Intestinal Involvement in Systemic Sclerosis: A Clinical Review.

Systemic sclerosis (SSc) is a chronic systemic disease characterized by microvasculopathy, autoantibodies, and extensive fibrosis. Intestinal involvement is frequent in SSc and represents a significant cause of morbidity. The pathogenesis of intestinal involvement includes vascular damage, nerve dysfunction, smooth muscle atrophy, and fibrosis, causing hypomotility, which leads to small intestinal bacterial overgrowth (SIBO), malabsorption, malnutrition, diarrhea, pseudo-obstruction, constipation, pneumatosis intestinalis, and fecal incontinence. Manifestations are often troublesome and reduce quality of life and life expectancy. Assessment of intestinal involvement includes screening for small intestine hypomotility, malnutrition, SIBO, and anorectal dysfunction. Current management of intestinal manifestations is largely inadequate. Patients with diarrhea are managed with low-fat diet, medium-chain triglycerides, avoidance of lactulose and fructose, and control of bacterial overgrowth with antibiotics for SIBO. In diarrhea/malabsorption, bile acid sequestrant and pancreatic enzyme supplementation may help, and nutritional support is needed. General measures are applied for constipation, and intestine rest plus antibiotics for pseudo-obstruction. Fecal incontinence is managed with measures for associated SIBO, or constipation, and with behavioral therapies. Pneumatosis intestinalis is usually an incidental finding that does not require any specific treatment. Immunomoduation should be considered early in intestinal involvement. Multidisciplinary approach of intestinal manifestations in SSc by gastroenterologists and rheumatologists is required for optimum management.

The role of hypercoagulability in ischemic colitis.

OBJECTIVE: The aim of this study is to evaluate the role of thrombophilia-hypercoagulability in ischemic colitis (IC). MATERIAL AND METHODS: Thrombophilia and fibrinogen were evaluated in 56 cases of IC and 44 controls with known predisposing factors but no evidence of IC. Thrombophilic factors tested were: protein C (PC), protein S, antithrombin (AT), resistance to activated protein C (APCR), lupus anticoagulant (LA), factor V G1691A mutation (FV Leiden), prothrombin G20210A mutation, methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C mutations and plasminogen activator inhibitor-1 (PAI-1) gene 5G/4G and 4G/4G polymorphisms. RESULTS: In IC group were recorded: i) low levels of PC and AT (p = 0.064 and p = 0.022, respectively); ii) low levels of APCR (normal: >2, p = 0.008); iii) high levels of fibrinogen (p = 0.0005); iv) higher number of homozygotes for MTHFR A1298C and C677T mutations (p = 0.061 and p = 0.525 (Pearson chi-square), respectively); v) greater prevalence of 5G/4G and 4G/4G polymorphisms (p = 0.031 (Pearson chi-square)) and vi) higher incidence of LA-positive individuals (p = 0.037, Fischer's exact test). Multivariate analysis was performed to determine the effects of prothrombotic factors in IC. 5G/4G polymorphism of PAI-1 gene (odds ratio (OR) 12.29; 95% confidence interval (CI) 2.26-67.00), APCR (OR 0.089; 95% CI 0.011-0.699) and fibrinogen (OR 1.013; 95% CI 1.003-1.023) were determined as predictors of IC. CONCLUSIONS: This study suggests that hypercoagulability, hereditary or acquired, plays an essential role in the manifestation of IC.

Lower fibroblast growth factor 23 levels in young adults with Crohn disease as a possible secondary compensatory effect on the disturbance of bone and mineral metabolism.

