IMMUNOREACT 7: Regular aspirin use is associated with immune surveillance activation in colorectal cancer.

BACKGROUND: Long-term daily use of aspirin reduces incidence and mortality due to colorectal cancer (CRC). This study aimed to analyze the effect of aspirin on the tumor microenvironment, systemic immunity, and on the healthy mucosa surrounding cancer. METHODS: Patients with a diagnosis of CRC operated on from 2015 to 2019 were retrospectively analyzed (METACCRE cohort). Expression of mRNA of immune surveillance-related genes (PD-L1, CD80, CD86, HLA I, and HLA II) in CRC primary cells treated with aspirin were extracted from Gene Expression Omnibus-deposited public database (GSE76583). The experiment was replicated in cell lines. The mucosal immune microenvironment of a subgroup of patients participating in the IMMUNOREACT1 (ClinicalTrials.gov NCT04915326) project was analyzed with immunohistochemistry and flow cytometry. RESULTS: In the METACCRE Cohort, 12% of 238 patients analyzed were aspirin users. Nodal metastasis was significantly less frequent (p = .008) and tumor-infiltrating lymphocyte infiltration was higher (p = .02) among aspirin users. In the CRC primary cells and selected cell lines, CD80 mRNA expression was increased following aspirin treatment (p = .001). In the healthy mucosa surrounding rectal cancer, the ratio of CD8/CD3 and epithelial cells expressing CD80 was higher in aspirin users (p = .027 and p = .034, respectively). CONCLUSIONS: These data suggested that regular aspirin use may have an active role in enhancing immunosurveillance against CRC.

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 ).

IMMUNOREACT 6: weak immune surveillance characterizes early-onset rectal cancer.

BACKGROUND: Colon cancer in young patients is often associated with hereditary syndromes; however, in early-onset rectal cancer, mutations of these genes are rarely observed. The aim of this study was to analyse the features of the local immune microenvironment and the mutational pattern in early-onset rectal cancer. METHODS: Commonly mutated genes were analysed within a rectal cancer series from the University Hospital of Padova. Mutation frequency and immune gene expression in a cohort from The Cancer Genome Atlas ('TCGA') were compared and immune-cell infiltration levels in the healthy rectal mucosa adjacent to rectal cancers were evaluated in the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 ('IMMUNOREACT') series. RESULTS: In the authors' series, the mutation frequency of BRAF, KRAS, and NRAS, as well as microsatellite instability frequency, were not different between early- and late-onset rectal cancer. In The Cancer Genome Atlas series, among the genes with the most considerable difference in mutation frequency between young and older patients, seven genes are involved in the immune response and CD69, CD3, and CD8ß expression was lower in early-onset rectal cancer. In the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 series, young patients had a lower rate of CD4+ T cells, but higher T regulator infiltration in the rectal mucosa. CONCLUSION: Early-onset rectal cancer is rarely associated with common hereditary syndromes. The tumour microenvironment is characterized by a high frequency of mutations impairing the local immune surveillance mechanisms and low expression of immune editing-related genes. A constitutively low number of CD4 T cells associated with a high number of T regulators indicates an imbalance in the immune surveillance mechanisms.

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.

Prognostic significance of pathological sub-classification of pT3 rectal cancer.

