Placental Histopathological Lesions and Adverse Neonatal Outcomes in Patients with Inflammatory Bowel Diseases- A retrospective Cohort Study.

Inflammatory bowel diseases (IBD) are significantly associated with adverse pregnancy and neonatal outcomes, though the pathomechanism is yet unknown. To investigate the relationship between IBD and adverse pregnancy outcomes by comparing neonatal outcomes and placental histopathology in two matched groups of patients with and without IBD. In this retrospective study, data of all patients who gave birth between 2008-2021 and were diagnosed with IBD were reviewed and compared to a control group matching two control cases for every IBD case. Neonatal outcomes and placental pathology were compared between the groups. Compared to the control group (n=76), the placentas of patients with IBD (n=36) were characterized by significantly lower placental weight (p < 0.001), and higher rates of maternal vascular malperfusion lesions (MVM, p < 0.001) and maternal and fetal inflammatory response lesions (p < 0.001). Neonates of patients with IBD were more frequently small for gestational age (SGA) (p=0.01), with increased rates of need for phototherapy (p = 0.03), respiratory morbidity and NICU admission (p < 0.001 for both outcomes). Multivariate logistic regression analyses adjusting for possible confounders (including maternal age, gestational age, chronic hypertension, smoking, and thrombophilia) confirmed the independent association between IBD and composite MVM lesions (aOR 4.31, p < 0.001), maternal inflammatory responses (aOR 40.22, p < 0.001) and SGA infants (aOR 4.31, p = 0.013). IBD is associated with increased rates of placental histopathological lesions and adverse pregnancy outcomes, including SGA infants. These novel findings imply the role of placental malperfusion and inflammatory processes in pregnancy complications of IBD patients, which should be followed accordingly. Approval of local ethics committee # WOMC-0219-20.

The diagnostic accuracy of endoscopic ultrasound vs. contrast-enhanced computed tomography in local staging of pancreatic adenocarcinoma: a bi-national multicenter study.

BACKGROUND: Identification of pancreatic cancer (PC) local invasion is crucial to optimize patients' selection for surgery. AIMS: To determine the diagnostic accuracy of contrast-enhanced computed tomography (CECT) and endoscopic ultrasound (EUS) in local staging of PC. METHODS: We performed a multicenter study including all patients with PC who underwent surgery. RESULTS: One hundred twelve patients were included. Surgical findings of peri-pancreatic lymph nodes (LN), vascular and adjacent organ involvement were seen in 67 (59.8%), 33 (29.5%) and 19 patients (17%), respectively. The diagnostic performance of EUS was better than CECT in peri-pancreatic LN. The sensitivity, specificity, positive predictive value (PPV) and negative predictive (NPV) of CECT vs. EUS were 28.4%, 80%, 67.9% and 42.9% vs. 70.2%, 75.6%, 81% and 63%, respectively. For vascular and adjacent organ involvement, the sensitivity, specificity, PPV and NPV were 45.5%, 93.7%, 75%, 80.4% and 31.6%, 89.2%, 37.5% and 86.5% for CECT, respectively, vs. 63.6%, 93.7%, 80.8%, 86.1% and 36.8%, 94.6%, 58.3% and 88% for EUS, respectively. Combining both CECT and EUS, the sensitivity for peri-pancreatic LN, vascular and adjacent organ involvement improved (76.1%, 78.8% and 42%), respectively. CONCLUSION: EUS was superior to CECT in local staging. Combined EUS and CECT had a higher sensitivity than either alone.

Colectomy Rates did not Decrease in Paediatric- and Adult-Onset Ulcerative Colitis During the Biologics Era: A Nationwide Study From the epi-IIRN.