Fibroblast growth factor 23 (FGF-23) is a bone-derived circulating phosphaturic factor that decreases serum concentration of phosphate and vitamin D, suggested to actively participate in a complex renal-gastrointestinal-skeletal axis. Serum FGF-23 concentrations, as well as various other laboratory parameters involved in bone homeostasis, were measured and analyzed with regard to various diseases and patients' characteristics in 44 patients with Crohn disease (CD) and 20 healthy controls (HCs) included in this cross-sectional study. Serum FGF-23 levels were significantly lower in patients with CD (900.42 ± 815.85pg/mL) compared with HC (1410.94 ± 1000.53pg/mL), p = 0.037. Further analyses suggested FGF-23 as a factor independent from various parameters including age (r = -0.218), body mass index (r = -0.115), 25-hydroxy vitamin D (r = 0.126), parathyroid hormone (r = 0.084), and bone mineral density (BMD) of hip and lumbar (r = 0.205 and r = 0.149, respectively). This observation remained even after multivariate analyses, exhibiting that BMD was not affected by FGF-23, although parameters such as age (p = 0.026), cumulative prednisolone dose (p < 0.0001), and smoking status (p = 0.024) were strong determinants of BMD regarding hip. Lower FGF-23 levels in patients with bowel inflammation are accompanied but not directly correlated with lower vitamin D levels, showing no impact on BMD determination of young adults with CD. The downregulation of serum FGF-23 levels in CD appears as a secondary compensatory effect on the bone and mineral metabolism induced by chronic intestinal inflammation.

Readressing the role of Toll-like receptor-4 alleles in inflammatory bowel disease: colitis, smoking, and seroreactivity.

BACKGROUND: Toll-like receptor (TLR) polymorphisms, and especially TLR-4 Asp299Gly and TLR-4 Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. AIMS: To address these issues, the distribution of TLR-4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. METHODS: TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti-Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti-laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. RESULTS: UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents (P = 0.002 and P < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR-4 compared to those with wild-type alleles (P = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 < P < 0.05). Despite the mutant TLR-4 predisposition for UC pancolitis, smoking was associated with more limited disease (P < 0.001). CONCLUSIONS: The presence of TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles.

Comparative performance and external validation of three different scores in predicting inadequate bowel preparation among Greek inpatients undergoing colonoscopy.

Background: Predictive scores aim to predict bowel preparation adequacy among hospitalized patients undergoing colonoscopy. We evaluated the comparative efficacy of these scores in predicting inadequate bowel cleansing in a cohort of Greek inpatients. Methods: We performed a post hoc analysis of data generated from a cohort of inpatients undergoing colonoscopy in 4 tertiary Greek centers to validate the 3 models currently available (models A, B and C). We used the Akaike information criterion to quantify the performance of each model, while Harrell's C-index, as the area under the receiver operating characteristics curve (AUC), verified the discriminative ability to predict inadequate bowel prep. Primary endpoint was the comparison of performance among models for predicting inadequate bowel cleansing. Results: Overall, 261 patients-121 (46.4%) female, 100 (38.3%) bedridden, mean age 70.7±15.4 years-were included in the analysis. Model B showed the highest performance (Harrell's C-index: AUC 77.2% vs. 72.6% and 57.5%, compared to models A and C, respectively). It also achieved higher performance for the subgroup of mobilized inpatients (Harrell's C-index: AUC 72.21% vs. 64.97% and 59.66%, compared to models A and C, respectively). Model B also performed better in predicting patients with incomplete colonoscopy due to inadequate bowel preparation (Harrell's C-index: AUC 74.23% vs. 69.07% and 52.76%, compared to models A and C, respectively). Conclusions: Predictive model B outperforms its comparators in the prediction of inpatients with inadequate bowel preparation. This model is particularly advantageous when used to evaluate mobilized inpatients.

Laparoendoscopic rendezvous versus preoperative ERCP and laparoscopic cholecystectomy for the management of cholecysto-choledocholithiasis: interim analysis of a controlled randomized trial.

