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 ).

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.

Role of Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Could It Be Considered a Predictor of Prognosis?

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment (TME). The aim of this study is to determine the potential significant TME immune markers of long-term survival. METHODS: We retrospectively included patients with a diagnosis of resectable PDAC having undergone upfront surgery. Immunohistochemical (IHC) staining using tissue microarray for PD-L1, CD3, CD4, CD8, FOXP3, CD20, iNOS and CD163 was performed in order to characterize the TME. The primary endpoint was long-term survival, defined as the Overall Survival > 24 months from surgery. RESULTS: A total of 38 consecutive patients were included, and 14 (36%) of them were long-term survivors. Long-term survivors showed a higher density of CD8+ lymphocytes intra- and peri-acinar (p = 0.08), and a higher CD8/FOXP3 intra- and peri-tumoral ratio (p = 0.05). A low density of intra- and peri-tumoral FOXP3 infiltration is a good predictor of long-term survival (p = 0.04). A significant association of the low density of intra- and peri-tumoral tumor-associated macrophages (TAMs) iNOS+ with long-term survival was detected (p = 0.04). CONCLUSIONS: Despite the retrospective nature and small sample size, our study showed that the high infiltration of CD8+ lymphocytes and low infiltration of FOXP3+ and TAMs iNOS+ are predictors of good prognosis. A preoperative assessment of these potential immune markers could be useful and determinant in the staging process and in PDAC management.

IMMUNOREACT 5: female patients with rectal cancer have better immune editing mechanisms than male patients - a cohort study.

BACKGROUND: Studies evaluating sex differences in colorectal cancer (CRC) tumor microenvironment are limited, and no previous study has focused on rectal cancer patients' constitutive immune surveillance mechanisms. The authors aimed to assess gender-related differences in the immune microenvironment of rectal cancer patients. METHODS: A systematic review and meta-analysis were conducted up to 31 May 2021, including studies focusing on gender-related differences in the CRC tumor microenvironment. Data on the mutational profile of rectal cancer were extracted from the Cancer Genome Atlas (TCGA). A subanalysis of the two IMMUNOREACT trials (NCT04915326 and NCT04917263) was performed, aiming to detect gender-related differences in the immune microenvironment of the healthy mucosa in patients with early (IMMUNOREACT 1 cohort) and locally advanced rectal cancer following neoadjuvant therapy (IMMUNOREACT 2 cohort). In the retrospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 442 patients (177 female and 265 male), while in the retrospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), we enrolled 264 patients (80 female and 184 male). In the prospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 72 patients (26 female and 46 male), while in the prospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), the authors enrolled 105 patients (42 female and 63 male). RESULTS: Seven studies reported PD-L1 expression in the CRC microenvironment, but no significant difference could be identified between the sexes. In the TGCA series, mutations of SYNE1 and RYR2 were significantly more frequent in male patients with rectal cancer. In the IMMUNOREACT 1 cohort, male patients had a higher expression of epithelial cells expressing HLA class I, while female patients had a higher number of activated CD4+Th1 cells. Female patients in the IMMUNOREACT 2 cohort showed a higher infiltration of epithelial cells expressing CD86 and activated cytotoxic T cells (P=0.01). CONCLUSIONS: Male patients have more frequent oncogene mutations associated with a lower expression of T-cell activation genes. In the healthy mucosa of female patients, more Th1 cells and cytotoxic T cells suggest a potentially better immune response to the tumor. Sex should be considered when defining the treatment strategy for rectal cancer patients or designing prognostic scores.

Validation of the Padova Prognostic Score for Colitis in Predicting Long-Term Outcome After Restorative Proctocolectomy.

