Role of visceral fat on postoperative complications and relapse in patients with Crohn's disease after ileocecal resection: Is it overrated?

INTRODUCTION: The role of visceral fat in disease development, particularly in Crohn´s disease (CD), is significant. However, its preoperative prognostic value for postoperative complications and CD relapse after ileocecal resection (ICR) remains unknown. This study aims to assess the predictive potential of preoperatively measured visceral and subcutaneous fat in postoperative complications and CD recurrence using magnetic resonance imaging (MRI). The primary endpoint was postoperative anastomotic leakage of the ileocolonic anastomosis, with secondary endpoints evaluating postoperative complications according to the Clavien Dindo classification and CD recurrence at the anastomosis. METHODS: We conducted a retrospective analysis of 347 CD patients who underwent ICR at our tertiary referral center between 2010 and 2020. We included 223 patients with high-quality preoperative MRI scans, recording demographics, postoperative outcomes, and CD recurrence rates at the anastomosis. To assess adipose tissue distribution, we measured total fat area (TFA), visceral fat area (VFA), subcutaneous fat area (SFA), and abdominal circumference (AC) at the lumbar 3 (L3) level using MRI cross-sectional images. Ratios of these values were calculated. RESULTS: None of the radiological variables showed an association with anastomotic leakage (TFA p = 0.932, VFA p = 0.982, SFA p = 0.951, SFA/TFA p = 0.422, VFA/TFA p = 0.422), postoperative complications, or CD recurrence (TFA p = 0.264, VFA p = 0.916, SFA p = 0.103, SFA/TFA p = 0.059, VFA/TFA p = 0.059). CONCLUSIONS: Radiological visceral obesity variables were associated with postoperative outcomes or clinical recurrence in CD patients undergoing ICR. Preoperative measurement of visceral fat measurement is not specific for predicting postoperative complications or CD relapse.

Muscarinic Acetylcholine Receptor M3 Expression and Survival in Human Colorectal Carcinoma-An Unexpected Correlation to Guide Future Treatment?

Muscarinic acetylcholine receptor M3 (M3R) has repeatedly been shown to be prominently expressed in human colorectal cancer (CRC), playing roles in proliferation and cell invasion. Its therapeutic targetability has been suggested in vitro and in animal models. We aimed to investigate the clinical role of MR3 expression in CRC for human survival. Surgical tissue samples from 754 CRC patients were analyzed for high or low immunohistochemical M3R expression on a clinically annotated tissue microarray (TMA). Immunohistochemical analysis was performed for established immune cell markers (CD8, TIA-1, FOXP3, IL 17, CD16 and OX 40). We used Kaplan-Meier curves to evaluate patients' survival and multivariate Cox regression analysis to evaluate prognostic significance. High M3R expression was associated with increased survival in multivariate (hazard ratio (HR) = 0.52; 95% CI = 0.35-0.78; p = 0.001) analysis, as was TIA-1 expression (HR = 0.99; 95% CI = 0.94-0.99; p = 0.014). Tumors with high M3R expression were significantly more likely to be grade 2 compared to tumors with low M3R expression (85.7% vs. 67.1%, p = 0.002). The 5-year survival analysis showed a trend of a higher survival rate in patients with high M3R expression (46%) than patients with low M3R expression CRC (42%) (p = 0.073). In contrast to previous in vitro and animal model findings, this study demonstrates an increased survival for CRC patients with high M3R expression. This evidence is highly relevant for translation of basic research findings into clinically efficient treatments.

[Effectiveness of Mucosal Advancement Flaps in Surgery of Perianal Fistulas from Crohn´s Disease and Cryptoglandular Fistulas - a Long-term Follow-up Study]. / Effektivität von Mukosa Muskel Flaps in der Behandlung von perianalen Fisteln bei Morbus Crohn und kryptoglandulären Fisteln ­ eine Langzeit-Follow-up-Studie.

