Disproportionately Low Albumin and High Neutrophil-to-Lymphocyte Ratio in Small Bowel Adenocarcinoma Patients With Long-Duration Crohn's Disease.

INTRODUCTION: Although Crohn's disease (CD) is a known risk factor of small bowel adenocarcinoma (SBA), early diagnosis remains a significant clinical challenge. Identification of biomarkers for SBA may lead to early detection. METHODS: This is a retrospective study comparing albumin levels and neutrophil-to-lymphocyte ratio (NLR) of patients with long-standing CD who underwent small bowel resection with and without malignancy. RESULTS: Forty-two patients with CD were included in this study (11 with SBA). Median NLR before surgery was 8.5 (interquartile range 6.2-31.3) in patients with SBA and 3.8 (interquartile range 2.8-5.3) for patients without SBA ( P < 0.05). Mean albumin levels before surgery were significantly lower among patients with SBA compared with patients without SBA (2.6 ± 0.6 g/dL vs 3.5 ± 0.6 g/dL, respectively, P < 0.05), despite patients with SBA being under longer total parenteral nutrition treatment duration. DISCUSSION: CD patients with SBA diagnosis have increased NLR and lower albumin before surgery compared with CD patients without detection of SBA.

Serum Syndecan-1: A Novel Biomarker for Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Syndecan-1 (SDC1) has multiple functions in tumorigenesis in general and specifically in pancreatic cancer. We aimed to evaluate SDC1 as a diagnostic and prognostic biomarker in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: In this case-control study, patients newly diagnosed with a biopsy-proven PDAC were enrolled alongside healthy individuals in a derivation-validation cohort design. Serum SDC1 was measured by enzyme-linked immunoassay. The diagnostic accuracy of SDC1 levels for diagnosing PDAC was computed. A unified cohort enriched with additional early-stage patients with PDAC was used to evaluate the association of SDC1 with survival outcomes and patient characteristics. RESULTS: In the derivation cohort, serum SDC1 levels were significantly higher in patients with PDAC (n = 39) compared with healthy controls (n = 20) (40.1 ng/mL, interquartile range 29.8-95.3 vs 25.6 ng/mL, interquartile range 17.1-29.8, respectively; P < 0.001). The receiver operating characteristic analysis area under the curve was 0.847 (95% confidence interval 0.747-0.947, P < 0.001). These results were replicated in a separate age-matched validation cohort (n = 38 PDAC, n = 38 controls; area under the curve 0.844, 95% confidence interval 0.757-0.932, P < 0.001). In the combined-enriched PDAC cohort (n = 110), using a cutoff of 35 ng/mL, the median overall 5-year survival between patients below and above this cutoff was not significantly different, although a trend for better survival after 1 year was found in the lower level group (P = 0.06). There were 12 of the 110 patients with PDAC (11%) who had normal CA 19-9 in the presence of elevated SDC1. DISCUSSION: These findings suggest serum SDC1 as a promising novel biomarker for early blood-based diagnosis of pancreatic cancer.

Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and Drug Concentrations: The POETIC Study.

OBJECTIVES: Adalimumab is usually self-injected at home, making prospective serial-sampling studies challenging and scarce. This has led to a gap in knowledge about evolution of anti-adalimumab antibodies (AAAs) over time and its correlation with clinical and inflammatory outcomes. METHODS: A program for home visits by physicians at induction, every 3 months and at event of relapse, was established prospectively for Crohn's disease (CD) patients. At each visit, patients' clinical scores were determined and sera were obtained for C-reactive protein, drug, and AAA levels. This cohort was compared to a parallel prospective cohort of infliximab-treated CD patients. In a subgroup of 29 patients, trough and in-between-trough levels were compared, to elucidate the importance of timing of sampling during the injection cycle. RESULTS: Ninety-eight CD patients starting adalimumab were prospectively followed (median follow-up 44 weeks) and 621 serum samples were analyzed. Thirty-three patients (32%) developed AAA; 18/33 (55%) of them as early as week 2, and 26/33 (79%) by week 14. Induction period AAAs were strongly associated with primary non-response (odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6-17.8, p = 0.005). As compared to antibodies-to-infliximab (ATI), AAA formation rate over time was significantly lower (p = 0.01) and AAA were much more specific-85% of AAA events were associated with loss-of-response compared with 58% rate for ATI (p = 0.01). In 29 patients sampled serially during an injection cycle, levels of drug and AAA seemed comparable between four time-points during a single cycle both in patients with or without AAA (n = 8, n = 21, respectively). CONCLUSIONS: When followed prospectively and serially, AAAs are found to arise earlier than previously appreciated and their impact may be more pronounced for primary rather than secondary, non-response. Drug and AAA levels were similar both at trough and in-between injections, enabling to simplify therapeutic drug monitoring of adalimumab.