BACKGROUND: Although the ideal management of cholecysto-choledocholi-thiasis is controversial, the 2-stage approach [endoscopic retrograde cholangiopancreatography (ERCP), sphincterotomy, and common bile duct (CBD) clearance followed by laparoscopic cholecystectomy] remains the standard way of management worldwide. One-stage approach using the so-called laparoendoscopic rendezvous (LERV) technique offers some advantages, mainly by reducing the hospital stay and the risk of post-ERCP pancreatitis. OBJECTIVE: To compare the LERV 1-stage approach with the standard 2-stage approach consisting of preoperative ERCP followed by laparoscopic cholecystectomy for the treatment of cholecysto-choledocholithiasis. SETTING: Controlled randomized trial, University/Teaching Hospital. METHODS: : Patients with cholecysto-choledocholithiasis were randomized either to LERV or to the 2-stage approach. Both elective and emergency cases were included in the study. Primary endpoint was to detect difference in overall hospital stay, whereas secondary endpoints were (i) to detect differences in morbidity (especially post-ERCP pancreatitis) and (ii) success of CBD clearance. This is an interim analysis of the first 100 randomized patients. RESULTS: Hospital stay was significantly shorter in the LERV group; median 4 (2-19) days versus 5.5 (3-22) days, P = 0.0004. There was no difference in morbidity and success of CBD clearance between the 2 groups. Post-ERCP amylase value was found significantly lower in the LERV group: median 65 (16-1159) versus 91 (30-1846), P = 0.02. CONCLUSIONS: Interim analysis of the results suggests the superiority of the LERV technique in terms of hospital stay and post-ERCP hyperamylasemia.

Inflammatory Bowel Disease-associated Fatty Liver Disease: the Potential Effect of Biologic Agents.

Inflammatory bowel diseases [IBD] exhibit intestinal and systemic manifestations. Nonalcoholic fatty liver disease [NAFLD] is a common co-existing condition, possibly contributing to the cardio-metabolic burden and overall morbidity. Εmerging therapeutic choices of biologic agents have modified the clinical course of IBD; however, their impact on IBD-associated NAFLD has not been extensively evaluated. The prevalence of NAFLD varies among IBD patients, but it appears higher than in the general population in the majority of quality studies. In terms of pathogenetic and risk factors of NAFLD, they may vary with IBD activity. Dysbiosis, mucosal damage, and cytokine release have been implicated in the pathogenesis during the relapses, whereas metabolic risk factors seem to play a dominant role during the remissions of IBD. Considering biologics, although quality data are scarce, agents suppressing tumour necrosis factor may offer potential benefits in IBD-associated NAFLD, whereas anti-integrins do not appear to confer any therapeutic advantage. In conclusion, IBD-associated NAFLD possibly follows two different patterns, one manifested during the relapses and one during the remissions of IBD. Some, but not all, biologics may benefit NAFLD in patients with IBD. Further mechanistic and prospective cohort studies are warranted to illuminate the effects of various biologics on NAFLD.

Efficacy and safety of transpancreatic sphincterotomy in endoscopic retrograde cholangiopancreatography: a retrospective cohort study.

Background: Difficult cannulation represents a common obstacle during endoscopic retrograde cholangiopancreatography (ERCP). We assessed the efficacy and adverse events of transpancreatic sphincterotomy (TPS), and investigated potential associated confounders. Methods: All patients referred to our department for ERCP during 2015-2020 were eligible if they had intact papilla and visceral anatomy. In addition to standard measures, TPS was combined with pancreatic stent placement. Apart from demographics, we retrieved data related to the indication, periampullary anatomy, necessity for TPS or fistulotomy, their outcomes and complications. Chi-square test was employed to investigate associations between TPS and independent variables. When significance was observed, the respective variables were inserted into a regression model. Results: A total of 1082 individual patients were eligible, with an equal female: male ratio and a mean age of 72.7±15.82 years. Seventy-three patients (6.7%) underwent TPS, with a 95.9% successful cannulation rate. Papilla morphology or regional diverticulum did not affect the decision to perform TPS, though it was significantly associated with malignant common bile duct (CBD) obstruction as the ERCP indication (P=0.001). Considering adverse events, TPS did not increase the incidence of post-ERCP pancreatitis (PEP), though it affected bleeding (P=0.005). Regression analysis revealed a protective role of TPS against PEP (risk ratio [RR] 0.015, 95% confidence interval [CI] 0.23-5.05; P<0.001), while the aforementioned risk of hemorrhage was attributed to previous precut attempts (RR 3.02, 95%CI 1.42-6.43; P=0.004). Conclusion: TPS combined with pancreatic stenting is an effective and safe modality in difficult cannulation cases and could be the first-choice alternative in malignant CBD obstruction.

