aim of our study was to test the role of preoperative NLR, PLR and PWR as predictors of patients undergoing surgery with curative intent for midgut NET. METHODS: We retrospectively enrolled seven foregut, 35 midgut and six hindgut NET patients with gastrointestinal neuroendocrine tumors operated in our Units from January 2005 to June 2016. Details about preoperative laboratory data, surgical operation, histology and follow-up were retrieved. Non-parametric statistics, ROC curve analysis and survival analysis were used. RESULTS: NLR was significantly higher in patients with distant metastasis (p = 0.04). The ROC curve analysis indicated that a threshold value of NLR of 2.6 predicted the presence of peritoneal metastasis with a specificity of 100% and a sensitivity of 71% and an overall accuracy of AUC = 0.81 (95%CI: 0.59-0.94), p = 0.05. PLR and PWR was not be associated to metastasis but tended to be associated to multifocal disease. CONCLUSION: In patients with midgut NET, an impaired adaptive immune response, as suggested by a high NLR ratio, was associated to the presence of distant metastasis and in particular of peritoneal metastasis. This information may be helpful when planning the treatment of a patient with a midgut NET.

Interferon-Gamma and Tumor Necrosis Factor-Related Weak Inducer of Apoptosis Expression in Neoangiogenesis in Colorectal Polypoid Lesions.

BACKGROUND: Interferon gamma (IFNγ) and tumor necrosis factor-related weak inducer of apoptosis (TWEAK) molecules seem to have a potential effect on angiogenic factors such as vascular endothelial growth factor (VEGF). The aim of this study was to assess a possible interplay between IFNγ and TWEAK cytokines and VEGF machinery in the different steps of colorectal carcinogenesis. METHODS: A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Polypoid lesion tissue samples were collected and frozen. Real-time reverse transcription polymerase chain reaction for IFNγ, TWEAK, and VEGF-A mRNA expression was performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Nonparametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used. RESULTS: IFNγ and TWEAK mRNA expression was higher in patients with T2 or more advanced colorectal cancer than in those with adenomas or T1 cancer (p < 0.001 and p = 0.01, respectively). IFNγ and TWEAK mRNA expression levels directly correlated with VEGF-A mRNA expression levels (rho = 0.44, p < 0.001 and rho = 0.29, p = 0.004, respectively). On the contrary, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGF-C protein levels (rho = -0.29, p = 0.04 and rho = -0.31, p = 0.03, respectively). Similarly, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGFR2 protein levels (rho = -0.38, p = 0.033 and rho = -0.40, p = 0.025, respectively). CONCLUSION: This study showed that in colorectal polypoid lesions, IFNγ and TWEAK expressions are directly correlated to VEGF-A expression but inversely correlated with VEGFR2 levels, suggesting a possible feedback mechanism in the regulation of VEGF-A expression.

Esophageal Cancer Clinical Presentation: Trends in the Last 3 Decades in a Large Italian Series.

OBJECTIVE: The aim of this study was to investigate trends in patients' characteristics and comorbidities in esophageal cancer (EC) patients. BACKGROUND: Identifying changing pattern is essential to understand and predict further changes and to plan surgical procedures and resource allocation. METHODS: Trends in patients' characteristics and comorbidities were evaluated in 4440 EC patients at the Center for Esophageal Diseases in Padova, Italy, during 1980 to 2011. Joinpoint regression analysis was performed to evaluate trends and to estimate annual percentage changes (APCs). RESULTS: During the study period, there has been a statistically significant increment of the rate of esophageal adenocarcinoma (APC 3.70). The rates of elderly and of asymptomatic patients increased over time (APCs 0.98 and 6.24), whereas the rates of malnutrition, alcoholic drinking, and gastric ulcer decreased (APCs -1.50, -1.72, and -5.20). Reflux rate increased until 1997 and decreased thereafter (APCs 6.96 and -4.48), whereas the rate of Barrett esophagus increased until 1992 (APC 35.84) and then leveled. The rates of patients with previous neoplasms increased over time (APCs 3.22 and 4.86). There have been significant changes in systemic comorbidities, with an increase of hypertension and cardiac disease (APCs 7.56 and 1.86) and a decrease of advanced liver disease and pulmonary disease (APCs -2.67 and -1.74). CONCLUSION: The current EC patient has more often an esophageal adenocarcinoma and is more frequently elderly, asymptomatic, a survivor of previous neoplasms, and a patient with hypertension and cardiac disease than 30 years ago. On the contrary, malnutrition, alcoholic drinking, gastric ulcer, pulmonary disease, and advanced liver disease decreased.