Stenting in malignant colonic obstruction--is it a real therapeutic option?

BACKGROUND: Malignant colonic obstruction is commonly treated surgically. Colonic stents are a therapeutic option for palliation or used as a bridge to surgery or chemotherapy. OBJECTIVE: The aim of the study was to evaluate the clinical success rate of stenting as a bridge to one-step surgery, chemotherapy, or as a palliative measure. DESIGN: This was a retrospective observational study. SETTINGS: The study was conducted at a university-affiliated tertiary referral center. PATIENTS AND INTERVENTIONS: From 2007 to 2014, 45 patients with malignant colonic obstruction were referred for stent insertion. MAIN OUTCOME MEASURES: Patients were grouped according to three pre-defined treatment goals: group 1: restorative one-step procedure without an ostomy, group 2: completion of scheduled chemotherapy before surgery, and group 3: palliation without surgical intervention. RESULTS: Group 1 included 11 patients. Three patients (27.3 %) met the treatment goal of one-step surgery. Eight patients (72.7 %) did not reach the primary goal due to stent insertion failure (four patients), stent-related complications (two patients), and failure to perform a one-step surgery after successful stent insertion (two patients). Group 2 included 12 patients. Chemotherapy was successfully completed prior to surgery in six patients (50 %). Six patients (50 %) did not achieve treatment goal due to stent insertion failure (two patients), stent migration (two patients), stent-related perforation (one patient), and mortality (one patient). Group 3 included 20 patients. Long-term palliation without surgical intervention was achieved in eight patients (40 %). Stent insertion failed in seven patients (35 %). Five patients (25 %) needed urgent surgery due to stent complications (three migrations and two perforations). LIMITATIONS: The study was limited by its retrospective nature and small sample size. CONCLUSIONS: This study demonstrates only a modest success rate of colonic stents in the treatment of malignant colonic obstruction. Although colonic stenting seems to be an effective method of relieving colonic obstruction, high failure rates limits its applicability.

Ashkenazi Jewish origin protects against formation of antibodies to infliximab and therapy failure.