Drug-induced nephrotoxicity in inflammatory bowel disease.

Conservative management of inflammatory bowel disease (IBD) is based on a combination of drugs, including aminosalicylates (ASAs), steroids, antibiotics, immunosuppressives and biologic agents. Although various side effects have been related to treatment regimens, drug-induced nephrotoxicity is rather uncommon. Furthermore, it is often underestimated since renal function deterioration may be attributed to the underlying disease. The nephrotoxicity of ASAs and cyclosporine A seems well established, but recent data have suggested a possible role of biologic agents such as infliximab and adalimubab in renal impairment. The aim of this review is to summarize the nephrotoxic effects of medical treatment as well as to express possible caveats in the administration of novel agents in IBD.

Calprotectin, calgranulin C, and other members of the s100 protein family in inflammatory bowel disease.

BACKGROUND: Since their discovery, S100 proteins have been associated with diverse diseases of inflammatory, degenerative, or malignant nature. Due to their participation in inflammation, they have also been studied with regard to inflammatory bowel disease (IBD). METHOD: To provide a review of available literature, a PubMed, MEDLINE, and Embase-based literature search was performed, using all available nomenclature for each member of the S100 protein family, along with the terms inflammatory bowel disease, ulcerative colitis, Crohn's disease, or indeterminate colitis. RESULT: S100A8/A9, also known as calprotectin, S100A12, or calgranulin C and in a lesser extent S100P, are involved in the pathogenesis, activity, diagnosis, and therapeutic management of IBD. The majority of available literature is focused primarily on S100A8/9, although there is growing evidence on the significance of S100A12. Most studies emphasize the potential merit of S100A8/A9 and S100A12, as markers for differential diagnosis, monitoring of activity, or disease relapse, in IBD. Limitations, regarding the diagnostic utility of these markers, seem to exist and are mainly related to the publication of conflicting results, i.e., for IBD activity, and to the fact that S100A8/A9 and S100A12 are not disease-specific. CONCLUSIONS: Although the existing data link specific S100 proteins with IBD, there are still several drawbacks in the use of these markers for diagnostic purposes. Thus, it seems that further research is mandatory in order to eliminate the impact of confounding factors but also to detect additional associations between S100 proteins and IBD or novel S100 proteins with a closer correlation with IBD.

Role of autophagy in gastric carcinogenesis.

Gastric cancer represents a common and highly fatal malignancy, and thus a pathophysiology-based reconsideration is necessary, given the absence of efficient therapeutic regimens. In this regard, emerging data reveal a significant role of autophagy in gastric oncogenesis, progression, metastasis and chemoresistance. Although autophagy comprises a normal primordial process, ensuring cellular homeostasis under energy depletion and stress conditions, alterations at any stage of the complex regulatory system could stimulate a tumorigenic and promoting cascade. Among others, Helicobacter pylori infection induces a variety of signaling molecules modifying autophagy, during acute infection or after chronic autophagy degeneration. Subsequently, defective autophagy allows malignant transformation and upon cancer establishment, an overactive autophagy is stimulated. This overexpressed autophagy provides energy supplies and resistance mechanisms to gastric cancer cells against hosts defenses and anticancer treatment. This review interprets the implicated autophagic pathways in normal cells and in gastric cancer to illuminate the potential preventive, therapeutic and prognostic benefits of understanding and intervening autophagy.

The impact of COVID-19 pandemic on gastrointestinal diseases: a single-center cross-sectional study in central Greece.