Background: In 10%-20% of cases it is impossible to make a differential diagnosis between ulcerative colitis and Crohn's colitis. A 50% failure rate of J pouch ilea-anal anastomosis is observed in Crohn's colitis. In 2009, we created the Padua Prognostic Score for Colitis (PPSC) to predict the long-term clinical and functional outcome and quality of life of patients undergoing restorative proctocolectomy with J pouch. The aim of the present study is to establish and validate the accuracy of a prognostic score for chronic inflammatory bowel diseases (IBD). Patient population and methods: The PPSC was created in 2009 by integrating clinical and histological information of patients undergoing RPC. It included preoperative perianal abscess or fistula, rectal sparing, terminal ileum involvement, skip lesions and histological diagnosis of indeterminate colitis or Crohn's colitis on the operative specimen. The validity of this score was tested in predicting postoperative abscess or fistula, anal canal disease, pouchitis, pouch failure and new diagnosis of Crohn's disease. Correlation analysis, ROC curve analysis and survival analysis were used to validate the PPSC in a different cohort from the previous one. Results: We retrospectively enrolled in this study 138 consecutive patients undergoing CPR for ulcerative colitis (n = 127) or indeterminate colitis (n = 11) in our institution since 2005 to 2020. In this period, we observed 11 patients with postoperative abscess or fistula, 3 with anal canal disease, 40 with pouchitis, 6 with pouch failure and 6 with new diagnosis of Crohn's disease. In the new validation cohort, the PPSC confirmed to have a good accuracy in predicting the onset of postoperative CD (AUC = 74.5%, p = 0.018). Kaplan Meier curves demonstrate how a PPSC over 1 can reliably predicts the long-term onset of, pouchitis (p = 0.002) and anal abscess or fistulae (p = 0.04). Conclusions: In this validation study we confirmed the accuracy of the PPSC in predicting postoperative fistulas or abscesses and pouchitis. Therefore, we believe that in clinical practice patients with a PPSC score greater than 1 should be warned of this risk of possible Crohn's disease diagnosis and pouch failure.

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.

Metachronous colorectal cancer have a similar microsatellite instability frequency but a lower infiltration of lymphomononuclear cells than primary lesions.

BACKGROUND: An increased risk of metachronous colorectal cancer is usually associated with microsatellite instability occurring in Lynch syndrome. However, not all patients with metachronous colorectal cancer have microsatellite instability. The density of tumor-infiltrating lymphocytes is an independent predictor of outcome in patients with colorectal cancer, and a fascinating hypothesis is that they can be involved in the onset of metachronous colorectal cancer. The aim of this study was to analyze the tumor microenvironment and tumor mutation frequency in sporadic and metachronous colorectal cancer. METHODS: The clinical and pathological records of a series of consecutive colorectal cancer patients who were operated on from 2015 to 2019 were retrieved for this retrospective study. We defined metachronous colorectal cancer as a second colorectal cancer that appeared at least 1 year after the primary one, and sporadic colorectal cancer as those that did not have a metachronous colorectal cancer. Histology for the infiltration of intratumoral lymphomononuclear cells, immunohistochemistry for MLH1, PMS2, MSH2, and MSH6, and mutational analysis of BRAF, KRAS, and NRAS were all performed. Sporadic colorectal cancer and metachronous colorectal cancer were compared. Nonparametric tests were used for small sample size comparison. RESULTS: In the study, 238 patients were operated on for colorectal cancer at the General Surgery Unit of the Azienda Ospedaliera di Padova from 2015 to 2019. We identified 26 patients with metachronous colorectal cancer, and only 3 of them had had adjuvant therapy after the primary colorectal cancer. No difference was observed in terms of cancer stage between metachronous and sporadic colorectal cancer. Mismatch repair gene deficiencies and microsatellite instability frequency was similar in metachronous colorectal cancer and in sporadic colorectal cancer (P = .77). Likewise, the mutation frequency of BRAF and KRAs was similar in the 2 groups (P = .75 and P = .21, respectively). To the contrary, the absence of infiltration of lymphomononuclear cells within the tumor (P = .004) in patients with metachronous colorectal cancer was more frequent and they tended to have a higher frequency of NRAS mutation (P = .06). CONCLUSION: Our study showed that, rather unexpectedly, microsatellite instability frequency was similar in metachronous and sporadic colorectal cancer. Moreover, our data suggest that an altered immune microenvironment may be a crucial factor, permitting the occurrence of metachronous colorectal cancer. In fact, the absence of lymphomononuclear cells can be the substrate for a weak immune response to cancer neoantigens, opening the way to a second primary colorectal cancer.

