Healing of rectal advancement flaps for anal fistulas in patients with and without Crohn’s disease: a retrospective cohort analysis

Background: Surgical closure of anal fistulas with rectal advancement flaps is an established standard method, but it has a high degree of healing failure in some cases. The aim of this study was to identify risk factors for anal fistula healing failure after advancement flap placement between patients with cryptoglandular fistulas and patients with Crohn's disease (CD). Methods: From January 2010 to October 2020, 155 rectal advancement flaps (CD patients = 55, non-CD patients = 100) were performed. Patients were entered into a prospective database, and healing rates were retrospectively analysed. Results: The median follow-up period was 189 days (95% CI: 109-269). The overall complication rate was 5.8%. The total healing rate for all rectal advancement flaps was 56%. CD patients were younger (33 vs. 43 years, p < 0.001), more often female (76% vs. 30%, p < 0.001), were administered more immunosuppressant medication (65% vs. 5%, p < 0.001), and had more rectovaginal fistulas (29% vs. 8%, p = 0.001) and more protective stomas (49% vs. 2%, p < 0.001) than patients without CD. However, no difference in healing rate was noted between patients with or without CD (47% vs. 60%, p = 0.088). Conclusions: Patients with anal fistulas with and without Crohn's disease exhibit the same healing rate. Although patients with CD display different patient-specific characteristics, no independent factors for the occurrence of anal fistula healing failure could be determined. Trial registration Not applicable due to the retrospective study design

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/m(2), 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

Clinical Outcomes in Patients With Nonobstructive, Labile, and Obstructive Hypertrophic Cardiomyopathy

Background-\u2014Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease characterized by varying degrees of left ventricular outflow tract obstruction. In a large cohort, we compare the outcomes among 3 different hemodynamic groups. Methods and Results-\u2014We prospectively enrolled patients fulfilling standard diagnostic criteria for HCM from January 2005 to June 2015. Detailed phenotypic characterization, including peak left ventricular outflow tract pressure gradients at rest and after provocation, was measured by echocardiography. The primary outcome was a composite cardiovascular end point, which included new-onset atrial fibrillation, new sustained ventricular tachycardia/ventricular fibrillation, new or worsening heart failure, and death. The mean follow-up was 3.42.8 years. Among the 705 patients with HCM (mean age, 5215 years; 62% men), 230 with obstructive HCM were older and had a higher body mass index and New York Heart Association class. The 214 patients with nonobstructive HCM were more likely to have a history of sustained ventricular tachycardia/ventricular fibrillation and implantable cardioverter defibrillator implantation. During follow-up, 121 patients experienced a composite cardiovascular end point. Atrial fibrillation occurred most frequently in the obstructive group. Patients with nonobstructive HCM had more frequent sustained ventricular tachycardia/ventricular fibrillation events. In multivariate analysis, obstructive (hazard ratio, 2.80; 95% confidence interval, 1.64\u20134.80) and nonobstructive (hazard ratio, 1.94; 95% confidence interval, 1.09\u20133.45) HCM were associated with more adverse events compared with labile HCM. Conclusions-\u2014Nonobstructive HCM carries notable morbidity, including a higher arrhythmic risk than the other HCM groups. Patients with labile HCM have a relatively benign clinical course. Our data suggest detailed sudden cardiac death risk stratification in nonobstructive HCM and monitoring with less aggressive management in labile HCM

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

Rethinking the TNM Classification Regarding Direct Lymph Node Invasion in Pancreatic Ductal Adenocarcinoma