AIM: Surgical treatment of perianal fistulae originating from Crohn's Disease (CD) or cryptoglandular abscess (CGA) remains a challenge. Data on long-term healing rates are scarce. We aimed to evaluate the long-term success rate of mucosal advancement flap (MAF) operations. METHODS: This single centre retrospective analysis was performed at a tertiary referral centre (Charité University Hospital Berlin, Campus Benjamin Franklin) between March 1, 2010 and March 31, 2020. Patients with complex perianal fistulae originating from CD or CGA treated with MAF were included. Long-time healing rates of MAF in CGA and CD were compared. Regression analysis was used to identify predictive factors for definitive healing. RESULTS: 83 patients (24 CD, 59 CGA,) were included. Median follow-up for CD was 5.4 and 1.9 years for CGA. Definitive healing of fistulae was achieved in 19 (79.2%) CD patients (p = 0.682) and in 44 (74.6%) CGA patients. Healing time was significantly shorter in CGA than in CD (9.3 months [standard deviation: SD= 11.3 months] vs. 30.9 months [SD = 23.5 months]; p < 0.001). Treatment with biologicals (hazard ratio: HR = 0.18, 95%-confidence interval: 95%-CI = 0.06-0.59, p = 0.004) and diverting ileostomy (HR = 0.29, 95%-CI = 0.10-0.85, p = 0.023) in CD were independent predictors for MAF success. Simultaneous medication with azathioprine in CD was an independent predictor for MAF failure (HR = 3.20, 95%-CI = 1.05-9.81, p = 0.041). CONCLUSION: This study demonstrates that surgical therapy of perianal fistulae with MAF is successful in about 75% of patients overall. Patients with MC benefit from biologicals and a diverting ileostomy. Treatment with azathioprine had a negative impact on recurrence rates. Repeated MAF operations did not increase the risk of failure in subsequent operations.

Inflammation of the rectal remnant endangers the outcome of ileal pouch-anal anastomosis: a case-control study.

BACKGROUND: Inflammation of the rectal remnant may affect the postoperative outcome of ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). We aimed to determine the extent of inflammation in the anastomotic area during IPAA and to investigate the impact of proctitis on postoperative complications and long-term outcomes. METHODS: Three hundred thirty-four UC patients with primary IPAA were included in this retrospective case-control study. The histopathologic degree of inflammation in the anastomotic area was graded into three stages of no proctitis ("NOP"), mild to medium proctitis ("MIP"), and severe proctitis ("SEP"). Preoperative risk factors, 30-day morbidity, and follow-up data were assessed. Kaplan-Meier analysis was performed in the event of pouch failure. RESULTS: The prevalence of proctitis was high (MIP 40.4%, and SEP 42.8%). During follow-up, the incidence of complications was highest among SEP: resulting in re-intervention (n = 40; 28.2%, p = 0.017), pouchitis (n = 36; 25.2%, p < 0.01), and pouch failure (n = 32; 22.4%, p = 0.032). The time interval to pouch failure was 5.0 (4.0-6.9) years among NOP, and 1.2 (0.5-2.3) years in SEP (p = 0.036). ASA 3, pouchitis, and pouch fistula were independent risk factors for pouch failure. CONCLUSION: Proctitis at the time of IPAA is common. A high degree of inflammation is associated with poor long-term outcomes, an effect that declines over time. In addition, a higher degree of proctitis leads to earlier pouch failure.

Impact of myopenia and myosteatosis on postoperative outcome and recurrence in Crohn's disease.

PURPOSE: Myopenia and myosteatosis have been proposed to be prognostic factors of surgical outcomes for various diseases, but their exact role in Crohn's disease (CD) is unknown. The aim of this study is to evaluate their impact on anastomotic leakage, CD recurrence, and postoperative complications after ileocecal resection in patients with CD. METHODS: A retrospective analysis of CD patients undergoing ileocecal resection at our tertiary referral center was performed. To assess myopenia, skeletal muscle index (skeletal muscle area normalized for body height) was measured using an established image analysis method at third lumbar vertebra level on MRI cross-sectional images. Muscle signal intensity was measured to assess myosteatosis index. RESULTS: A total of 347 patients were retrospectively analyzed. An adequate abdominal MRI scan within 12 months prior to surgery was available for 223 patients with median follow-up time of 48.8 months (IQR: 20.0-82.9). Anastomotic leakage rate was not associated with myopenia (SMI: p = 0.363) or myosteatosis index (p = 0.821). Patients with Crohn's recurrence had a significantly lower SMI (p = 0.047) in univariable analysis, but SMI was not an independent factor for recurrent anastomotic stenosis in multivariable analysis (OR 0.951, 95% CI 0.840-1.078; p = 0.434). Postoperative complications were not associated with myopenia or myosteatosis. CONCLUSION: Based on the largest cohort of its kind with a long follow-up time, we could provide some data that MRI parameters for myopenia and myosteatosis may not be reliable predictors of postoperative outcome or recurrence in patients with Crohn's disease undergoing ileocecal resection.