BACKGROUND: The current COVID-19 pandemic induced a suppressive environment for healthcare professionals and patients, especially during the lockdown period. Except for the direct burden of the COVID-19, collateral damage has been identified concerning other diseases. The aim of this study was to evaluate the potential impact of the lockdown on the non-COVID-19 patients' outcome in a tertiary gastroenterology department. METHODS: Patients admitted to our department during the lockdown period (23 March- 4 May 2020) and during the respective previous year's timeframe were recruited. Sex, age, comorbidities, presenting symptoms, final diagnosis, therapeutic management, duration of hospitalization, and outcome were evaluated. A direct comparison was performed to investigate the potential impact of the lockdown on the duration of hospitalization and the final outcome. RESULTS: A total of 161 patients were included to our analysis with 1:1 male:female ratio and mean age 70.86 years. Most of the cases experienced gastrointestinal tract bleeding, biliary stone disease manifestations, or gastrointestinal malignancy complications, and 85.1% were discharged. Fewer patients were hospitalized during the lockdown period (40%), whereas the duration of hospitalization was significantly longer (7.69±4.55 vs. 5.76±4.36 days). Binary logistic regression analysis and sensitivity analysis demonstrated that the quarantine was associated with increased prevalence of negative outcomes (odds ratio 5.21, 95% confidence interval 1.66-16.34; P=0.005), especially in cases with gastrointestinal malignancy and acute pancreatitis (P=0.045 and P=0.041, respectively). CONCLUSION: The increase in the negative outcomes of common gastrointestinal diseases and the duration of hospitalization during the lockdown raise reasonable concerns regarding healthcare policies against further outbreaks.

Impact of simple, specific, verbal instructions on the quality of bowel preparation in hospitalized patients undergoing colonoscopy: a multicenter randomized controlled trial.

Background and study aims Bowel preparation for colonoscopy is frequently inadequate in hospitalized patients. We explored the impact of specific verbal instructions on the quality of inpatients bowel preparation and factors associated with preparation failure. Patients and methods Randomized (1:1), two strata (mobilized vs. bedridden; 3:2) trial of consecutive inpatients from four tertiary centers, who received either specific, verbal instructions or the standard of care (SOC) ward instructions about bowel preparation. The rate of adequate bowel preparation (Boston Bowel Preparation Score [BBPS] ≥ 6, no segment < 2) comprised the primary endpoint. Mean BBPS score, good (BBPS score ≥ 7, no segment score < 2) and excellent (BBPS = 9) were among secondary endpoints. Results We randomized 300 inpatients (180 mobile) aged 71.7 ±â€Š15.1 years in the intervention (49.7 %) and SOC (50.3 %) groups, respectively. Overall, more patients in the intervention group achieved adequate bowel preparation, but this difference did not reach statistical significance neither in the intention-to-treat [90/149 (60.4 %) vs. 82/151 (54.3 %); P  = 0.29] nor in the per-protocol analysis [90/129 (69.8 %) vs. 82/132 (62.1 %); P  = 0.19]. Overall BBPS score did not differ statistical significantly in the two groups, but the provision of specific verbal instructions was associated with significant higher rates of good (58.1 % vs. 43.2 %; P  = 0.02) and excellent (31.8 % vs. 16.7 %; P  = 0.004) bowel preparation compared to the SOC group. Administration of same-day bowel preparation and patient American Society of Anesthesiologists score > 2 were identified as risk factors for inadequate bowel preparation. Conclusions Provision of specific verbal instructions did not increase the rate of adequate bowel preparation in a population of mobilized and bedridden hospitalized patients.

The natural history of COVID-19 in patients with inflammatory bowel disease: a nationwide study by the Hellenic Society for the study of IBD.