PURPOSE: Patients with pT3 rectal cancer represent a heterogeneous prognostic group. A more accurate histological sub-classification of pT status has been suggested as an improvement of the TNM staging system. The aim of the study was to evaluate the prognostic implication of a histopathologic sub-classification of pT3 rectal cancer. METHODS: In this retrospective single-center study, pT3 rectal cancer patients who underwent surgery from January 2000 to December 2018 were evaluated. The maximum depth of tumor invasion beyond the muscularis propria was recorded. A ROC curve identified the best prognostic cutoff value to classify patients in two prognostic groups. Survival curves were estimated by the Kaplan-Meier method, and univariate and multivariate analyses with the Cox regression model were used to find independent factors influencing survival. RESULTS: Overall, 203 patients were included. Four millimeters was identified as the best cutoff value: 82 patients showed a depth of invasion < 4 mm (group A) and 121 ≥ 4 mm (group B). Both the estimated 5-year OS and DFS were statistically better in group A than in group B (OS: 83.9% vs 62.2%, p < 0.01; DFS: 78.3% vs 40.6%, p < 0.01). The depth of tumor invasion was an independent risk factor for OS (HR 2.25, 95% CI 1.26-3.99, p = 0.006) and DFS (HR 2.30, 95% CI 1.40-3.78, p = 0.001). CONCLUSION: Our findings suggest that a sub-classification of pT3 rectal cancer, based on the depth of tumor invasion, should be considered to be introduced in the TNM staging system.

The impact of anastomotic leak on long-term oncological outcomes after low anterior resection for mid-low rectal cancer: extended follow-up of a randomised controlled trial.

PURPOSE: The impact of anastomotic leaks (AL) on oncological outcomes after low anterior resection for mid-low rectal cancer is still debated. The aim of this study was to evaluate overall survival (OS), disease-free survival (DFS), and local and distant recurrence in patients with AL following low anterior resection. METHODS: This is an extension of a multicentre RCT (NCT01110798). Kaplan-Meier method and the log-rank test were used to estimate and compare the 3-, 5-, and 10-year OS and DFS, and local and distant recurrence in patients with and without AL. Predictors of OS and DFS were evaluated using the Cox regression analysis as secondary aim. RESULTS: Follow-up was available for 311 patients. Of them, 252 (81.0%) underwent neoadjuvant chemoradiotherapy and 138 (44.3%) adjuvant therapy. AL occurred in 63 (20.3%) patients. At a mean follow-up of 69.5 ± 31.9 months, 23 (7.4%) patients experienced local recurrence and 49 (15.8%) distant recurrence. The 3-, 5-, and 10-year OS and DFS were 89.2%, 85.3%, and 70.2%; and 80.7%, 75.1%, and 63.5% in patients with AL, and 88.9%, 79.8% and 72.3%; and 83.7, 74.2 and 62.8%, respectively in patients without (p = 0.89 and p = 0.84, respectively). At multivariable analysis, AL was not an independent predictor of OS (HR 0.65, 95%CI 0.34-1.28) and DFS (HR 0.70, 95%CI 0.39-1.25), whereas positive circumferential resection margins and pathological stage impaired both. CONCLUSIONS: In the context of modern multimodal rectal cancer treatment, AL does not affect long-term OS, DFS, and local and distant recurrence in patients with mid-low rectal cancer.

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.

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.

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.

Colorectal cancer in the young: a possible role for immune surveillance?

BACKGROUND: Younger patients with colorectal cancer (CRC) generally have better survival in spite of worse clinical and pathological features. METHODS: Twenty-six patients under 50 years operated for primary CRC were enrolled and matched 1:2:2 according to stage, tumor site and gender with 52 patients from 50 to 70 years and 52 patients over 70 years old. RESULTS: Patients under 50 years had a significantly longer overall, cancer specific and disease free survival (p = .001, p = .007 and p = .05, respectively). However, they had more frequently lymphovascular invasion (p = .006) and they more frequently developed metachronous CRC at follow-up (p = .03). Nevertheless, preoperative lymphocytes blood count/white blood count (LBC/WBC) ratio inversely correlated with age at operation (rho = -.21, p = .04) and it predicted CRC recurrence with an accuracy of 70%, p < .001 (threshold value LBC/WBC = 0.21%) and better overall, cancer specific and disease free survival (p < .0001 for all). At multivariate analysis, stage and LBC/WBC ratio resulted independent predictors of disease free survival (p = .0001 and p = .01, respectively). CONCLUSIONS: Patients under 50 years had a significantly longer survival with a higher LBC/WBC ratio. These results could suggest a possible role of immunosurveillance in neoplastic control.

