Tumor budding outperforms ypT and ypN classification in predicting outcome of rectal cancer after neoadjuvant chemoradiotherapy.

BACKGROUND: Budding is a complementary prognostic factor for colorectal cancer. In this study, we aimed to clarify the role of tumor budding in rectal cancer patients after preoperative chemoradiotherapy. METHODS: A total of 124 patients with rectal cancer treated with neoadjuvant chemoradiotherapy and consecutive surgery were included. Surgical specimens were evaluated for budding and routine clinicopathological features. Budding was evaluated on hematoxylin and eosin (H&E)-stained slides and by cytokeratin immunohistochemical (IHC) staining. RESULTS: A budding rate of 36.9% (n = 38) by H&E and 55.6% (n = 55) by IHC was observed. Budding was significantly associated with a high ypT and ypN status, poor differentiation, and low degrees of tumor regression. Moreover, budding was strongly predictive of a worse patient outcome, as measured by tumor recurrence or death. In multivariate analyses, budding remained the only significant parameter for overall survival and was even superior to the ypT and ypN status (budding in H&E: hazard ratio (HR) 2.72, 95% confidence interval (95% CI) 1.15-6.44, p = 0.023; budding in IHC: HR 5.19, 95% CI 1.62-16.61, p = 0.006). CONCLUSION: Budding is a strong prognostic predictor of survival in rectal cancer patients after neoadjuvant therapy. A standardized evaluation of tumor budding after neoadjuvant therapy may thus aid in risk stratification and guide the clinical management of patients with rectal cancer. Immunostaining can help to enhance the diagnostic accuracy and prognostic significance.

Different Prevalence of Alarm, Dyspeptic and Reflux Symptoms in Patients with Cardia and Non-cardia Gastric Cancer.

BACKGROUND AND AIMS: Symptoms of patients with gastric cancer (GC) are often unspecific and differences in symptoms between patients with cardia and non-cardia GC have been poorly investigated. We aimed to characterize symptoms of patients with cardia and non-cardia GC. METHODS: Patients with cardia (Siewert type II and III) and non-cardia GC were recruited in the German multicenter cohort of the Gastric Cancer Research (staR) study between 2013 and 2017. Alarm, dyspeptic and reflux symptoms at the time of presentation were documented using a self-administered questionnaire. RESULTS: A completed self-administered questionnaire was available for 568/759 recruited patients (132 cardia GC, 436 non-cardia GC, male 61%, mean age 64 years). Dyspeptic symptoms were more common in patients with non-cardia GC (69.0 vs. 54.5%, p=0.0024). Cardia GC patients reported more frequently alarm symptoms (69.7 vs. 44.7%, p<0.0001), and were more likely to have Union for International Cancer Control (UICC) stage III-IV (54.1vs. 38.9%, p=0.0034). Especially, dysphagia and weight loss were more common in patients with cardia GC (49.2 vs. 6.4 %, p<0.0001 and 37.1 vs. 25.7%, p=0.02, respectively). No differences between the two groups were observed with respect to reflux symptoms. Patients with alarm symptoms were more likely to have UICC stage III-IV at presentation (69.4 vs. 42.9%, p<0.0001). CONCLUSIONS: In clinical practice the symptom pattern at presentation may serve as a hint for tumor localization. Despite the fact that they are common in the general population, dyspeptic symptoms offer a chance for earlier GC detection. Thus, in patients with dyspeptic symptoms who fail empiric approaches, endoscopy should not be delayed.

Gastric cancer in autoimmune gastritis: A case-control study from the German centers of the staR project on gastric cancer research.

OBJECTIVES: Patients with autoimmune gastritis (AIG) are reported to have an increased risk of developing gastric cancer (GC). In this study, we assess the characteristics and outcomes of GC patients with AIG in a multicenter case-control study. METHODS: Between April 2013 and May 2017, patients with GC, including cancers of the esophagogastric junction (EGJ) Siewert type II and III, were recruited. Patients with histological characteristics of AIG were identified and matched in a 1:2 fashion for age and gender to GC patients with no AIG. Presenting symptoms were documented using a self-administered questionnaire. RESULTS: Histological assessment of gastric mucosa was available for 572/759 GC patients. Overall, 28 (4.9%) of GC patients had AIG (67 ± 9 years, female-to-male ratio 1.3:1). In patients with AIG, GC was more likely to be localized in the proximal (i.e. EGJ, fundus, corpus) stomach (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.0-7.1). In GC patients with AIG, pernicious anemia was the leading clinical sign (OR 22.0, 95% CI 2.6-187.2), and the most common indication for esophagogastroduodenoscopy (OR 29.0, 95% CI 7.2-116.4). GC patients with AIG were more likely to present without distant metastases (OR 6.2, 95% CI 1.3-28.8) and to be treated with curative intention (OR 3.0, 95% CI 1.0-9.0). The five-year survival rates with 95% CI in GC patients with and with no AIG were 84.7% (83.8-85.6) and 53.5% (50.9-56.1), respectively (OR 0.25, 95% CI 0.08-0.75, p = 0.001). CONCLUSIONS: Pernicious anemia leads to earlier diagnosis of GC in AIG patients and contributes significantly to a better clinical outcome.