Mechanisms of lymph node invasion seem to play a prognostic role in pancreatic ductal adenocarcinoma (PDAC) after resection. However, the 8th edition of the TNM classification of the American Joint Committee on Cancer (AJCC) does not consider this. The aim of this study was to analyse the prognostic role of different mechanisms of lymph node invasion on PDAC. One hundred and twenty-two patients with resected PDAC were examined. We distinguished three groups: direct (per continuitatem, Nc) from the main tumour, metastasis (Nm) without any contact to the main tumour, and a mixed mechanism (Ncm). Afterwards, the prognostic power of the different groups was analysed concerning overall survival (OS). In total, 20 patients displayed direct lymph node invasion (Nc = 16.4%), 44 were classed as Nm (36.1%), and 21 were classed as Ncm (17.2%). The difference in OS was not statistically significant between N0 (no lymph node metastasis, n = 37) and Nc (p = 0.134), while Nm had worse OS than N0 (p < 0.001). Direct invasion alone had no statistically significant effect on OS (p = 0.885). Redefining the N0 stage by including Nc patients showed a more precise OS prediction among N stages (p = 0.001 vs. p = 0.002). Nc was more similar to N0 than to Nm; hence, we suggest a rethinking of TNM classification based on the mechanisms of lymph node metastases in PDAC. Overall, this novel classification is more precise

Die Expression von phosphoryliertem Östrogenrezeptor beta stellt einen unabhängigen negativen prognostischen Faktor beim duktalen Pankreasadenokarzinom dar

Background: The role of estrogen receptor beta (ER-β) expression in ductal pancreatic adenocarcinoma (PDAC) is largely unknown. Ligand-independent phosphorylation and activation of ER-β may play a relevant role in the IL-6/STAT3 signaling pathway and, as a result, in tumor progression. Here, we examined the effect of ER-β, phosphorylated ER-β (pER-β), STAT3, phosphorylated STAT3 (pSTAT3) and IL-6 expression on the overall and recurrence-free survival in a cohort of patients with resected PDAC. Methods: We identified 175 patients who underwent pancreatic resection for PDAC. Tissue microarrays were constructed from archival tumor specimens. These were stained with specific antibodies for the above molecules. The expression of ER-β and pER-β was evaluated using the immunoreactive score (IRS) by Remmele. The expression of the markers was then correlated with clinicopathological parameters and survival analysis was performed. Results: More than half of the tumor samples showed high expression of all the five markers. Univariate survival analysis showed that higher UICC stage, tumor grade, residual tumor (R1) and expression of pER-β were correlated to shorter overall and disease- free survival. All the other markers investigated showed no prognostic relevance. Cox multivariate analysis revealed that pER-β expression was an independent factor correlating with a shorter overall survival (hazard ratio 1.9; P= 0.021) and disease-free survival (hazard ratio 1.9; P= 0.033). Conclusions: Expression of pER-β constitutes an independent prognostic marker for PDAC and is correlated with poor prognosis. The underlying molecular mechanisms require further investigation. These data may help in identifying patients who could benefit from additional therapeutic regimens, including selective estrogen receptor modulators.Einleitung: Die Rolle der Expression vom Östrogenrezeptor beta (ER-β) beim duktalen Pankreasadenokarzinom (PDAC) ist weitgehend unbekannt. Präklinische Daten deuten zusätzlich zur klassischen ligandenabhängigen nuklearen Aktivität auf eine östrogenunabhängige Aktivierung des ER durch andere Signalwege hin. In dieser Studie untersuchten wir den Effekt der Expression von ER-β, phosphoryliertem ER-beta (pER-β), STAT3, phosphoryliertem STAT3 (pSTAT3) und IL-6 auf das Gesamtüberleben und das rezidivfreie Überleben bei Patienten mit reseziertem PDAC. Methodik: 175 Patienten, bei denen im Zeitraum zwischen 2003 und 2010 ein duktales Adenokarzinom des Pankreas reseziert wurde, wurden identifiziert. Aus dem paraffin-eingebetteten Tumormaterial wurden Tissue Microarrays (TMA) konstruiert, die mit spezifischen Antikörpern für die oben genannten Moleküle gefärbt wurden. Die Expression von ER-β und pER-β wurde standardisiert mit Hilfe des immunoreaktiven Scores nach Remmele (IRS) ausgewertet. Die Expression der Marker wurde dann mit klinischen und pathologischen Parametern korreliert und anschließend wurde eine univariate sowie multivariate Überlebensanalyse (Kaplan-Meier bzw. Cox-Regression) durchgeführt. Ergebnisse: Alle fünf Marker wurden in der Mehrheit der Tumoren (>50%) exprimiert. Die univariate Analyse der Überlebensdaten ergab, dass ein höheres UICC Stadium, ein niedrigerer Tumordifferenzierungsgrad, das Vorhandensein von Residualtumor (R1) und die Expression von pER-β jeweils mit einer signifikant kürzeren gesamten und rezidivfreien Überlebenszeit einhergingen. Für die anderen Marker ergab sich keine signifikante Korrelation mit dem Überleben. Die multivariate Analyse bestätigte die pER-β-Expression als unabhängigen prognostischen Faktor. Die pER-β-Expression korrelierte mit einem kürzeren gesamten (hazard ratio 1.9; P=0.021) und tumorfreien Überleben (hazard ratio 1.9; P=0.033). Schlussfolgerung: Die Expression von pER-β korreliert mit einer ungünstigen Prognose und stellt damit einen unabhängigen negativen prognostischen Faktor für das PDAC dar. Die zugrundeliegenden molekularen Mechanismen sind nicht ausreichend charakterisiert und bedürfen weiterer Untersuchung. Anhand dieser Daten könnte ein Kollektiv von Patienten identifiziert werden, die neben einer adjuvanten zytotoxischen Therapie von einer Therapie mit SERMs profitieren könnten