The Simultaneous Presence of Isolated Tumour Cells and Bone Marrow Micrometastases in Stage I and II Colon Cancer-Challenging the Theory of a Chronological Pathway of Tumour Cell Dissemination.

BACKGROUND: According to the common tenet, tumour progression is a chronological process starting with lymphatic invasion. In this respect, the meaning of bone marrow micrometastases (BMM) in patients with lymph node negative colon cancer (CC) is unclear. This study examines the relationship of isolated tumour cells (ITC) in sentinel lymph nodes (SLN) and BMM in patients in early CC. METHODS: BM aspirates were taken from both pelvic crests and in vivo SLN mapping was done during open oncologic colon resection in patients with stage I and II CC. Stainings were performed with the pancytokeratin markers A45-B/B3 and AE1/AE3 as well as H&E. The correlation between the occurrence of ITC+ and BMM+ and their effects on survival was examined using Cox regression analysis. RESULTS: In a total of 78 patients with stage I and II CC, 11 patients (14%) were ITC+, 29 patients (37%) BMM+. Of these patients, only two demonstrated simultaneous ITC+ /BMM+. The occurrence of BMM+ was neither associated with ITC+ in standard correlation (kappa = - 0.13 [95% confidence interval [CI] = - 0.4-0.14], p = 0.342) nor univariate (odds ratio [OR] = 0.39, 95%CI:0.07-1.50, p = 0.180) or multivariate (OR = 0.58, 95%CI: 0.09-2.95, p = 0.519) analyses. Combined detection of ITC+ /BMM+ demonstrated the poorest overall (HR = 61.60, 95%CI:17.69-214.52, p = 0.032) and recurrence free survival (HR = 61.60, 95%CI: 17.69-214.5, p = 0.032). CONCLUSIONS: These results indicate that simultaneous and not interdependent presence of very early lymphatic and haematologic tumour spread may be considered as a relevant prognostic risk factor for patients with stage I and II CC, thereby suggesting the possible need to reconsider the common assumptions on tumour spread proposed by the prevalent theory of sequential tumour progression.

The impact of surgical site infection-a cost analysis.

PURPOSE: Surgical site infection (SSI) occurs in up to 25% of patients after elective laparotomy. We aimed to determine the effect of SSI on healthcare costs and patients' quality of life. METHODS: In this post hoc analysis based on the RECIPE trial, we studied a 30-day postoperative outcome of SSI in a single-center, prospective randomized controlled trial comparing subcutaneous wound irrigation with 0.04% polyhexanide to 0.9% saline after elective laparotomy. Total medical costs were analyzed accurately per patient with the tool of our corporate controlling team which is based on diagnosis-related groups in Germany. RESULTS: Between November 2015 and May 2018, 456 patients were recruited. The overall rate of SSI was 28.2%. Overall costs of inpatient treatment were higher in the group with SSI: median 16.685 €; 19.703 USD (IQR 21.638 €; 25.552 USD) vs. median 11.235 €; 13.276 USD (IQR 11.564 €; 13.656 USD); p < 0.001. There was a difference in surgery costs (median 6.664 €; 7.870 USD with SSI vs. median 5.040 €; 5.952 USD without SSI; p = 0.001) and costs on the surgical ward (median 8.404 €; 9.924 USD with SSI vs. median 4.690 €; 5.538 USD without SSI; p < 0.001). Patients with SSI were less satisfied with the cosmetic result (4.3% vs. 16.2%; p < 0.001). Overall costs for patients who were irrigated with saline were median 12.056 €; 14.237 USD vs. median 12.793 €; 15.107 USD in the polyhexanide group (p = 0.52). CONCLUSION: SSI after elective laparotomy increased hospital costs substantially. This is an additional reason why the prevention of SSI is important. Overall costs for intraoperative wound irrigation with saline were comparable with polyhexanide.