Combination of p53 expression and p21 loss has an independent prognostic impact on sporadic colorectal cancer.

There is no clear evidence on the prognostic and predictive value of abnormal p53 expression in colorectal cancer. The major downstream protein, p21, a cell cycle inhibitor, is transcriptionally regulated by p53. The prognostic impact of p21 expression in colorectal carcinomas is still under debate. In this study, we investigated the expression of p21 and p53 in a prospective cohort of 116 sporadic colorectal carcinomas at UICCII/III stage. We observed an expression of p21 in 26% and p53 in 63% of the carcinomas by immunohistochemistry. Patients with p21-negative colorectal carcinomas had a significant better recurrence-free and overall survival than patients with p21-positive carcinomas (p=0.02 and p=0.005). Expression of p53 was related to a better overall survival (p=0.048). The combination of p21-negative/p53-positive expression was significantly related to better recurrence-free and overall survival (p=0.007 and p=0.0001) and gained independent prognostic significance (HR: 3.4, p=0.01). Moreover, patients with combined p21-/p53+ expression had a remarkable benefit in overall survival after adjuvant chemotherapy as compared to the p21-/p53- subgroup (HR: 3.6, p=0.027). Our data suggest that the assessment of both p53 and p21 expression may provide prognostic information in colorectal cancer patients. This combination might be helpful to identify patients who could benefit from chemotherapy.

Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level.

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10-04 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10-09 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10-11 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10-47 ). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10-09 ). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.

16-MDCT angiography of aortoiliac and lower extremity arteries: comparison with digital subtraction angiography.

OBJECTIVE: The objective of our study was to prospectively compare CT angiography (CTA) performed on a 16-MDCT scanner and digital subtraction angiography (DSA) in patients with peripheral arterial disease. SUBJECTS AND METHODS: CTA and DSA were compared in 50 patients. CTA was independently evaluated by two blinded observers. DSA was evaluated by two additional blinded observers in consensus. Consensus DSA served as the reference standard for comparisons with CTA in terms of diagnostic quality, grading of stenoocclusive lesions, visualization of collaterals, impact on patient management, and time required for analysis. RESULTS: No significant differences in diagnostic quality were observed between CTA and DSA above the ankle; both CTA observers noted significantly better visualization of pedal arteries (70 and 72 segments, respectively) than on DSA (57 segments). Of 958 stenoocclusive lesions on DSA, CTA observers 1 and 2 detected 933 and 929 lesions, respectively. Sensitivity and specificity for the detection of hemodynamically relevant (> 50%) lesions was 93.3% and 96.5% for observer 1 and 90.1% and 95.6% for observer 2. Collaterals were seen at 150 arterial levels on DSA compared with 97 and 92 levels on CTA (p < 0.05, both observers). Patient management decisions based on CTA were equivalent to those based on DSA in 49 of the 50 patients. CONCLUSION: CTA is an effective noninvasive alternative to DSA for the evaluation of peripheral arterial disease.

Poorly Differentiated Medullary Phenotype Predicts Poor Survival in Early Lymph Node-Negative Gastro-Esophageal Adenocarcinomas.

BACKGROUND: 5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S) in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0). METHODS: Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming), expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival. RESULTS: 129 patients (48 female) with a mean follow-up of 129.1 months were identified. 5-year overall survival was 83.9%, 5-year tumor related survival was 95.1%. Poorly differentiated medullary cancer subtypes (p<0.001) and positive vein invasion (p<0.001) were identified as risk factors for decreased overall-and tumor related survival. Ki-67 (p = 0.012) and TP53 mutation (p = 0.044) were the only immunohistochemical markers associated with worse overall survival but did not reach significance for decreased tumor related survival. CONCLUSION: In the presented study patients with AGE/S in stage UICC-I-N0 had a better prognosis as previously reported for Caucasian patients. Poorly differentiated medullary subtype was associated with reduced survival and should be considered when studying prognosis in these patients.