BACKGROUND: It is still of debate whether the advent of biologics has been associated with a change in the natural history of ulcerative colitis [UC]. In this nationwide study we evaluated trends of long-term outcomes in all patients diagnosed with UC in Israel during the biologic era. METHODS: Data in the epi-IIRN cohort were retrieved from the four Israeli Health Maintenance Organizations covering 98% of the population, and linked to the Ministry of Health prospective registry on surgeries and hospitalizations. Joinpoint Regression and Kaplan-Meier survival analyses were used, reporting annual average percentage change [AAPC] for each outcome. RESULTS: A total of 13 231 patients were diagnosed with UC since 2005 (1426 [11%] paediatric-onset, 10 310 [78%] adults, 1495 [11%] elderly) with 93 675 person-years of follow-up. The probabilities of surgery after 1, 3 and 5 years from diagnosis were 1.1, 2.3 and 4.1%, respectively, and the corresponding rates of hospitalizations were 22, 33 and 41%. The overall utilization of biologics in UC increased from 0.1% in 2005 to 9.6% in 2019 [AAPC 22.1%] and they were prescribed earlier during the disease course (median of 5.6 years [interquartile range 2.8-9.1] in 2005-2008 vs 0.8 years [0.4-1.5] in 2015-2018; p < 0.001]. Annual rates of surgeries [AAPC -1.3; p = 0.6] and steroid-dependency [AAPC -1.2; p = 0.3] remained unchanged, while rates of hospitalizations slightly decreased [AAPC -1.2; p < 0.001]. Outcomes were consistently worse in paediatric-onset disease than in adults, despite higher utilization of biologics [28% vs 12%, respectively; p < 0.001]. CONCLUSION: During the biologic era rates of surgeries and steroid-dependency have remained unchanged in patients with UC, while rates of hospitalizations have slightly decreased.

Improved Outcomes of Paediatric and Adult Crohn's Disease and Association With Emerging Use of Biologics-A Nationwide Study From the Epi-IIRN.

BACKGROUND: The effectiveness of biologics for improving long-term outcomes in patients with Crohn's disease [CD] is still controversial. In this nationwide study, we aimed to evaluate trends of long-term outcomes in all CD patients in Israel during the biologics era. METHODS: Trends of outcomes were analysed using data from the four Israeli health maintenance organisations, covering 98% of the population; joinpoint regression models were used to explore changes of these trends over 2005 to 2019. RESULTS: A total of 16 936 patients were diagnosed with CD in Israel since 2005 (2932 [17%] paediatric onset, 14 004 [83%] adult onset) with 114 947 person-years of follow-up. The cumulative rate of any CD related surgery was 5%, 9%, 11%, and 14% at 1, 3, 5, and 10 years from diagnosis. The increase in use of biologics was sharp (from 8.9% to 36%; average annual percent change [AAPC], 14.3%), and the time to biologics was shorter in recent years (median time of 4.8 [1.9-8.1] years in those diagnosed in 2005-2008 compared with 0.5 [0.2-1.1] years in those diagnosed in 2015-2018; p < 0.001). A significant decrease was noted in the hazard of hospitalisations (1.3 [0.1-4.6] years compared with 0.2 [0.02-0.9] years; p < 0.001), steroid dependency (1.5 [0.2-5.4] years compared with 0.1 [0.02-0.4] years; p < 0.001), and intestinal surgeries [4.7 [1.6-8.2] years compared with 0.6 [0.2-1.4] years; p < 0.001), but not of perianal surgery (4.2 [1.1-7.7] years compared with 0.6 [0.2-1.4] years; p = 0.2). Outcomes were consistently worse in paediatric onset compared with adults. CONCLUSIONS: The rates of hospitalisations, steroid dependency, and intestinal resections decreased in association with increased use of biologics both in children and in adults, but not the rate of perianal surgeries.

[TREATMENTS OF PERIANAL CROHN'S DISEASE].

INTRODUCTION: Perianal Crohn's disease is correlated with a significant decrease in quality of life and can predict unfavorable outcomes. In this condition, it is recommended that a multidisciplinary team including a gastroenterologist, colorectal surgeon and radiologist will be involved to optimize therapeutic decisions. Despite the advent of biologic and surgical therapies, the success rate of therapy is unsatisfactory and may result in a high chance of recurrence. In recent years, novel therapies have been introduced which include local injection of mesenchymal stem cells and surgical techniques which can improve the outcome and quality of life of the patients. The goal of this review, is to raise the awareness and summarize the therapeutic options available for the treatment of perianal Crohn's disease.

An International Multicenter Comparison of IBD-Related Disability and Validation of the IBDDI.