Nestin and CD34 expression in colorectal cancer predicts improved overall survival.

BACKGROUND: Nestin, a class VI intermediate filament protein of the cytoskeleton, and CD34, a transmembrane phosphoglycoprotein, are markers of progenitor cells. This study aimed to evaluate their expression and clinical significance in colorectal cancer. METHODS: A clinically annotated tissue microarray, including 599 patients with colorectal cancer, was analyzed by immunohistochemistry. Furthermore, nestin and CD34 correlations with HIF-1a and a panel of cytokines and chemokines were assessed using quantitative reverse transcription PCR and The Cancer Genome Atlas dataset. RESULTS: Expression of nestin and CD34 was observed only in the tumor stroma. Patients displaying high expression of nestin and CD34 demonstrated higher rates of T1 and T2 tumors (p = .020), lower vascular invasion (p < .001) and improved 5-year overall survival (65%; 95% CI = 55-73 vs 45%; 95% CI = 37-53) after adjusting for clinicopathological characteristics (HR: 0.67; 95% CI = 0.46-0.96). A moderate to strong correlation (r = 0.37-0.78, p < .03) of nestin and CD34 was demonstrated for the following markers; HIF-1α, CD4, CD8, FOXP3, IRF1, GATA3, CCL2, CCL3, CXCL12 and CCL21. CONCLUSIONS: Combined expression of nestin and CD34 expression is associated with better overall survival possibly by modulating a favorable immune response.

Evaluation of the prognostic relevance of the recommended minimum number of lymph nodes in colorectal cancer-a propensity score analysis.

PURPOSE: Nodal status in colorectal cancer (CRC) is an important prognostic factor, and adequate lymph node (LN) staging is crucial. Whether the number of resected and analysed LN has a direct impact on overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) is much discussed. Guidelines request a minimum number of 12 LN to be analysed. Whether that threshold marks a prognostic relevant cut-off remains unknown. METHODS: Patients operated for stage I-III CRC were identified from a prospectively maintained database. The impact of the number of analysed LN on OS, CSS and DFS was assessed using Cox regression and propensity score analysis. RESULTS: Of the 687 patients, 81.8% had ≥ 12 LN resected and analysed. Median LN yield was 17.0 (IQR 13.0-23.0). Resection and analysis of ≥ 12 LN was associated with improved OS (HR = 0.73, 95% CI: 0.56-0.95, p = 0.033), CSS (HR 0.52, 95% CI: 0.31-0.85, p = 0.030) and DFS (HR = 0.73, 95% CI: 0.57-0.95, p = 0.030) in multivariate Cox analysis. After adjusting for biasing factors with propensity score matching, resection of ≥ 12 LN was significantly associated with improved OS (HR = 0.59; 95% CI: 0.43-0.81; p = 0.002), CSS (HR = 0.34; 95% CI: 0.20-0.60; p < 0.001) and DFS (HR = 0.55; 95% CI: 0.41-0.74; p < 0.001) compared to patients with < 12 LN. CONCLUSION: Eliminating biasing factors by a propensity score matching analysis underlines the prognostic importance of the number of analysed LN. The set threshold marks the minimum number of required LN but nevertheless represents a cut-off regarding outcome in stage I-III CRC. This analysis therefore highlights the significance and importance of adherence to surgical oncological standards.

Validation of the German Classification of Diverticular Disease (VADIS)-a prospective bicentric observational study.