Diagnostic confidence of run-off CT-angiography as the primary diagnostic imaging modality in patients presenting with acute or chronic peripheral arterial disease.

OBJECTIVES: To investigate the reliability of CT-angiography of the lower extremities (run-off CTA) to derive a treatment decision in patients with acute and chronic peripheral artery disease (PAD). MATERIALS AND METHODS: 314 patients referred for run-off CTA were includ-ed in this retrospective study. First, diagnostic confidence of run-off CTA to derive a treat-ment decision was assessed in an interdisciplinary vascular conference using a 2 point scale (sufficient or not sufficient diagnostic confidence) and compared with the image quality eval-uated by two readers in consensus in four different levels (abdominopelvic, thigh, calf, foot arteries). Second, reliability of treatment decision was verified in all patients undergoing re-vascularization therapy. RESULTS: Diagnostic confidence of run-off CTA to derive a treatment deci-sion was sufficient in all patients with acute and in 97% of patients (215/221) with chronic PAD, whereas the rate of run-off CTA with non-diagnostic image quality was considerably higher in the calf and foot level (acute vs. chronic; calf: 28% vs.17%; foot: 52% vs. 20%). Reliability of treatment decision was superior for patients with chronic (123/133 = 92%) than for patients with acute PAD (64/78 = 82%, P = 0.02). CONCLUSION: Run-off CTA is a reliable imaging modality for primary diag-nostic work-up of patients with acute and chronic PAD.

Is reduced expression of mismatch repair genes MLH1 and MSH2 in patients with sporadic colorectal cancer related to their prognosis?

The majority of mutations in hereditary nonpolyposis colon carcinoma (HNPCC) patients affect the mismatch-repair genes (MMRG) MLHI and MSH2. In addition, mutations of these genes were found in about 15% of sporadic colorectal carcinomas which appear to be related to microsatellite instability (MSI). However, mutations in MMRG were not found in all MSI-positive carcinomas, but MMRG mutations may be relevant for the assessment of tumor characteristics and patients' prognosis. Therefore, we investigated the relationship between expression of MMRG, tumor biology and patients' survival. In 127 patients with sporadic colorectal carcinomas and a minimum of 5 years follow-up after curative surgery immunohistochemical detection of MLHI and MSH2 was analyzed semiquantitatively. Lost expression of MLHI has been found in tumor specimens from 10 patients, whereas MSH2 expression was missing in 5 patients. This reduced expression did not correlate with tumor stage, lymph node involvement, grading or tumor invasion into blood vessels. However, a significant correlation was found for lymphovascular invasion (P = 0.02) and localization within the colorectum (P = 0.003) in MLH1-negative carcinomas. In addition, although there was a clear tendency for longer overall survival (72 vs. 63 months) for patients with MLH1-negative carcinomas, significant differences for overall and recurrence-free survival were not seen. In conclusion of our results and a critical review of literature, the prognostic importance of the MMR genes in sporadic colorectal carcinomas remains controversial.

Histopathological regression grading matches excellently with local and regional spread after neoadjuvant therapy of rectal cancer.

Histopathological regression grading has been shown to predict outcome in chemoradiated rectal cancer. Lymph node spread is still considered the most important single prognostic parameter. Therefore, we investigated the association of regression grading with tumor spread in a single center retrospective cohort. 102 consecutive patients who had undergone neoadjuvant therapy for rectal adenocarcinoma were included. Surgery was performed, including total mesorectal excision. Pathological examination included UICC staging and Dworak's five-tier tumor regression grading. Histological complete response was achieved in 16.7% of cases. Dworak's regression grading and a simplified two tier scheme both correlated excellently with ypT, ypN and UICC stage. However, cases with poor histological response were strongly represented in ypN0. Tumor regression grading is a reliable method for assessment of response to neoadjuvant therapy, but the optimal cut-off for separating good and poor response remains to be established based on clinical outcome.

Increased Pontin expression is a potential predictor for outcome in sporadic colorectal carcinoma.