Expression of phosphorylated estrogen receptor beta is an independent negative prognostic factor for pancreatic ductal adenocarcinoma

The role of estrogen receptor beta (ER-beta) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Ligand-independent phosphorylation and activation of ER-beta may play a relevant role in the IL-6/STAT3 signaling pathway and, as a result, in tumor progression. Here, we examined the effect of ER-beta, phosphorylated ER-beta (pER-beta), STAT3, phosphorylated STAT3 (pSTAT3) and IL-6 expression on the overall and recurrence-free survival in a cohort of patients with resected PDAC. We identified 175 patients who underwent pancreatic resection for PDAC. Tissue microarrays were constructed from the archival tumor specimens. These were stained with specific antibodies for the above molecules. The expression of the markers was then correlated with clinicopathological parameters and survival analysis was performed. High nuclear expression of ER-beta was found in 61.7% and pER-beta in 80.6% of the tumors. STAT3 was expressed in 54.3% of the tumor samples, pSTAT3 in 68% and IL-6 in 76.6%. The median overall survival for patients with low pER-beta expression was 29 months, whereas for patients with high pER-beta expression was 15.1 months (p = 0.016). Multivariate analysis revealed that pER-beta expression was an independent factor correlating with shorter overall survival (hazard ratio 1.9; p = 0.013) and disease-free survival (hazard ratio 1.9; p = 0.029). Expression of pER-beta constitutes an independent prognostic marker for PDAC and is correlated with poor prognosis. These data may help in identifying novel drug targets in PDAC and patients who could benefit from additional therapeutic regimens, including selective estrogen receptor modulators

Optimizing Indocyanine Green Dosage for Near-Infrared Fluorescence Perfusion Assessment in Bowel Anastomosis: A Prospective, Systematic Dose-Ranging Study