PURPOSE: The German Classification of Diverticular Disease was introduced a few years ago. The aim of this study was to determine whether Classification of Diverticular Disease enables an exact stratification of different types of diverticular disease in terms of course and treatment. METHODS: This was a prospective, bicentric observational trial. Patients aged ≥ 18 years with diverticular disease were prospectively included. The primary endpoint was the rate of recurrence within 2 year follow-up. Secondary outcome measures were Gastrointestinal Quality of Life Index, Quality of life measured by SF-36, frequency of gastrointestinal complaints, and postoperative complications. RESULTS: A total of 172 patients were included. After conservative management, 40% of patients required surgery for recurrence in type 1b vs. 80% in type 2a/b (p = 0.04). Sixty percent of patients with type 2a (micro-abscess) were in need of surgery for recurrence vs. 100% of patients with type 2b (macro-abscess) (p = 0.11). Patients with type 2a reached 123 ± 15 points in the Gastrointestinal Quality of Life Index compared with 111 ± 14 in type 2b (p = 0.05) and higher scores in the "Mental Component Summary" scale of SF-36 (52 ± 10 vs. 43 ± 13; p = 0.04). Patients with recurrent diverticulitis without complications (type 3b) had less often painful constipation (30% vs. 73%; p = 0.006) when they were operated compared with conservative treatment. CONCLUSION: Differentiation into type 2a and 2b based on abscess size seems reasonable as patients with type 2b required surgery while patients with type 2a may be treated conservatively. Sigmoid colectomy in patients with type 3b seems to have gastrointestinal complaints during long-term follow-up. TRIAL REGISTRATION: https://www.drks.de ID: DRKS00005576.

Risk factors for upper and lower type prolonged postoperative ileus following surgery for Crohn's disease.

PURPOSE: Prolonged postoperative ileus (PPOI) is common after bowel resections, especially in Crohn's disease (CD). The pathophysiology of PPOI is not fully understood. PPOI could affect only the upper or lower gastrointestinal (GI) tract. The aim of this study was to assess risk factors for diverse types of PPOI, particularly to differentiate PPOI of upper and lower GI tract. METHODS: A retrospective analysis of 163 patients with CD undergoing ileocecal resection from 2015 to 2020 in a single center was performed. PPOI of the upper GI tract was predefined as the presence of vomiting or use of nasogastric tube longer than the third postoperative day. Lower PPOI was predefined as the absence of defecation for more than three days. Independent risk factors were identified by multivariable logistic regression analysis. RESULTS: Overall incidence of PPOI was 42.7%. PPOI of the upper GI tract was observed in 30.7% and lower PPOI in 20.9% of patients. Independent risk factors for upper PPOI included older age, surgery by a resident surgeon, hand-sewn anastomosis, prolonged opioid analgesia, and reoperation, while for lower PPOI included BMI ≤ 25 kg/m2, preoperative anemia, and absence of ileostomy. CONCLUSION: This study identified different risk factors for upper and lower PPOI after ileocecal resection in patients with CD. A differentiated upper/lower type approach should be considered in future research and clinical practice. High-risk patients for each type of PPOI should be closely monitored, and modifiable risk factors, such as preoperative anemia and opioids, should be avoided if possible.

Abdominal Decompression after Cardiac Surgery: Outcome of 42 Patients with Abdominal Compartment Syndrome.

BACKGROUND: Up to 50% of patients in intensive care units develop intraabdominal hypertension (IAH) in the course of medical treatment. If not detected on time and treated adequately, IAH may develop into an abdominal compartment syndrome (ACS) which is associated with a high mortality rate. Patients undergoing cardiac surgery are especially prone to develop ACS due to several risk factors including intraoperative hypothermia, fluid resuscitation and acidosis. We investigated patients who developed ACS after cardiac surgery and analyzed potential risk factors, treatment and outcome. METHODS: From 2011 to 2016, patients with ACS after cardiac surgery requiring decompressive laparotomy were prospectively recorded. Patient characteristics, details on the cardiac surgery, mortality rate and type of treatment of the open abdomen were analyzed. RESULTS: Incidence of ACS in cardiac surgery patients was 1.0% (n = 42/4128), with a mortality rate of 57%. Ejection fraction, Euroscore2 as well as the perfusion time are independent risk factors for the development of ACS. The outcome of patients with ACS was independent of elective versus emergency surgery, gender, age, BMI or ASA score. In the 18 surviving patients, fascial closure was achieved in 72% after a median of 9 days. CONCLUSION: Abdominal compartment syndrome is a rare but serious complication after cardiac surgery with a high mortality rate. Independent risk factors for ACS were identified. Negative pressure wound therapy seems to promote and allow early fascia closure of the abdomen and represents therefore a likely benefit for the patient.