OBJECTIVES: COVID-19 has evolved into a global health crisis, variably affecting the management of patients with chronic illnesses. Patients with inflammatory bowel disease (IBD) may represent a vulnerable population due to frequent administration of immune-modifying treatments. We aimed to depict the natural history of COVID-19 infection in Greek patients with IBD at a nationwide level via unbiased reporting of all cases that were registered during the sequential waves of the pandemic. METHODS: Following a national call from the Hellenic Society for the study of IBD, we enrolled all IBD patients with established diagnoses of COVID-19. Clinical and epidemiological data, including COVID-19 modifying factors and IBD-associated therapies, were analyzed against adverse outcomes (hospitalization, ICU admission and death). RESULTS: We identified 154 IBD patients who were diagnosed with COVID-19 (men: 58.4%; mean age=41.7 years [SD = 14.9]; CD: 64.3%). Adverse outcomes were reported in 34 patients (22.1%), including 3 ICU admissions (1.9%) and two deaths (1.3%). Multivariate logistic regression analysis showed that age (OR = 1.04, 95% CI, 1-1.08) and dyspnea at presentation (OR = 7.36, 95% CI, 1.84-29.46) were associated with worse outcomes of COVID-19 infection. In contrast, treatment with biologics, in particular anti-TNF agents, exerted a protective effect against an unfavorable COVID-19 disease course (OR = 0.4, 95% CI, 0.16-0.99). Patients on subcutaneous biologics were more likely to halt treatment due to the infection as compared to those on intravenous biologics. CONCLUSIONS: IBD patients who developed COVID-19 had a benign course with adverse outcomes being infrequent. Treatment with anti-TNF biologics had a protective effect, thus, supporting continuation of therapy during the pandemic.

Moderate performance of serum S100A12, in distinguishing inflammatory bowel disease from irritable bowel syndrome.

BACKGROUND: S100A12, a calcium-binding proinflammatory protein secreted by granulocytes, has been associated with different diseases of inflammatory origin, including inflammatory bowel disease (IBD). In this study, the utility of serum S100A12, in discriminating IBD from irritable bowel syndrome (IBS), was tested. METHODS: S100A12 serum levels were determined in 64 patients with ulcerative colitis (UC), 64 with Crohn's disease (CD) and 73 with IBS, by means of an enzyme-linked immunosorbent assay. S100A12 serum levels were evaluated with respect to the levels of known inflammatory markers and patients' characteristics. RESULTS: The median values of serum S100A12 levels were 68.2 ng/mL (range: 43.4-147.4) in UC, 70 ng/mL (41.4-169.8) in CD and 43.4 ng/mL (34.4-74.4) in IBS patients. UC and CD patients had significantly higher serum S100A12 levels compared to IBS patients (P = 0.001 for both comparisons). Moreover, a cut-off for serum S100A12 levels of 54.4 ng/mL could predict both UC and CD with a 66.7% sensitivity and a 64.4% specificity. The area under curve was estimated at 0.67 with a 95% confidence interval of 0.60-0.75 (P < 0.001). Considering standard activity indices, higher serum S100A12 levels in active compared to inactive IBD were observed, although the recorded difference did not reach statistical significance. C-reactive protein (CRP) and serum amyloid A (SAA) levels, showed a statistically significant positive correlation with S100A12 (r = 0.39, P = 0.001 and r = 0.23, P = 0.02 respectively). CONCLUSIONS: Increased levels of circulating S100A12 are found in IBD, compared to IBS. When used to distinguish IBD from IBS adult patients, serum S100A12 levels exhibit moderate performance. On the other hand, serum S100A12 may serve as an inflammatory marker in IBD, since it is well correlated with CRP and SAA.

Laparoendoscopic rendezvous: an effective alternative to a failed preoperative ERCP in patients with cholecystocholedocholithiasis.