Background: Indocyanine green (ICG) near-infrared fluorescence (NIRF) has emerged as a promising technique for visualizing tissue perfusion. However, within the wide range of dosages and imaging conditions currently being applied, the optimal dosage of ICG remains unclear. This study aimed to investigate the feasibility and implications of implementing lower dosages of ICG than commonly used for visual and quantitative perfusion assessment in a standardized setting. Methods: A prospective single-center cohort study was conducted on patients undergoing ileostomy reversal by hand-sewn anastomosis. ICG-NIRF visualization was performed before (T1) and after (T2) anastomosis with one of four different dosages of ICG (5 mg, 2.5 mg, 1.25 mg, or 0.625 mg) and recorded. Postoperatively, each visualization was evaluated for signal strength, completeness, and homogeneity of fluorescence. Additionally, perfusion graphs were generated by a software-based quantitative perfusion assessment, allowing an analysis of perfusion parameters. Statistical analysis comparing the effect of the investigated dosages on these parameters was performed. Results: In total, 40 patients were investigated. Visual evaluation demonstrated strong, complete, and homogeneous fluorescence signals across all dosages. Perfusion graph assessment revealed a consistent shape for all dosages (ingress followed by egress phase). While the average signal intensity decreased with dosage, it was sufficient to enable perfusion assessment even at the lowest dosages of 1.25 mg and 0.625 mg of ICG. The baseline intensity at T2 (the second intraoperative visualization) significantly decreased with dosage. The slope of the egress phase steepened with decreasing dosage. Conclusions: Lower dosages of ICG were sufficient for intraoperative perfusion assessment, while causing lower residual fluorescence and quicker egress in subsequent visualizations

Expression of estrogen receptor beta correlates with adverse prognosis in resected pancreatic adenocarcinoma

Abstract Background The relevance of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Clinical trials targeting ER with selective estrogen receptor modulators in pancreatic cancer did not show any benefit. Here, we analyze the impact of recently characterized ER isoform beta on survival in a cohort of patients with resected PDAC. Methods Eighty-four patients having undergone pancreatic resection for PDAC at a single institution were identified. Tissue microarrays were constructed of archival tumor specimens. The expression of ER beta was determined by immunohistochemistry and quantified by a system established for estrogen receptor expression in breast cancer. ER beta expression was then correlated with clinicopathological parameters, and univariate and multivariate survival analyses were performed. Results Nuclear expression of ER beta was found in 31% of tumors. No significant correlation was found between ER beta expression and TNM status, tumor grade, age or sex. Univariate analysis revealed nodal metastasis and the expression of ER beta as factors correlating with a shorter overall survival and disease free survival. When comparing ER beta expression in patients surviving more than 24 months with those who died from the tumor within 12 or 24 months, respectively, a significantly lower ER beta expression was found in the long term survivors. In multivariate analysis, ER beta expression was demonstrated to be an independent predictor of shorter overall survival. Conclusions In resected PDAC, expression of ER beta seems to correlate with poor prognosis. These data may help to identify patients who may benefit from additional systemic therapy including selective estrogen receptor modulators

Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ERβ and IL-6/gp130/STAT3 signaling

Purpose: Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERβ correlates with a poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here, we hypothesized that raloxifene, a FDA-approved selective ER modulator (SERM), may suppress PDAC tumor growth by interfering with ERβ signaling. To test this hypothesis, we studied the impact of raloxifene on interleukin-6/glycoprotein-130/signal transducer and activator of transcription-3 (IL-6/gp130/STAT3) signaling. Methods: Human PDAC cell lines were exposed to raloxifene after which growth inhibition was assessed using a BrdU assay. ER knockdown was performed using siRNAs specific for ERα and ERβ. The effects of raloxifene on IL-6 expression and STAT3 phosphorylation in PDAC cells were assessed by ELISA and Western blotting, respectively. In addition, raloxifene was administered to an orthotopic PDAC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry was performed. Results: Raloxifene inhibited the in vitro growth of PDAC cells, and this effect was reversed by siRNA-mediated knockdown of ERβ, but not of ERα, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3Y705 in PDAC cells. In vivo, we found that orthotopic PDAC tumor growth, lymph node and liver metastases as well as Ki-67 expression were reduced in mice treated with raloxifene. Conclusions: Inhibition of ERβ and the IL-6/gp130/STAT3 signaling pathway by raloxifene leads to potent reduction of PDAC growth in vitro and in vivo. Our results suggest that ERβ signaling and IL-6/gp130 interaction may serve as promising drug targets for pancreatic cancer and that raloxifene may serve as an attractive therapeutic option for PDAC patients expressing the ERβ isotype