Molecular Lymph Node Staging with One-Step Nucleic Acid Amplification and its Prognostic Value for Patients with Colon Cancer: The First Follow-up Study.

BACKGROUND: Molecular lymph node workup with one-step nucleic acid amplification (OSNA) is a validated diagnostic adjunct in breast cancer and also appealing for colon cancer (CC) staging. This study, for the first time, evaluates the prognostic value of OSNA in CC. PATIENTS AND METHODS: The retrospective study includes patients with stage I-III CC from three centres. Lymph nodes were investigated with haematoxylin and eosin (H&E) and with OSNA, applying a 250 copies/µL threshold of CK19 mRNA. Diagnostic value of H&E and OSNA was assessed by survival analysis, sensitivity, specificity and time-dependent receiver operating characteristic curves. RESULTS: Eighty-seven patients were included [mean follow-up 53.4 months (± 24.9)]. Disease recurrence occurred in 16.1% after 19.8 months (± 12.3). Staging with H&E independently predicted worse cancer-specific survival in multivariate analysis (HR = 10.77, 95% CI 1.07-108.7, p = 0.019) but not OSNA (HR = 3.08, 95% CI 0.26-36.07, p = 0.197). With cancer-specific death or recurrence as gold standard, H&E sensitivity was 46.7% (95% CI 21.3-73.4%) and specificity 84.7% (95% CI 74.3-92.1%). OSNA sensitivity and specificity were 60.0% (95% CI 32.3-83.7%) and 75.0% (95% CI 63.4-84.5%), respectively. CONCLUSIONS: In patients with CC, OSNA does not add relevant prognostic value to conventional H&E contrasting findings in other cancers. Further studies should assess lower thresholds for OSNA (< 250 copies/µL).

Tumor Infiltration by OX40+ Cells Enhances the Prognostic Significance of CD16+ Cell Infiltration in Colorectal Cancer.

OBJECTIVES: Analysis of tumor immune infiltration has been suggested to outperform tumor, node, metastasis staging in predicting clinical course of colorectal cancer (CRC). Infiltration by cells expressing OX40, a member of the tumor necrosis factor receptor family, or CD16, expressed by natural killer cells, monocytes, and dendritic cells, has been associated with favorable prognosis in patients with CRC. We hypothesized that assessment of CRC infiltration by both OX40+ and CD16+ cells might result in enhanced prognostic significance. METHODS: Colorectal cancer infiltration by OX40 and CD16 expressing cells was investigated in 441 primary CRCs using tissue microarrays and specific antibodies, by immunohistochemistry. Patients' survival was evaluated by Kaplan-Meier and log-rank tests. Multivariate Cox regression analysis, hazard ratios, and 95% confidence intervals were also used to evaluate prognostic significance of OX40+ and CD16+ cell infiltration. RESULTS: Colorectal cancer infiltration by OX40+ and CD16+ cells was subclassified into 4 groups with high or low infiltration levels in all possible combinations. High levels of infiltration by both OX40+ and CD16+ cells were associated with lower pT stage, absence of peritumoral lymphocytic (PTL) inflammation, and a positive prognostic impact. Patients bearing tumors with high infiltration by CD16+ and OX40+ cells were also characterized by significantly longer overall survival, as compared with the other groups. These results were confirmed by analyzing an independent validation cohort. CONCLUSIONS: Combined infiltration by OX40+ and CD16+ immune cells is an independent favorable prognostic marker in CRC. The prognostic value of CD16+ immune cell infiltration is significantly improved by the combined analysis with OX40+ cell infiltration.

Improved quality of colon cancer surveillance after implementation of a personalized surveillance schedule.