Colorectal cancer is one of the leading causes of cancer-related death worldwide. Molecular biomarkers could help to predict patient outcome and to identify patients who benefit from adjuvant therapy. Pontin and Reptin are ATPases which are involved in transcriptional regulation, DNA damage repair and regulation of cell proliferation. Many interaction partners of Pontin and Reptin such as ß-catenin and c-myc are important factors in carcinogenesis. We hypothesized that Pontin and Reptin expression may be a negative predictor for survival in colorectal carcinoma. Specimens from 115 patients with primary colon adenocarcinomas UICC stage III and primary rectal adenocarcinomas UICC stage II and III curatively resected at the Department of Surgery, Charité Berlin, were evaluated. Clinical follow-up data were complete and mean follow-up time of patients was 51.8 months. We evaluated the expression of Pontin, Reptin and Ki-67 by immunohistochemistry. Patients with Pontin-positive carcinomas showed no differences in recurrence-free survival (p=0.109) and overall survival (p=0.197). There were no differences in Reptin-positive carcinomas and Ki-67-positive carcinomas in recurrence-free survival (p=0.443 and p=0.160) and overall survival (p=0.477 and p=0.687). Patients with Pontin-positive colorectal carcinomas receiving adjuvant therapy had a significantly worse recurrence-free survival (p=0.008) and overall survival (p=0.011) than Pontin-negative patients with adjuvant therapy. In UICC stage III, Pontin-positive colorectal carcinomas had a significantly worse recurrence-free survival (p=0.028). Pontin-positivity seems to be a negative predictor for response to adjuvant therapy in colorectal cancer patients and may help to identify patients with adverse outcome in advanced tumor stages.

The Prognostic Impact of p53 Expression on Sporadic Colorectal Cancer Is Dependent on p21 Status.

The prognostic value of p53 and p21 expression in colorectal cancer is still under debate. We hypothesize that the prognostic impact of p53 expression is dependent on p21 status. The expression of p53 and p21 was immunohistochemically investigated in a prospective cohort of 116 patients with UICC stage II and III sporadic colorectal cancer. The results were correlated with overall and recurrence-free survival. The mean observation period was 51.8 ± 2.5 months. Expression of p53 was observed in 72 tumors (63%). Overall survival was significantly better in patients with p53-positive carcinomas than in those without p53 expression (p = 0.048). No differences were found in recurrence-free survival (p = 0.161). The p53+/p21- combination was seen in 68% (n = 49), the p53+/p21+ combination in 32% (n = 23). Patients with p53+/p21- carcinomas had significantly better overall and recurrence-free survival than those with p53+/p21+ (p < 0.0001 resp. p = 0.003). Our data suggest that the prognostic impact of p53 expression on sporadic colorectal cancer is dependent on p21 status.

Epigenetic quantification of tumor-infiltrating T-lymphocytes.

The immune system plays a pivotal role in tumor establishment. However, the role of T-lymphocytes within the tumor microenvironment as major cellular component of the adaptive effector immune response and their counterpart, regulatory T-cells (Treg), responsible for suppressive immune modulation, is not completely understood. This is partly due to the lack of reliable technical solutions for specific cell quantification in solid tissues. Previous reports indicated that epigenetic marks of immune cells, such as the Treg specifically demethylated region (TSDR) within the FOXP3 gene, may be exploited as robust analytical tool for Treg-quantification. Here, we expand the concept of epigenetic immunophenotyping to overall T-lymphocytes (oTL). This tool allows cell quantification with at least equivalent precision to FACS and is adoptable for analysis of blood and solid tissues. Based on this method, we analyse the frequency of Treg, oTL and their ratio in independent cohorts of healthy and tumorous ovarian, colorectal and bronchial tissues with 616 partly donor-matched samples. We find a shift of the median ratio of Treg-to-oTL from 3-8% in healthy tissue to 18-25% in all tumor entities. Epigenetically determined oTL frequencies correlate with the outcome of colorectal and ovarian cancers. Together, our data show that the composition of immune cells in tumor microenvironments can be quantitatively assessed by epigenetic measurements. This composition is disturbed in solid tumors, indicating a fundamental mechanism of tumor immune evasion. Epigenetic quantification of T-lymphocytes serves as independent clinical parameter for outcome prognosis.

Improving results of elective abdominal aortic aneurysm repair at a low-volume hospital by risk-adjusted selection of treatment in the endovascular era.