Infliximab is an anti-tumor necrosis factor (TNF) used for treatment of inflammatory bowel disease (IBD) as well as rheumatoid arthritis, psoriasis, and other inflammatory conditions. Antibodies to infliximab (ATI) develop in approximately 45% of infliximab-treated IBD patients and are correlated with loss of clinical response. Scarce data exist as to factors which predict infliximab immunogenicity.To investigate factors that may predict formation of antibodies to infliximab (ATI) and infliximab therapy failure an observational study of consecutive IBD patients treated with infliximab between 2009 and 2013 was performed. Trough levels of ATI were measured. Patients were monitored for disease activity using clinical activity indexes and were classified according to ATI formation and clinical response. All clinical and demographic parameters were analyzed for association with the designated outcomes.One hundred fifty-nine patients were included and 1505 sera were tested. On multivariate analysis, Jewish Ashkenazi ethnicity was protective against both development of ATI (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.17-0.7, P = 0.005) and treatment failure (OR 0.29, 95% CI 0.13-0.66, P = 0.003). Concomitant immunomodulator therapy was also negatively associated with immunogenicity and infliximab therapy failure (OR 0.31, 95% CI 0.15-0.65, P = 0.002; OR 0.42 95% CI 0.18-0.99, p = 0.04, respectively), whereas episodic therapy was positively associated with both outcomes (OR 4.2 95% CI 1.07-16.1, p = 0.04, OR 4.45 95% CI 1.2-16.6, p = 0.026 respectively). All other variables, including IBD type, gender, weight, age, smoking status and disease duration, were not predictive of ATI formation or clinical failure. However, among Crohn's disease patients, a non-stricturing non-penetrating phenotype was protective against ATI formation (OR 0.4, 95% CI 0.14-0.96, p = 0.04). P = 0.04, respectively), whereas episodic/interrupted therapy was positively associated with both outcomes (OR 4.2, 95% CI 1.07-16.1, P = 0.04; OR 4.45, 95% CI 1.2-16.6, P = 0.026, respectively). All other variables, including IBD type, sex, weight, age, smoking status, and disease duration, were not predictive of ATI formation or clinical failure. However, among Crohn disease patients, a nonstricturing nonpenetrating phenotype was protective against ATI formation (OR 0.4, 95% CI 0.14-0.96, P = 0.04).Jewish Ashkenazi ethnicity is protective of ATI formation and infliximab therapy failure. These findings suggest a role for ethnicity, and implicitly for genetic predisposition, in modulating the risk of anti-TNF immunogenicity and treatment unresponsiveness.

[Curcumin add-on therapy for ulcerative colitis].

Ulcerative Colitis (UC) is a chronic inflammatory disease of colon mucosa, which results from inappropriate inflammatory response. Pharmacological treatments that are used to manage UC are usually targeted to moderate the inflammatory response, however, they are associated with significant adverse effects, which call for finding additional treatment options. Curcumin is a polyphenol that is extracted from turmeric (Curcuma longa). This medicinal plant has been traditionally used in India and in China since ancient times. Recently curcumin has been demonstrated to possess anti-inflammatory, anti-proliferative and antibacterial properties. Based on these reports, our article describes a case report of a patient treated with curcumin in addition to 5-Aminosalicylic acid (5ASA) and presents an integrative approach for the treatment of ulcerative colitis.

Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial.

BACKGROUND & AIMS: The phytochemical compound curcumin was reported to be effective in maintaining remission in patients with ulcerative colitis (UC). We investigated curcumin's efficacy in inducing remission in patients with active mild-to-moderate UC. METHODS: We performed a multicenter randomized, placebo-controlled, double-blind study of 50 mesalamine-treated patients with active mild-to-moderate UC (defined by the Simple Clinical Colitis Activity Index [SCCAI]) who did not respond to an additional 2 weeks of the maximum dose of mesalamine oral and topical therapy. Patients were randomly assigned to groups who were given curcumin capsules (3 g/day, n = 26) or an identical placebo (n = 24) for 1 month, with continued mesalamine. The primary outcome was the rate of clinical remission (SCCAI ≤2) at week 4. Clinical and endoscopic responses were also recorded. RESULTS: In the intention-to-treat analysis, 14 patients (53.8%) receiving curcumin achieved clinical remission at week 4, compared with none of the patients receiving placebo (P = .01; odds ratio [OR], 42; 95% confidence interval [CI], 2.3-760). Clinical response (reduction of ≥3 points in SCCAI) was achieved by 17 patients (65.3%) in the curcumin group vs. 3 patients (12.5%) in the placebo group (P < .001; OR, 13.2; 95% CI, 3.1-56.6). Endoscopic remission (partial Mayo score ≤1) was observed in 8 of the 22 patients evaluated in the curcumin group (38%), compared with none of 16 patients evaluated in the placebo group (P = .043; OR, 20.7; 95% CI, 1.1-393). Adverse events were rare and comparable between the 2 groups. CONCLUSIONS: Addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients with mild-to-moderate active UC, producing no apparent adverse effects. Curcumin may be a safe and promising agent for treatment of UC. Clinicaltrials.gov number: NCT01320436.