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.

Esophageal squamous cell carcinoma metachronous to head and neck cancers.

BACKGROUND: In some HNSCC patients, a metachronous ESCC may develop. No information is available on the HNSCC-associated ESCCs microenvironment and etiology. METHODS: Among 134 ESCCs surgically treated between 2009 and 2015, a series of 6 HNSCC-associated ESCCs was collected. A series of 12 sex-, age- and stage-matched ESCCs with no previous oncological medical history was selected for comparison. Histologic assessment of intratumoral inflammatory infiltration and immunohistochemistry for CD4, CD8, CD80, PD1, PD-L1 and p53 were performed. HPV detection/genotyping was assessed by PCR single step and reverse line blot. RESULTS: HPV DNA was negative in all the HNSCC-associated ESCCs. In comparison to non-HNSCC-associated carcinomas, the 6 cases presented a lower lymphomonocytic infiltration, which also corresponded to a lower prevalence of CD4 + T cell infiltration and, 5/6 cases presented a PD-L1 CPS ≥ 1. All the HNSCC-associated ESCCs resulted positive for p53 immunostaining in ≥50 % of cancer cells. CONCLUSION: Our study suggests that HPV infection is not an etiological factor associated to ESCC after HNSCC. On the other hand, p53 overexpression is a common finding. Moreover, our data suggest that an altered immune microenvironment, conditioned by a dysregulation in lymphomonocytic infiltration, may be a crucial factor allowing the occurrence of a metachronous ESCC.

Impact on Quality of Life of Seton Placing in Perianal Crohn's Disease.

INTRODUCTION: Often, in perineal Crohn's disease (CD), a seton is placed to guarantee a constant drainage and prevent septic complication while biologic therapy is ongoing. This study aimed to assess the long-term quality of life after surgery for perineal CD in relation to seton placing. PATIENTS AND METHODS: Data of 65 consecutive patients with CD and non-CD operated on from 2014 to 2019 for perianal fistula or abscess were retrieved. Forty-three had CD and 14 of them had a seton placed during surgery and they kept it on while they had anti-TNF-alpha therapy. Patients were interviewed with the Cleveland Global Quality of Life (CGQL) and SF-12 quality of life questionnaires. Disease activity was defined as Harvey-Bradshaw Index (HBI) and Perianal Disease Activity Index (PDAI). Comparisons between groups were carried out with the nonparametric tests, and multiple regression models were used to assess predictors of quality of life. RESULTS: The total CGQL score and SF-12 mental component score (MCS) were significantly higher (and thus better) in the seton group than in patients treated without seton. On the contrary, SF-12 physical component score (PCS) was not different between the two groups. HBI was significantly better in patients in the seton group. At multivariate analysis, seton placement and HBI were confirmed to be independent predictors of long-term SF-12 MCS whereas only HBI confirmed to be a predictor of total CGQL score. CONCLUSIONS: Seton placing during anti-TNF-alpha therapy is independently associated with a better MCS. Unexpectedly, this device, instead of to cause psychological distress, seems to assure patients during their biologic therapy providing psychological benefit beyond the mere medical effect.

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.

Laparoscopic Ventral Rectopexy for Obstructed Defecation: Functional Results and Quality of Life.