Several studies have observed both higher mortality rates and lower utilization of endovascular aneurysm repair (EVAR) at low-volume centers. This article presents the results of elective abdominal aortic aneurysm (AAA) repair at a low-volume center in the endovascular era and investigates whether postprocedural mortality can be improved by extension of EVAR application also in this setting. This is an 11.6-year retrospective cohort study of 132 patients undergoing elective surgical or endovascular AAA repair at a tertiary care academic hospital between 1997 and July 2008, i.e., a median volume of 12 cases per year. The study was divided into two periods of time according to the respective indications and contraindications for EVAR, which substantially changed in 2005. During period 1, only aneurysms with necks > or =20 mm long and not involving the iliac arteries were treated endoluminally. Beginning in 2005, indication for EVAR was expanded to aortoiliac aneurysms with a minimum neck length of 15 mm. Preoperative risk was assessed by the SVS/AAVS comorbidity score. During the first period (1997-2004) 18.4% (16/87) of all patients received EVAR. By extending anatomical confines and indications for EVAR in 2005, the utilization rate of EVAR increased to 40.0% (18/45) during the second period (2005-July 2008; p = 0.007). Prevalence of preoperative risk factors did not change during the two observation periods. In contrast to period 1, high-risk patients were preferentially treated endoluminally during the second period, resulting in a significantly higher median SVS/AAVS score in the EVAR group (p < 0.001). A significant decrease in median length of stay at the intensive/intermediate care unit (5 vs. 2 days; p = 0.006) and length of in-hospital stay (20 vs. 12.5 days; p < 0.001) was observed during period 2. Overall perioperative mortality was reduced from 6.9% during the first period to 2.2% during the second period (p = 0.256). EVAR mortality was 0%, mortality after open repair was reduced from 8.5% to 3.7% (p = 0.414). In conclusion, by risk-adjusted selection of treatment and frequent application of EVAR, it is possible to improve perioperative outcome of elective AAA repair at a low-volume hospital. Mortality figures are similar to those of recent trials at high-volume centers, as reported in the literature.

Effect of anastomosis level on continence performance and quality of life after colonic J-pouch reconstruction.

Total mesorectal excision (TME) has become the recommended method for treatment of cancer in the middle or lower third of the rectum. Thus very low anastomoses are necessary to preserve continence, and pouch reconstruction is favored. It is unclear whether the level of anastomosis is important for continence and quality of life in colonic J-pouch reconstruction. In this investigation all patients were included who underwent curative elective anterior continuity resection with colorectal or coloanal J-pouch reconstruction for primary rectal cancer between January 2001 and December 2004. Exclusion criteria were distant metastases and any signs of recurrence at the time of investigation. Evaluation of continence performance by Wexner and Holschneider questionnaire and quality of life using the QLQ-C30 and QLQ-CR38 (EORTC) questionnaires was done 220 +/- 38 days after closure of the protective Ileostomy, which was performed 106 +/- 48 days after primary intervention. Fifty-two patients (79%) were analyzed. Colopouch rectal anastomosis was performed in eighteen cases and colopouch anal anastomosis in thirty-four cases. Fifty percent of the patients in both groups were continent for solid stool. Patients with a colopouch anal anastomosis had a significantly higher rate of incontinence for liquid stool, however. They took stool-regulating medicine more frequently and complained of fecal soiling and a restricted quality of life. Patients with a colopouch anal anastomosis had a significantly lower score on the most important points of the QLQ-C30 (emotional functioning, social functioning, pain, and quality of life). The same applied to the QLQ-CR38 for body image and problems with defecation. The quality of life of patients with a colopouch anal anastomosis was still considered acceptable compared with reference data for the normal healthy population, however. Both continence and quality of life are substantially affected by the level of the anastomosis after colonic pouch reconstruction. This suggests preservation of a small part of the rectum when oncologically feasible and performing a colopouch rectal anastomosis.

Risk factors for clinical anastomotic leakage and postoperative mortality in elective surgery for rectal cancer.