Severe and morbid obesity in Crohn's disease patients: prevalence and disease associations.

BACKGROUND: Crohn's disease (CD) is frequently associated with weight loss and malnutrition. However, as the prevalence of obesity increases worldwide, it may become a clinical problem even in CD. AIM: To assess the prevalence of severe/morbid obesity in CD patients and to compare their disease characteristics to nonobese CD patients. METHODS: A retrospective analysis of a computerized CD patient database was performed to identify severely/morbidly obese patients (BMI >35). Prevalence was compared to data of the general population. Severely/morbidly obese CD patients were then compared to randomly selected nonobese CD patients (BMI <30) in a 1:3 ratio. RESULTS: Thirteen severely/morbidly obese patients out of 560 CD patients were found (2.3%), which is significantly lower than the prevalence in the general population (5.6%, p = 0.001). When compared to 39 nonobese CD patients, colonic disease was significantly more common among severely/morbidly obese CD patients (odds ratio: 6, 95% CI: 1.35-26.3, p = 0.02), while there was no difference in other disease parameters. Interestingly, 4 morbidly obese CD patients had undergone laparoscopic sleeve gastrectomy for treatment of morbid obesity with a favorable surgical course. CONCLUSION: CD in severely/morbidly obese patients is more often colonic, but otherwise no different than CD in nonobese patients. Sleeve gastrectomy is a viable therapeutic option for morbidly obese CD patients.

Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: a pilot prospective study.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) patients suffer from significant morbidity and diminished life quality. The plant cannabis is beneficial in various gastrointestinal diseases, stimulating appetite and causing weight gain. Our aims were to assess whether treatment with inhaled cannabis improves quality of life, disease activity and promotes weight gain in these patients. METHODS: Patients with long-standing IBD who were prescribed cannabis treatment were included. Two quality of life questionnaires and disease activity indexes were performed, and patient's body weight was measured before cannabis initiation and after 3 months' treatment. RESULTS: Thirteen patients were included. After 3 months' treatment, patients reported improvement in general health perception (p = 0.001), social functioning (p = 0.0002), ability to work (p = 0.0005), physical pain (p = 0.004) and depression (p = 0.007). A schematic scale of health perception showed an improved score from 4.1 ± 1.43 to 7 ± 1.42 (p = 0.0002). Patients had a weight gain of 4.3 ± 2 kg during treatment (range 2-8; p = 0.0002) and an average rise in BMI of 1.4 ± 0.61 (range 0.8-2.7; p = 0.002). The average Harvey-Bradshaw index was reduced from 11.36 ± 3.17 to 5.72 ± 2.68 (p = 0.001). CONCLUSIONS: Three months' treatment with inhaled cannabis improves quality of life measurements, disease activity index, and causes weight gain and rise in BMI in long-standing IBD patients.

Travel-associated health risks for patients with inflammatory bowel disease.

BACKGROUND & AIMS: There are few data on risk of travel for patients with inflammatory bowel disease (IBD). We assessed rates of illness while traveling among patients with IBD. METHODS: We performed a retrospective, case-controlled study of illnesses among 222 patients with IBD and 224 healthy individuals (controls) during 1099 total trips. Data were retrieved by structured questionnaires, personal interviews, and chart review. RESULTS: Participants had 142 episodes of illness during the trips; 92% were enteric disease. An episode of illness occurred during 79/523 (15.1%) trips made by patients with IBD compared with 63/576 (10.9%) trips made by controls (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.01-2.0; P = .04). However, this difference was mostly attributable to the increased incidence of illness among IBD patients traveling in industrialized countries. In contrast, the rate of illness among travelers to developing countries was similar among patients with IBD and controls (34/200, 17% vs 52/243, 21% of trips, respectively; P = .24). Moreover, numerically more controls that traveled to the tropics developed illness than travelers with IBD (43/135 vs 23/97, respectively; P = .18). In multivariate analysis, factors that increased risk for travel illness included frequent flares of IBD (OR, 1.9; 95% CI, 1.1-3.4; P = .02) and prior IBD-related hospitalizations (OR, 3.5; 95% CI, 1.3-9.3; P = .01); remission within 3 months before traveling reduced the risk for illness (OR, 0.3; 95% CI, 0.16-0.5; P < .001). Use of immunomodulatory drugs was not independently associated with risk of illness during travel. CONCLUSIONS: Patients with IBD have a higher rate of illness compared with controls during trips to industrialized countries, but not to developing or tropical regions. These findings indicate that most travel-associated illnesses stem from sporadic IBD flares rather than increased susceptibility to enteric infections.

Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease.

INTRODUCTION: Limited data suggest the absence of infliximab in breast milk, thereby implying the safety of this drug during breast-feeding. We aimed to re-evaluate the presence of infliximab in breast milk of nursing IBD patients. METHODS: Serum and breast milk were obtained post-partum from 3 breast-feeding patients with Crohn's disease before and after re-initiation of infliximab. ELISA assay was employed to measure infliximab level in maternal serum and in breast milk. The level of infliximab was also measured in breast milk of a control group of 8 nursing healthy mothers. RESULTS: Infliximab was undetectable in breast milk prior to the first infusion and was also not measurable in 8 lactating women not exposed to infliximab. Infliximab levels in breast milk rose up to 101ng/ml within 2-3days of the infusion. These levels of infliximab in breast milk were roughly 1/200th of the level in blood. CONCLUSIONS: In contrast with prior reports, infliximab can be detected in the breast milk of nursing mothers. The miniscule amounts of infliximab transferred in breast milk are unlikely to result in systemic immune-suppression of the infant. Nonetheless, local effects of this exposure on the neonates' intestine and potential immune sensitization or tolerization towards the drug can not be excluded and merit further investigations.

Familial ulcerative colitis in Israeli Jews: its prevalence and clinical severity compared to sporadic disease.

BACKGROUND: A family history of inflammatory bowel disease (IBD) is present in some ulcerative colitis (UC) patients. We aimed to investigate the familial occurrence of UC and its impact on disease severity. METHODS: A structured questionnaire was distributed to patients with UC. Parameters pertaining to disease severity were compared for patients with or without positive family history of IBD. RESULTS: The study group consisted of 168 UC patients with a total of 952 first degree relatives. Positive family history for IBD in a first degree relative was reported in 24 patients (14%). Six of the 336 parents (1.8%) had IBD (all with UC). There were 13 siblings with IBD (4 CD, 9 UC) out of 249 (5.4%). Seven of 376 (1.9%) offsprings had IBD (4 CD, 3 UC). Familial patients were more commonly females and have reported significantly more disease exacerbations than the sporadic group (17.7±15 versus 6.8±11, respectively, p=0.006). On multivariate analysis, familial disease was significantly and independently associated with both female sex (OR 4.1, 95% CI 1.1-14.9, p=0.04) and more exacerbations per year (annual OR 1.05, 95% CI 1.01-1.1, p=0.02). However, similar proportions of sporadic and familial patients wherever hospitalized, underwent colectomy or were treated by immune-suppressors. CONCLUSIONS: Familial occurrence of UC is not uncommon among Jewish patients in Israel. The familial-genetic component may preferentially influence disease occurrence among females, and is possibly associated with more disease flares although other parameters of disease severity do not seem to be impacted.

Lidocaine inhibits epithelial chemokine secretion via inhibition of nuclear factor kappa B activation.