BACKGROUND: Although the ideal management of cholelithiasis and concomitant choledocholithiasis is controversial, the two-stage approach [endoscopic retrograde cholangiopancreatography (ERCP), sphincterotomy, and common bile duct (CBD) clearance followed by laparoscopic cholecystectomy] is the most popular treatment regimen worldwide. However, sometimes ERCP fails to solve the problem of choledocholithiasis preoperatively. The aim of this study was to evaluate the use of intraoperative ERCP using the laparoendoscopic "rendezvous" technique in patients in whom preoperative ERCP has failed or was not possible to attempt. METHODS: Twenty-two patients (13 female, nine male), in whom ERCP failed or was not possible to be performed as a separate procedure before laparoscopic cholecystectomy, were treated with the one-stage approach of intraoperative ERCP during laparoscopic cholecystectomy using the so-called laparoendoscopic "rendezvous" technique. RESULTS: The one-stage approach was completed successfully in a median time of 110 min (range = 75-160 min) in 21 cases; however, in two cases the wire introduced via the cystic duct could not be advanced through Vater's ampulla into the duodenum and the CBD was cannulated from the endoscopic route, in the usual way. There was no mortality or morbidity and most patients were discharged within 48 h after the procedure. CONCLUSION: The laparoendoscopic "rendezvous" is a valuable alternative in treating patients with cholecystocholedocholithiasis. It appears to be a reliable method when preoperative ERCP fails to clear the CBD, while it also offers a one-stage solution to the problem.

A Systematic Review of Medical Nutrition Therapy Guidelines for Liver Cirrhosis: Do We Agree?

BACKGROUND: Nutrition can play a significant role in the management of liver cirrhosis and its complications. However, adherence to the clinical practice guidelines (CPGs) is essential for the practice of evidence-based medicine and is considered as a health-quality indicator. METHODS: A systematic search was conducted in scientific databases, and retrieved CPGs fulfilling the inclusion criteria were independently reviewed and appraised from 3 experienced researchers, based on the Appraisal of Guidelines for Research and Evaluation II instrument. RESULTS: A total of 13 relevant CPGs were retrieved, published by 7 associations/societies, focusing on the nutrition management (enteral nutrition and/or parenteral nutrition) on cirrhosis, decompensated cirrhosis, liver transplantation, and cirrhosis-related complications. Most CPGs scored low in the stakeholder, rigor of development, and applicability domains. Half of the CPGs recognized the need for counseling patients with cirrhosis on nutrition-related issues. Small meals spread throughout the day, including a late-night snack, were suggested, with protein intake ranging between 1.2 and 1.5 g/kg of body weight. In ascites, Na restriction recommendation appeared unanimous. CONCLUSIONS: Several shortcomings and bias were recognized in cirrhosis-related medical nutrition therapy CPGs, indicating the need of improving CPG methodology.

Silencing of caveolin-1 in fibroblasts as opposed to epithelial tumor cells results in increased tumor growth rate and chemoresistance in a human pancreatic cancer model.

Caveolin­1 (Cav­1) expression has been shown to be associated with tumor growth and resistance to chemotherapy in pancreatic cancer. The primary aim of this study was to explore the significance of Cav­1 expression in pancreatic cancer cells as compared to fibroblasts in relation to cancer cell proliferation and chemoresistance, both in vitro and in vivo, in an immunodeficient mouse model. We also aimed to evaluate the immunohistochemical expression of Cav­1 in the epithelial and stromal component of pancreatic cancer tissue specimens. The immunohistochemical staining of poorly differentiated tissue sections revealed a strong and weak Cav­1 expression in the epithelial tumor cells and stromal fibroblasts, respectively. Conversely, the well­differentiated areas were characterized by a weak epithelial Cav­1 expression. Cav­1 downregulation in cancer cells resulted in an increased proliferation in vitro; however, it had no effect on chemoresistance and growth gain in vivo. By contrast, the decreased expression of Cav­1 in fibroblasts resulted in a growth advantage and the chemoresistance of cancer cells when they were co­injected into immunodeficient mice to develop mixed fibroblast/cancer cell xenografts. On the whole, the findings of this study suggest that the downregulation of Cav­1 in fibroblasts is associated with an increased tumor proliferation rate in vivo and chemoresistance. Further studies are warranted to explore whether the targeting of Cav­1 in the stroma may represent a novel therapeutic approach in pancreatic cancer.