BACKGROUND AND AIMS: Clinical anastomotic leakage remains a major problem after anterior or low anterior resection for rectal cancer. The aim of this study was to assess the association between risk factors and anastomotic leakage and postoperative mortality. MATERIALS AND METHODS: Two hundred seventy-six elective anterior or low anterior resections with anastomosis were performed and documented on-line from January 1995 to December 2004. Univariate and multivariate analyses with Bonferroni adjustment were carried out to identify relevant risk factors. RESULTS: The rate of anastomotic leakage was 14.9% (41 of 276 patients) with a mortality of 12.2% (5 of 41 patients). Overall mortality was 2.5% (7 of 276 patients). Multiple regression analysis showed that smokers had an increased risk of anastomotic leakage [odds ratio (OR), 6.42; 95% confidence interval (CI), 2.68-15.36] as well as patients with coronary heart disease (OR, 7.79; 95% CI, 2.52-24.08). Smokers (OR, 13.20; 95% CI, 2.48-7.24) and patients with coronary heart disease (OR, 23.46; 95% CI, 4.33-27.04) also had an increased risk of postoperative mortality in the univariate analysis as well as patients with anastomotic leakage (OR, 16.25; 95% CI, 3.04-16.92). CONCLUSIONS: Smoking and coronary heart disease are important risk factors for anastomotic leakage and postoperative mortality after elective resection for rectal cancer.

Endothelin-1 receptor antagonist (LU-135252) improves the microcirculation and course of TNBS colitis in rats.

The role of microcirculation in the pathogenesis and course of chronic inflammatory bowel disease is still unclear. The aim of this study was the evaluation of the role of microcirculation in colitis activity in the rat TNBS (trinitrobenzenesulfonic acid) colitis model using endothelin-1 and a selective endothelin-1 receptor antagonist (LU-135252). Target parameters were capillary blood flow, functional capillary density, vascular permeability, and leukocyte sticking as well as recording of hematocrit, weight course, diuresis, stool quality, and degree of inflammation using a histological colitis score. The acute phase of TNBS colitis is characterized by an extensive disturbance of microcirculation (a significant decrease in capillary blood flow and capillary density and a significant increase in capillary permeability and leukocyte sticking in the mucosa). There is also a significant increase in hematocrit and a significant decrease in diuresis and weight. An exogenous supply of endothelin-1 does not lead to an aggravation of these disorders because of a possible blockage of the endothelin-1 receptors by endogenous endothelin-1 in this florid inflammatory phase. Applying the selective endothelin-1 receptor A antagonist LU-135252 leads to a significant improvement of all microcirculatory parameters and clinical findings compared to the untreated colitis group. Direct improvement of capillary blood flow in the early phase of colitis leads to reduced colitis activity, which underscores the pathogenetic role of the microcirculation in the progression of colitis.

Selective COX-2 inhibition reduces leukocyte sticking and improves the microcirculation in TNBS colitis.

The role of cyclooxygenase-2 inhibitors in the course of experimental colitis is controversially discussed. The aim of this study was to evaluate leukocyte-endothelium interaction and colitis activity after applying the selective cyclooxygenase-2 inhibitor NS-398 in a rat trinitrobenzene sulfonic acid (TNBS) colitis model. The acute phase of TNBS colitis is characterized by a significant reduction of capillary blood flow, capillary density, diuresis, and weight and a significant increase in capillary permeability, leukocyte sticking, and hematocrit. Applying the selective cyclooxygenase-2 inhibitor NS-398 leads to a significant improvement of all microcirculatory parameters and clinical findings compared to the (untreated) colitis group. There are no histopathological differences between the individual colitis groups. Acute colitis is characterized by an extensive disturbance of microcirculation together with signs of systemic inflammatory response syndrome. These alterations are significantly improved by inhibiting cyclooxygenase-2. The results support the described correlation between cyclooxygenase activation and leukocyte-endothelium interaction. Moreover, they underscore the postulated relation between leukocyte-endothelium interaction and capillary blood flow.

Gallbladder involvement of Henoch-Schönlein purpura mimicking acute acalculous cholecystitis.

BACKGROUND/AIMS: We report the case of a 53-year-old man with fever and severe abdominal pain following an upper respiratory tract infection. METHODS/RESULTS: The clinical signs, the laboratory markers, and the ultrasound findings were consistent with acute acalculous cholecystitis and he underwent cholecystectomy. Histologically the gallbladder showed vasculitis and the patient developed postoperatively a purpuric rash of the legs with transient ankle arthritis. Gastroscopy revealed prepyloric ulcers consistent with vasculitis. The patient was diagnosed as having Henoch-Schönlein purpura. Gastric ulcers as well as arthritis disappeared upon treatment with corticosteroids and proton pump inhibitors. CONCLUSION: Taken together, Henoch-Schönlein purpura can mimic acute cholecystitis and should be considered as a rare differential diagnosis of acute cholecystitis.