AIM: To study the antiinflammatory effect of lidocaine in intestinal epithelial cells. METHODS: HT-29 and T-84 cells were grown in culture with and without TNF-alpha, lidocaine, aconitine and veratridine. The secretion of IL-8 and IP-10 was measured by ELISA. A cDNA microarray was used to assess gene expression. Real-time PCR was used to confirm the results. Western blots and a modified electromobility shift assay (EMSA) were used to assess NFkappaB activation. RESULTS: Lidocaine inhibited spontaneous and TNF-alpha induced secretion of IL-8 and IP-10. The combination of veratridine or aconitine, voltage-gated sodium channels (VGSC) agonists that open VGSCs, with lidocaine did not alter the effect of lidocaine on cytokine secretion. Gene array analysis revealed that IkappaB transcription was induced by TNF-alpha and inhibited by lidocaine. IkappaB real-time PCR confirmed this observation. A Western blot analysis demonstrated that the degradation of IkappaB following TNF-alpha treatment was markedly inhibited by lidocaine. Lidocaine treatment resulted in decreased generation of phosphorylated IkappaB. A modified EMSA was complementary and demonstrated marked inhibition of NFkappaB nuclear binding. CONCLUSION: Lidocaine inhibits IL-8 and IP-10 secretion from intestinal cells. This effect is mediated by inhibition of NFkappaB activation via decreased IkappaB phosphorylation and is not mediated by lidocaine's effect on VGSC.

Familial clustering of Crohn's disease in Israel: prevalence and association with disease severity.

BACKGROUND: There is limited data addressing the severity of Crohn's disease (CD) in patients with a family history of inflammatory bowel disease (IBD) compared to sporadic cases. METHODS: We investigated the familial occurrence of IBD and its correlation with disease behavior in CD patients attending the Israeli IBD Foundation meeting using a structured questionnaire. RESULTS: The study group consisted of 181 CD patients with a total of 825 1(st) degree relatives. Positive family history for IBD in a 1(st) degree relative was reported in 30 patients (16%). Nine out of the 360 parents (2.5%) had IBD (4 CD, 5 UC). There were 17 siblings with IBD (15 CD, 2 UC) out of 351 (4.8%). Ten out of 114 (8.8%) offsprings had IBD (6 CD, 4 UC). When two siblings were affected, their respective age of disease onset was strikingly concordant (r = 0.76, p = 0.008). There was no difference between sporadic and familial CD patients in the age of disease onset, the location of disease, proportion of smokers or percentage of Ashkenazi origin. Furthermore, similar proportions of sporadic and familial patients underwent intestinal surgery, had penetrating or obstructive complications or were treated by immunomodulators and/or biologics. There was also no difference in the reported percentage of time with active disease or the number of flare-ups. CONCLUSIONS: The prevalence of familial disease among Jewish CD patients in Israel is at the high range of the rate found in other ethnicities. Having a positive family history of IBD has no impact on the severity of the disease.

Functional voltage-gated sodium channels are expressed in human intestinal epithelial cells.

BACKGROUND AND AIM: Local anesthetics which preferentially interact with voltage-gated sodium channels (VGSCs) were shown to have a clinical beneficial effect in ulcerative colitis and to regulate the secretion of inflammatory mediators from intestinal epithelial cells. However, expression of VGSCs in epithelial cells was not demonstrated. Herein we assessed whether intestinal epithelial cells express VGSCs. METHODS: The expression of VGSCs in normal human colonic tissue and in the TNFalpha-treated or untreated intestinal epithelial cell line HT-29 was studied by immunofluorescence staining and FACS analysis, Western blot, immunohistochemistry, and RT-PCR using primers specific for several VGSC alpha subunits. The function of VGSCs was assessed by measuring changes in the membrane potential of the intestinal epithelial cells following incubation with lidocaine, veratridine, or both. RESULTS: HT-29 cells were shown to express the VGSC alpha protein. mRNA analysis revealed the expression of nine of ten VGSC alpha isoforms. Immunohistochemical staining of normal colonic tissue confirmed the expression of VGSCs in colonic epithelial cells, smooth muscle cells, and nerves. Lidocaine induced membrane depolarization of HT-29 cells and its effect was blocked by veratridine. CONCLUSION: Malignant and normal intestinal epithelial cells express functional VGSCs. These molecules may play a role in the regulation of inflammation in gut physiology and pathology.