Imbalance of tissue inhibitors of metalloproteinases (TIMP) - 1 and - 4 serum levels, in patients with inflammatory bowel disease.

BACKGROUND: Tissue inhibitors of metalloproteinases (TIMPs) play a key role in tissue degradation and remodeling. Since chronic inflammation is associated with tissue remodeling in inflammatory bowel disease (IBD), we evaluated serum TIMP-1 and TIMP-4 levels in IBD patients, in comparison with healthy controls (HC). METHODS: TIMP-1, TIMP-2 and TIMP-4 serum levels were determined in 53 patients with ulcerative colitis (UC), 52 patients with Crohn's disease (CD) and 50 HC, by means of commercially available enzyme-linked immunosorbent assays. The levels of TIMPs were evaluated with regard to the levels of inflammatory markers, such as C reactive protein (CRP) and serum amyloid A (SAA) and the clinical characteristics of patients, so that potential correlations could be recorded. RESULTS: Mean serum TIMP-1 levels were 414.9 +/- 17.6 ng/mL in UC patients, 446.1 +/- 22.8 ng/mL in CD patients and 296.5 +/- 20.6 ng/mL in HC. UC and CD patients had significantly higher serum TIMP-1 levels when compared to HC, (p < 0.0001 in both groups). Mean serum TIMP-1 levels were significantly higher in patients with active IBD (450.5 ng/mL) in comparison with patients with inactive disease (417.3 ng/mL, p = 0.03). Moreover, males showed significantly higher mean serum TIMP-1 levels (399.8 ng/mL), compared to females (368.5 ng/mL, p = 0.04). Mean serum TIMP-2 levels did not differ between UC and CD patients or HC (p > 0.05 in all cases). Mean serum TIMP-4 levels were 1761.2 +/- 67.7 pg/mL in UC patients, 1708.1 +/- 73.4 pg/mL in CD patients and 5573.4 +/- 1246.3 pg/mL in HC. UC and CD patients had significantly lower serum TIMP-4 levels when compared to HC (p = 0.008 and p = 0.02 respectively). Mean serum TIMP-4 levels were significantly lower in males (2772.9 pg/mL), compared to females (3299.0 pg/mL, p = 0.01). In addition, CRP levels showed a statistically significant correlation with TIMP-1 (r = 0.247, p = 0.01), and TIMP-4 levels (r = 0.217, p = 0.03). Similarly, there was a statistically significant correlation between SAA levels and both TIMP-1 (r = 0.264, p = 0.008) and TIMP-4 serum levels (r = 0.212, p = 0.03). CONCLUSION: An imbalance between TIMP-1 and TIMP-4 serum levels is present in IBD patients. TIMP-1 levels could be used not only for diagnostic purposes but also for the assessment of activity in IBD. Gender tends to influence TIMP-1 and TIMP-4 serum levels. These new findings bring into question the potential role of TIMPs in IBD, thus underlining the need for future studies which could offer new insight into this matter.

Hemobilia as the initial manifestation of cholangiocarcinoma in a hemophilia B patient.

Hemobilia is a rare manifestation of hemophilia and is usually iatrogenic following liver biopsy. There are only few reports of spontaneous hemobilia in hemophilia patients. Cholangiocarcinoma is a well-established cause of hemobilia. We describe a case of a 70-year-old male, with known haemophilia B and a past history of papillotomy, who presented with classical symptoms of hemobilia. The initial diagnostic work-up failed to demonstrate a potential cause of bleeding other than the coagulopathy. Three months later, he was readmitted to our hospital with a second episode of hemobilia. During the second work-up, a cholangiocarcinoma was diagnosed both by imaging studies and by a significant elevation of cancer antigen 19-9. Although hemobilia could be attributed to hemophilia, especially in a patient with previous papillotomy, an underlying malignancy of the biliary tree should be suspected.