Colorectal polypoid lesions and expression of vascular endothelial growth factor in a consecutive series of endoscopic and surgical patients.

Colorectal cancer incidence in patients undergoing screening protocols is decreasing because of the higher rate of discovered preneoplastic colonic lesions; however, adenomatous polyps may not always be removable endoscopically and surgery may still be necessary. The aim of this study was to assess the vascular endothelial growth factor expression in the different steps of colorectal carcinogenesis to explore its potential role as a marker of malignancy in polypoid lesions. A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Real-time reverse transcription polymerase chain reaction for VEGF-A messenger RNA expression and immunohistochemistry for VEGF-A were performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Non-parametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used. VEGF-A messenger RNA expression was higher in patients with high-grade dysplasia or colorectal cancer than in those with low-grade dysplasia adenomas (p = 0.01). At immunohistochemistry, VEGF-A expression was significantly higher in colorectal cancer patients compared to dysplastic adenomas (p < 0.001), and the accuracy of VEGF-A expression for prediction of malignancy was 91.7 (95% confidence interval = 78.7-97.9). VEGF-C protein expression was lower in colorectal cancer patients than in simple adenomas (p = 0.02). VEGF-A levels were directly correlated to polyp size (rho = 0.73, p = 0.0062). Multivariate analysis demonstrated that malignancy and polyp size were independent predictors of VEGF-A mucosal levels. This study demonstrated that the VEGF-A expression changes along the colorectal carcinogenesis pathway showing a neat step up at the passage from high-grade dysplasia to invasive cancer. This feature might potentially be useful to stratify colorectal polyps in different risks of progression classes. Moreover, the high level of VEGF-A expression predicted the presence of lymphovascular invasion with good accuracy.

Synchronous polyps predict metachronous colorectal lesions after curative resection of colorectal cancer.

BACKGROUND: The principal aim of endoscopic follow-up programs after curative resection of colorectal cancer (CRC) is to improve survival and identify local recurrence and metachronous CRC. The aim of our study was to identify the possible predictors of metachronous colorectal lesions. METHODS: The records of 348 consecutive patients with CRC and who completed at least 1 year of endoscopic follow-up after surgery were analyzed. In this group, 336 patients underwent surgery for primitive CRC and 12 for metachronous cancer. Patients' characteristics, operative details, and endoscopical follow-up findings were retrieved. Multivariate survival analyses were used to identify patient categories at risk of metachronous colonic lesions. RESULTS: 128 patients presented a metachronous lesion: 118 adenomas and 10 adenocarcinomas. At multivariate analysis, active smoke (HR = 1.84, p = 0.03), neoadjuvant therapy (HR = 0.24, p = 0.01), and presence of synchronous polyps (HR = 1.55, p = 0.04) resulted independent predictors of metachronous adenoma after CRC removal while neoadjuvant therapy (HR = 0.25, p = 0.02), active smoke (HR = 1.54, p = 0.04), and presence of synchronous polyps (HR = 1.86, p = 0.02) resulted independent predictors of metachronous lesions after CRC removal. CONCLUSIONS: This study demonstrated a high rate of metachronous lesions in the early follow-up after curative CRC resection. The negative effects of synchronous polyps should be carefully evaluated when planning patients' follow-up.

Intestinal Surgery for Crohn's Disease: Role of Preoperative Therapy in Postoperative Outcome.