BACKGROUND: Laparoscopic ventral mesh rectopexy (LVR) is gaining wider acceptance as the preferred procedure to correct internal and external rectal prolapse with obstructed defecation syndrome (ODS) and/or fecal incontinence. The aim of our study was to analyze functional outcome and quality of life (Health-Related Quality of Life) after LVR for symptomatic internal prolapse and/or rectocele with ODS. METHODS: Prospectively collected data on LVR for internal rectal prolapse were analyzed in 50 consecutive female patients operated between January 2011 and December 2018. In all cases, we performed a LVR according to the D'Hoore technique. Patients had ODS and internal rectal prolapse (grade 3 or 4) confirmed at the defecogram study. We registered only 1 major complication that required surgical treatment (Clavien-Dindo IIIb). The median hospital stay was 4 days [interquartile range (IQR): 2 to 5 d]. Functional results were measured with the Wexner Constipation Score and the 36-Item Short-Form Health Survey, and were analyzed before surgery and after 3, 6, or 12 months. RESULTS: After a median follow-up of 16.5 months (IQR: 10 to 44.25 mo), the Wexner Total Score was significantly improved in almost all items passing from 14 (IQR: 11 to 18) to 11 (IQR: 6.25 to 14.75) after surgery (P<0.0001). Incontinence was cured in 8 of 11 patients (P=0.036). Compared with the preoperative score, the 36-Item Short-Form Health Survey score improved, especially for physical activity, varying from 75 to 87.5 (P=0.0156). No worsening of continence status, constipation, or sexual function was observed. CONCLUSION: LVR appears to provide a sustained improvement in Health-Related Quality of Life, constipation, and incontinence in patients with ODS without worsening constipation with low morbidity and recurrence.

Impact of Age on Short- and Long-Term Outcomes after Pancreatoduodenectomy for Periampullary Neoplasms.

BACKGROUND: Although mortality and morbidity of pancreatoduodenectomy (PD) have improved significantly over the past years, the impact of age for patients undergoing PD is still debated. This study is aimed at analyzing short- and long-term outcomes of PD in elderly patients. METHODS: 124 consecutive patients who have undergone PD for pancreas neoplasms in our center between 2012 and 2017 were analyzed. Patients were divided into two groups: group I (<75 years) and group II (≥75 years). Demographic features and intraoperative and clinical-pathological data were collected. Primary endpoints were perioperative morbidity and mortality; complications were classified according to the Clavien-Dindo Score. Secondary endpoints included feasibility of adjuvant treatment and overall survival rates. RESULTS: A total of 106 patients were included in this study. There were 73 (68.9%) patients in group I and 33 (31.1%) in group II. Perioperative deceases were 4 (3.6%), and postoperative pancreatic fistulas were 34 (32.1%). Significant difference between two groups was demonstrated for the ASA Score (p = 0.004), Karnofsky Score (p = 0.025), preoperative jaundice (p = 0.004), and pulmonary complications (p = 0.034). No significance was shown for diabetes, radicality of resection, stage of disease, operative time, length of stay, postoperative complications according to the Clavien-Dindo Score, postoperative mortality, pancreatic fistula, and reoperation rates. 69.9% of the patients in group I underwent adjuvant treatment vs. 39.4% of the older ones (p = 0.012). Mean overall survival was 28.5 months in group I vs. 22 months in group II (p = 0.909). CONCLUSION: PD can be performed safely in elderly patients. Advanced age should not be an absolute contraindication for PD, even if greater frailty should be considered. The outcome of elderly patients who have undergone PD is similar to that of younger patients, even though adjuvant treatment administration is significantly lower, demonstrating that surgery remains the main therapeutic option.

Characterization of subcutaneous and omental adipose tissue in patients with obesity and with different degrees of glucose impairment.

Although obesity represents a risk factor for the development of type 2 diabetes mellitus (T2DM), the link between these pathological conditions is not so clear. The manner in which the different elements of adipose tissue (AT) interplay in order to grow has been suggested to have a role in the genesis of metabolic complications, but this has not yet been fully addressed in humans. Through IHC, transmission electron microscopy, cytometry, and in vitro cultures, we described the morphological and functional changes of subcutaneous and visceral AT (SAT and VAT) in normoglycemic, prediabetic and T2DM patients with obesity compared to lean subjects. In both SAT and VAT we measured a hypertrophic and hyperplastic expansion, causing similar vascular rarefaction in obese patients with different degrees of metabolic complications. Capillaries display dysfunctional basement membrane thickening only in T2DM patients evidencing VAT as a new target of T2DM microangiopathy. The largest increase in adipocyte size and decrease in adipose stem cell number and adipogenic potential occur both in T2DM and in prediabetes. We showed that SAT and VAT remodeling with stemness deficit is associated with early glucose metabolism impairment suggesting the benefit of an AT-target therapy controlling hypertrophy and hyperplasia already in prediabetic obese patients.