BACKGROUND: Early detection of recurrence through surveillance after curative surgery for primary colon cancer is recommended. We previously reported inadequate quality of surveillance among patients operated for colon cancer. These poor results led to the introduction of a personalized surveillance schedule. This study reassesses the quality of surveillance after the introduction of the personalized schedule. PATIENTS AND METHODS: A total of 93 patients undergoing curative surgery for colon cancer between January 2009 and December 2014 (prospective data registration) were included in this retrospective single-center cohort study. Written informed consent was given by all patients. Compliance with surveillance was compared with national guidelines, as well as with the previous results and analyzed depending on where surveillance was conducted (general practitioner or outpatient clinic). RESULTS: Adherence to surveillance was higher when performed by oncologists compared to general practitioners with an odds ratio (OR), 6.03 (95%CI: 3.41-10.67, P = .001). Compared with the previous study, adherence to surveillance was significantly higher in the later cohort with an OR = 4.55 (95%CI: 2.50-8.33, P < 0.001). CONCLUSION: This study demonstrates that the implementation of a personalized surveillance schedule improves adherence to recommendations and that awareness can be increased with this simple measure.

Gut microbiota modulate T cell trafficking into human colorectal cancer.

OBJECTIVE: Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers. DESIGN: Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing. RESULTS: CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival. CONCLUSIONS: Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.

High OX40 expression in recurrent ovarian carcinoma is indicative for response to repeated chemotherapy.

BACKGROUND: Ovarian carcinoma (OC) is the fifth most common female cancer and mostly diagnosed at an advanced stage. Surgical debulking is usually followed by adjuvant platinum-based chemotherapy. Only few biomarkers are known to be related to chemosensitivity. OX40 is a TNF receptor member and expressed on activated CD4+ and CD8+ T cells. It is known that OX40 signaling promotes survival and responds to various immune cells of the innate and adaptive immune system. Therefore we investigated the indicative value of OX40 expression for recurrence and survival in OC. METHODS: A tissue microarray of biopsies of mostly high-grade primary serous OC and matched recurrences of 47 patients was stained with OX40. Recurrence within 6 months of the completion of platinum-based chemotherapy was defined as chemoresistance. RESULTS: Chemosensitivity correlated significantly with high OX40 positive immune cell density in primary cancer biopsies (p = 0.027). Furthermore patients with a higher OX40 expression in recurrent cancer biopsies showed a better outcome in recurrence free survival (RFS) (p = 0.017) and high OX40 expression was associated with chemosensitivity (p = 0.008). OX40 positive TICI in recurrent carcinomas significantly correlated with IL-17 positive tumor infiltrating immune cells in primary carcinomas (r s = 0.34; p = 0.023). Univariate cox regression analysis revealed a significant longer RFS and higher numbers of chemotherapy cycles for high OX40 tumor cell expression in recurrent cancer biopsies (HR 0.39, 95%CI 0.16-0.94, p = 0.036 and 1.28, 95%CI 1.05-1.55; p = 0.013). CONCLUSION: High OX40 expression in OC is correlated with chemosensitivity and improved RFS in OC. Patients might therefore benefit from a second line therapy.

Sentinel Lymph Node Mapping with Isosulfan Blue or Indocyanine Green in Colon Cancer Shows Comparable Results and Identifies Patients with Decreased Survival: A Prospective Single-Center Trial.

BACKGROUND: Sentinel lymph node (SLN) mapping was reported to improve lymph node staging in colon cancer. This study compares isosulfan blue (IB) with indocyanine green (ICG)-based SLN-mapping and assesses the prognostic value of isolated tumor cells (ITC) and micro-metastases in upstaged patients. METHODS: A total of 220 stage I-III colon cancer patients were included in this prospective single-center study. In 170 patients, SLN-mapping was performed in vivo with IB and in 50 patients ex vivo with ICG. Three levels of each SLN were stained with H&E. If negative for tumor infiltration, immunostaining for cytokeratin (AE1/3; cytokeratin-19) was performed. RESULTS: SLN detection rate for IB and ICG was 100 and 98%, respectively. Accuracy and sensitivity was 88 and 75% for IB, 82 and 64% for ICG, respectively (p = 0.244). Overall, 149 (68%) patients were node negative. In these patients, ITC and micro-metastases were detected in 26% (31/129) with IB and 17% (5/29) with ICG (p = 0.469). Patients with ITC and micro-metastases did show decreased overall survival (hazard ratio = 1.96, p = 0.09) compared to node negative disease. CONCLUSIONS: This study demonstrates a high diagnostic accuracy for both the IB and the ICG SLN-mapping. SLN-mapping upstaged a quarter of patients with node negative colon cancer, and the detected ITC and micro-metastases were an independent negative prognostic marker in multivariate analysis.