PURPOSES: Patients affected by Crohn's disease (CD) require lifelong medical therapy, but they can also often require abdominal surgery. The effect of CD therapy on postoperative course is still unclear. The aim of this study was to evaluate the effect of preoperative medical therapy on the outcome of intestinal surgery in these patients. METHODS: Data from a consecutive series of 167 patients with CD operated on at the University of Padova Hospital from 2000 to 2013 were retrieved. Data of preoperative therapy during the 6 months before surgery were available for 146 patients who were enrolled in this retrospective study. Clinical data and surgical details were retrieved and postoperative complications and reoperation were considered outcome measures. Univariate and multivariate analysis were performed. RESULTS: No significant difference was observed between patients without data about their preoperative therapy and those with them. Eight patients underwent reoperation in the first 30 postoperative days: two of them for anastomotic leak, three for bleeding, one for obstruction and two for abdominal wound dehiscence. At multivariate analysis, preoperative adalimumab and budesonide resulted to be an independent predictor of reoperation (OR = 7.67 (95% CI = 1.49-39.20), p = 0.01 and OR = 6.7749 (95% CI = 0.98-46.48), p = 0.05, respectively). At multivariate analysis neither pharmacological nor clinical variables resulted to predict anastomotic leak. CONCLUSIONS: In our series, adalimumab seemed to be associated to early reoperation after intestinal surgery. This may be due to a worst disease severity in patients who needed surgery in spite of biological therapy. Preoperative tapering of budesonide dose seems a safe option before elective abdominal surgery for CD.

Short-Chain Fatty Acids and Human Health: From Metabolic Pathways to Current Therapeutic Implications.

The gastrointestinal tract is home to trillions of diverse microorganisms collectively known as the gut microbiota, which play a pivotal role in breaking down undigested foods, such as dietary fibers. Through the fermentation of these food components, short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are produced, offering numerous health benefits to the host. The production and absorption of these SCFAs occur through various mechanisms within the human intestine, contingent upon the types of dietary fibers reaching the gut and the specific microorganisms engaged in fermentation. Medical literature extensively documents the supplementation of SCFAs, particularly butyrate, in the treatment of gastrointestinal, metabolic, cardiovascular, and gut-brain-related disorders. This review seeks to provide an overview of the dynamics involved in the production and absorption of acetate, propionate, and butyrate within the human gut. Additionally, it will focus on the pivotal roles these SCFAs play in promoting gastrointestinal and metabolic health, as well as their current therapeutic implications.

Minimally invasive surgery for colorectal cancer: quality of life and satisfaction with care in elderly patients.

BACKGROUND: The purpose of this multicentric prospective study was to evaluate postoperative HRQL and satisfaction with care after laparoscopic colonic resection for colorectal cancer in elderly patients. METHODS: A total of 116 patients were enrolled in this study: 33 patients older than age 70 years had laparoscopic colectomy, whereas 24 had open colectomy; 44 patients younger than age 70 years had laparoscopic colectomy and 15 of them had open colectomy. The patients answered to three questionnaires about generic (EORTC QLQ C30) and disease-specific quality of life (EORTC CR29) and about treatment satisfaction (EORTC IN-PATSAT32). Nonparametric tests and forward stepwise multiple regression analysis were used for statistical analysis. RESULTS: One month after surgery, global quality of life (QL2 item) was significantly impaired in elderly patients who had laparoscopic colectomy compared with younger patients who had the same operation (p = 0.003). Similarly, role function (RF), physical function (PF), emotional function (EF), cognitive function (CF), and social function (SF) were impaired in elderly patients who had laparoscopic colectomy compared with younger patients (p < 0.001, p < 0.001, p = 0.013, p < 0.001, p = 0.01, respectively). Fatigue (FA), sleep disturbances (SL), appetite loss (AP), and dyspnea (DY) affected the quality of life of these patients more than younger patients (p < 0.001, p = 0.055, p = 0.051, and p = 0.003, respectively). CONCLUSIONS: Elderly patients undergoing laparoscopic colectomy for cancer experience less postoperative local complications than elderly patients undergoing open colectomy. Nevertheless, in the first postoperative month, these patients experience a worse global quality of life than younger patients undergoing the same operation with impairment of all the functions and the presence of fatigue, sleep disturbances, appetite loss, and dyspnea.

Treatment and Prognosis of Fibrolamellar Hepatocellular Carcinoma: a Systematic Review of the Recent Literature and Meta-analysis.