Weak Cytotoxic T Cells Activation Predicts Low-Grade Dysplasia Persistence in Ulcerative Colitis.

INTRODUCTION: In patients with ulcerative colitis (UC), dysplasia develops in 10%-20% of cases. The persistence of low-grade dysplasia (LGD) in UC in 2 consecutive observations is still an indication for restorative proctocolectomy. Our hypothesis is that in the case of weak cytotoxic activation, dysplasia persists. We aimed to identify possible immunological markers of LGD presence and persistence. METHODS: We prospectively enrolled 112 UC patients who underwent screening colonoscopy (T0) who had biopsies taken from their sigmoid colon. Ninety of them had at least a second colonoscopy (T1) with biopsies taken in the sigmoid colon and 8 patients had dysplasia in both examinations suggesting a persistence of LGD in their colon. Immunohistochemistry and real time polymerase chain reaction for CD4, CD69, CD107, and CD8ß messenger RNA (mRNA) expression and flow cytometry for epithelial cells expressing CD80 or HLA avidin-biotin complex were performed. Non-parametric statistics, receiver operating characteristic curves analysis, and logistic multiple regression analysis were used. RESULTS: Thirteen patients had LGD diagnosed at T0. The mucosal mRNA expression of CD4, CD69, and CD8ß was significantly lower than in patients without dysplasia (P = 0.033, P = 0.046 and P = 0.007, respectively). A second colonoscopy was performed in 90 patients after a median follow-up of 17 (12-25) months and 14 of the patients were diagnosed with LGD. In these patients, CD8ß mRNA expression at T0 was significantly lower in patients without dysplasia (P = 0.004). A multivariate survival analysis in a model including CD8ß mRNA levels and age >50 demonstrated that both items were independent predictors of dysplasia at follow-up (hazard ratio [HR] = 0.47 [95% confidence interval [CI]: 0.26-0.86], P = 0.014, and HR = 13.32 [95% CI: 1.72-102.92], P = 0.013). DISCUSSION: These data suggest a low cytotoxic T cell activation in the colonic mucosa of UC patients who do not manage to clear dysplasia. Thus, low level of CD8ß mRNA expression in non-dysplastic colonic mucosa might be considered in future studies about the decision making of management of LGD in UC.

Epithelial CD80 promotes immune surveillance of colonic preneoplastic lesions and its expression is increased by oxidative stress through STAT3 in colon cancer cells.

BACKGROUND: One of the most potent costimulatory molecules involved in the recognition and killing of tumor cells is CD80. However, its role and the molecular mechanisms regulating its expression in sporadic colorectal carcinogenesis remain elusive. Here, we provide evidence for CD80 overexpression in human colon epithelial cells derived from preneoplastic mucosa. METHODS: Expression of CD80 on colonic epithelial cells isolated from normal human colonic mucosa, preneoplastic and neoplastic specimens was assessed by flow cytometry. WT and CD80KO mice received azoxymethane to induce colon preneoplastic lesions and sacrificed to perform histology, flow cytometry analysis and immunohistochemistry of colonic mucosa. Some WT mice were treated with a monoclonal anti-CD80 antibody following AOM administration. Primary colon epithelial cells and CT26 cell line were used to quantify the expression of CD80 in response to pro-oxidant stimuli. Specific pharmacological inhibitors and siRNA silencing were used to inhibit MAPK pathways and STAT3. RESULTS: CD80 expression was significantly increased in colon epithelial cells of human preneoplastic lesions. In the AOM model, CD80 impairment by administration of neutralizing antibodies or use of CD80 knockout mice enhanced dysplasia development. In vitro, CD80 upregulation was induced by oxidative stress in colon cancer cells and primary colon epithelial cells. In addition, reactive oxygen species could induce CD80 expression via the JNK and p38 MAPK pathways, that activated STAT3 transcription factor in colon cancer epithelial cells. CONCLUSION: This study provide evidence for a major role of CD80 in orchestrating immune surveillance of colon preneoplastic lesions and might help to develop novel approaches that exploit anti-tumor immunity to prevent and control colon cancer.