Urgent surgery after emergency presentation for colorectal cancer has no impact on overall and disease-free survival: a propensity score analysis.

BACKGROUND: It remains a matter of debate whether colorectal cancer resection in an emergency setting negatively impacts on survival. Our objective was therefore to assess the impact of urgent versus elective operation on overall and disease-free survival in patients undergoing resection for colorectal cancer by using propensity score adjusted analysis. METHODS: In a single-center study patients operated for colorectal cancer between 1989 and 2013 were identified from a prospectively maintained database. Median follow-up was 44 months. Patients with neoadjuvant treatment were excluded. The impact of urgent operation on overall and disease-free survival was assessed using both Cox regression and propensity score analyses. RESULTS: Of 747 patients with colorectal cancer, 84 (11%) had urgent and 663 elective cancer resection. The propensity score revealed strongly biased patient characteristics (0.22 ± 0.16 vs. 0.10 ± 0.09; P < 0.001). In unadjusted analysis urgent operation was associated with a 35% increased risk of overall mortality (hazard ratio(HR) of death = 1.35, 95% confidence interval(CI):1.02-1.78, P = 0.045). In risk-adjusted Cox regression analysis urgent operation was not associated with poor overall (HR = 1.08, 95%CI:0.79-1.48; P = 0.629) or disease-free survival (HR = 1.02, 95%CI:0.76-1.38; P = 0.877). Similarly in propensity score analysis urgent operation did not influence overall (HR = 0.98, 95% CI:0.74-1.29), P = 0.872) and disease-free survival (HR = 0.89, 95%CI:0.68 to 1.16, P = 0.387). CONCLUSIONS: This study provides evidence that worse oncologic outcomes after urgent operation for colorectal cancer are caused by clinical circumstances and not due to the urgent operation itself. Urgent operation is not a risk factor for colorectal cancer resection.

MPO density in primary cancer biopsies of ovarian carcinoma enhances the indicative value of IL-17 for chemosensitivity.

BACKGROUND: Cancer of the ovary is mostly discovered at a late stage and cannot be removed by surgery alone. Therefore surgery is usually followed by adjuvant chemotherapy. However, few reliable biomarkers exist to predict response to chemotherapy of ovarian cancer. Previously, we could demonstrate that IL-17 density is indicative for chemosensitivity. This study focuses on the predictive value of myeloperoxidase (MPO) concerning response to chemotherapy of ovarian cancer. METHODS: Biopsies of mostly high-grade primary serous ovarian carcinomas and their matched recurrences were stained with MPO after fixation in formalin and embedding in paraffin. For this staining the technique of tissue-microarray was used. Recurrence within 6 months of the completion of platinum-based chemotherapy was defined as chemoresistance as previously publised. Data for MPO could be analyzed in 92 biopsies. RESULTS: MPO and IL-17 positive immune cells correlated significantly in biopsies of primary and recurrent carcinomas (r s = 0.41; p = 0.004 and r s = 0.40; p = 0.007, respectively). MPO expression alone did not predict response to chemotherapy, but in multivariate cox regression analysis including age, residual disease, number of chemotherapy cycles, FIGO classification and combined categorized MPO and IL-17 cell densities of primary cancer biopsies, the combination of both immune markers was an independent prognostic factor for recurrence-free survival (p = 0.013, HR = .23, 95CI = 0.07-0.73). There was no chemoresistant patient in the subgroup of MPO + IL-17+, neither in primary nor in recurrent cancer biopsies. CONCLUSIONS: High MPO positive cell density enhances the indicative value of IL-17 for response to chemotherapy in ovarian carcinoma. Although, these results have to be validated in a larger cohort.