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare disease and current efforts are focused on the prognosis and on the development of efficient and specific treatments. This study aimed to review the latest evidence regarding FL-HCC treatment and prognosis. METHODS: A systematic review of the literature over the past 10 years regarding FL-HCC, and meta-analysis of 1-, 3-, and 5-year overall survival (OS) comparing FL-HCC and conventional HCC were performed. RESULTS: Overall, 1567 articles were screened, of them 21 were selected for the systematic review, and 6 for meta-analysis. Twenty-one studies included a total of 2168 patients with FL-HCC, with a median age ranging from 11 to 56 years. The majority of patients underwent surgical resection or liver transplantation. After a median follow-up ranging from 24 to 58 months, 1-year OS was 67-100% and 5-year OS was 28-65%. A total of 743 patients with FL-HCC and 163,472 with conventional HCC were included in the meta-analysis. There was a significantly improved 1-, 3-, and 5-years OS in the FL-HCC group compared to the conventional HCC group, although high heterogeneity was found. When excluding population-based studies, and including 96 FL-HCC and 221 conventional HCC patients, the heterogeneity was low, and the meta-analysis showed a significantly longer 1-year OS in patients with FL-HCC than conventional HCC; however, there were no differences at 3- and 5-years OS. CONCLUSIONS: Surgical resection for FL-HCC is currently the only curative treatment available. FL-HCC is plagued by high-recurrence rates and poor long-term outcomes which may be related to the absence of specific treatment for advanced and recurrent disease.

Extraintestinal Cancers in Inflammatory Bowel Disease: A Literature Review.

BACKGROUND: Inflammatory bowel disease (IBD) is a group of chronic multifactorial inflammatory disorders including two major entities: Crohn's disease (CD) and ulcerative colitis (UC). Preliminary evidence suggests that patients with IBD may be at increased risk of developing intestinal and extraintestinal cancers (EICs). Actually, little is known about the association between IBD and EICs, and there is ever-growing concern regarding the safety of immunomodulators and biological therapy, which may represent a risk factor for carcinogenesis. AIMS: The aim of this review is to summarize the evidence regarding the association between IBD and EICs, the safety of immunomodulators and biological therapy and the management of immunomodulators and biologic agents in IBD patients with prior or current EICs. RESULTS: IBD patients have a higher risk of developing different forms of extraintestinal solid organ tumors and hematological malignancies. Immunomodulators and biological therapy may increase the risk of developing some types of EICs and may be consciously used in patients with IBD and current or prior history of malignancy. CONCLUSIONS: Decisions regarding the use of immunomodulators or biological therapies should be made on an individual basis, considering a multidisciplinary approach involving oncologists.

Rectal Sparing Approaches after Neoadjuvant Treatment for Rectal Cancer: A Systematic Review and Meta-Analysis Comparing Local Excision and Watch and Wait.

Local Excision (LE) or Watch and Wait (WW) for patients with complete clinical response or near-complete clinical response after neoadjuvant chemoradiotherapy (nCRT) were proposed to avoid morbidity and impairment of quality of life after rectal resection. The aim of this study is to perform a systematic review of the literature, and to compare rectal-sparing approaches, in terms of rectum-preservation rate, local control, and distant recurrences. A systematic review and meta-analysis were performed of studies published until July 2022 (PROSPERO, registration CRD42022341480), and the quality of evidence was assessed using a GRADE approach. Seven retrospective studies and one prospective trial were included. In six studies, patients were treated with standard long-course nCRT, and in two with Total Neoadjuvant Therapy (TNT). Overall, there were 213 and 188 patients in WW and LE group, respectively, and no difference was found between WW and LE when considering rectum-preservation rate (OR 0.80 95%CI 0.31-2.01, p = 0.63), local disease (OR 1.60 95%CI 0.75-3.42, p = 0.22), locoregional failure (OR 0.85 95%CI 0.20-3.66, p = 0.83) and distant recurrence (OR 0.76 95%CI 0.37-1.55, p = 0.45). Studies directly comparing WW and LE are still lacking, even though no differences between WW and LE in terms of rectum-preservation, local control, and distant recurrences have been found.

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.