Superior Mesenteric Artery Syndrome: a Prospective Study in a Single Institution.

BACKGROUND: Superior mesenteric artery syndrome (SMAS) is a rare cause of duodenal obstruction, resulting from the compression of the duodenum between superior mesenteric artery and aorta. This prospective registry aims to describe demographic, clinical, and outcome features of patients suffering from SMAS and to point out the indications for surgery. METHODS: Between 2008 and 2016, patients with chronic gastrointestinal symptoms and diagnosis of SMAS were included. Demographics, clinical presentation, diagnosis, and surgical outcome were recorded. Symptoms were investigated with a standardized questionnaire. The diagnosis was achieved through barium swallow, CT/MR angiography (aortomesenteric angle ≤ 22°, distance ≤ 8 mm), endoscopy. All patients underwent duodenojejunostomy ± distal duodenum resection. At follow-up, symptom score and barium swallow were re-evaluated. RESULTS: Thirty-nine patients (11 M/28 F, median age 38 years, median BMI 17.8 kg/m2) were included. Barium swallow showed a gastroduodenal dilation in 57% of patients, and a delayed gastroduodenal emptying in 38%. Median aortomesenteric angle was 11° and distance was 5 mm. All patients underwent duodenojejunostomy, and in 32 patients, a distal duodenum resection was also performed. At a median follow-up of 47 months, the overall symptom score significantly dropped (10 vs. 32, p < 0.0001) and BMI increased (19.5 vs. 17.8, p < 0.0001). Barium swallow at 2 months postoperatively showed an improvement in terms of gastroduodenal dilation and emptying in 38% of patients with preoperative pathological findings. CONCLUSIONS: SMAS is a rare condition that should be suspected in cases of chronic, refractory upper digestive symptoms, particularly in females with low BMIs. Surgical treatment may improve symptoms and quality of life, although it is not curative in all cases. ClinicalTrials.gov Identifier: NCT03416647.

Correction: Effects of immune suppression for transplantation on inflammatory colorectal cancer progression.

At the time of publication, the html version of this paper contained an error; the authors Imerio Angriman and Lucrezia Furian were not tagged as equally contributing authors. This has now been fixed in the html version of the paper, the PDF was correct at the time of publication.

Effects of immune suppression for transplantation on inflammatory colorectal cancer progression.

BACKGROUND: Ulcerative colitis patients and transplant recipients are at risk for colorectal cancer. Here, we show that immunosuppressive regimens for kidney transplants are associated with the progression of ulcerative colitis-related carcinogenesis. METHODS: We describe the case of a patient diagnosed with colorectal cancer in ulcerative colitis while on immunosuppressive therapy for a kidney transplant. The immunological microenvironment of the cancer and its mutational status were analyzed, and a mouse colon cancer model was created to replicate the unique clinical conditions. AOM/DSS mice were randomized into seven experimental groups that received different immunosuppressants and an untreated control group to assess the frequencies of adenocarcinoma and high-grade dysplasia. Histopathology, immunohistochemistry, and flow cytometry were also performed on the harvested mouse colons. RESULTS: All mice treated with an immunosuppressive regimen developed at least an adenoma, and several of those receiving anti-CD3, anti-CD8, and mycophenolate mofetil also developed adenocarcinomas. In contrast, mice receiving rapamycin did not develop adenocarcinomas, and the extent of high-grade dysplasia in those mice was similar to that in control mice. CONCLUSIONS: Patients with pre-neoplastic conditions, such as ulcerative colitis, who are undergoing a solid organ transplant might benefit from the use of mTOR inhibitors given their intrinsic anti-tumor properties.