BACKGROUND: The IBD disability index (IBDDI) has been shown to be valid and reliable. We compared the distributional and predictive properties of the IBDDI, when collected from five populations of people living with IBD- from Winnipeg, Chicago, Toronto, Hong Kong, and Jerusalem. METHODS: People with IBD from five jurisdictions were invited to complete a survey including the IBDDI, the World Health Organization Disability Assessment Scale, the Work and Social Adjustment Scale, the IBDQ, the Kessler-6 distress scale, and the Stanford presenteeism scale. Between sites, we compared the correlation between IBDDI and the other 4 measures of disability/quality of life/distress, and the association between IBDDI and presenteeism and having been hospitalized in the past year. RESULTS: There were 1121 participants from Winnipeg, 511 from Chicago, 147 from Toronto, 97 from Hong Kong, and 96 from Jerusalem. The majority had Crohn's disease. Although the mean IBDDI score varied by site, the correlation between IBDDI and each of the other 4 measures of disability/QOL/distress was nearly identical. Similarly, the regression coefficient showing the association between IBDDI and presenteeism was nearly identical in all sites, and the risk ratios showing the association between hospitalization and high IBDDI was similar in all sites. CONCLUSION: The correlation between IBDDI and different measures of disability/QOL/distress was similar across all sites. There is strong evidence of the association between IBD-related disability and presenteeism, and between hospitalization and high IBD-related disability, and that the associations are the same across different populations. The severity of disability that an individual with a given IBDDI score has is directly comparable across populations.

Colon Cancer-Associated Fusobacterium nucleatum May Originate From the Oral Cavity and Reach Colon Tumors via the Circulatory System.

Fusobacterium nucleatum is a common oral bacterium that is enriched in colorectal adenomas and adenocarcinomas (CRC). In humans, high fusobacterial CRC abundance is associated with chemoresistance and poor prognosis. In animal models, fusobacteria accelerate CRC progression. Targeting F. nucleatum may reduce fusobacteria cancer progression and therefore determining the origin of CRC F. nucleatum and the route by which it reaches colon tumors is of biologic and therapeutic importance. Arbitrarily primed PCR performed previously on matched same-patients CRC and saliva F. nucleatum isolates, suggested that CRC F. nucleatum may originate from the oral cavity. However, the origin of CRC fusobacteria as well as the route of their arrival to the tumor have not been well-established. Herein, we performed and analyzed whole genome sequencing of paired, same-patient oral, and CRC F. nucleatum isolates and confirmed that CRC-fusobacteria originate from the oral microbial reservoir. Oral fusobacteria may translocate to CRC by descending via the digestive tract or using the hematogenous route during frequent transient bacteremia caused by chewing, daily hygiene activities, or dental procedures. Using the orthotropic CT26 mouse model we previously showed that IV injected F. nucleatum colonize CRC. Here, we compared CRC colonization by gavage vs. intravenous inoculated F. nucleatum in the MC38 and CT26 mouse orthotropic CRC models. Under the tested conditions, hematogenous fusobacteria were more successful in CRC colonization than gavaged ones. Our results therefore provide evidence that the hematogenous route may be the preferred way by which oral fusobacteria reach colon tumors.

Safety and effectiveness of ustekinumab for induction of remission in patients with Crohn's disease: A multicenter Israeli study.

INTRODUCTION: Ustekinumab is an effective treatment of Crohn's disease (CD). Real-world data addressing the efficacy and safety of ustekinumab are scarce. AIM: Our aim was to assess the safety and efficacy of ustekinumab in a large national patient cohort. METHODS: A prospective multicenter study, in which we followed patients with active CD treated with ustekinumab for 24 weeks. Induction dose was intravenous ranging from 260 to 520 mg, according to body weight, followed by 90 mg doses given subcutaneously every 8 weeks. Clinical response was defined as a reduction of at least 1 severity category, as defined by Harvey-Bradshaw index (HBI). Patients with HBI < 5 were considered to be in clinical remission. Patients who stopped needing steroids at week 24 were defined as being in steroid-free clinical remission. RESULTS: A total of 106 CD patients from eight Israeli centers were included. All patients were previously exposed to at least one biological agent. Our cohort consisted of 65 (61.3%) females. Mean age was 41 ± 14 years with an average disease duration of 12.2 ± 8 years. A total of 96 (90.5%) patients continued treatment throughout week 24. Clinical response was observed in 52% of these patients with mean HBI reduction from 8.34 ± 3.8 to 6.8 ± 4.4 at week 24 (p = 0.001). Clinical remission was achieved in 33 patients (31.1%). Moreover, the number of patients requiring steroid treatment was reduced by 66% at week 24. Out of 106 patients, 11 patients (10.4%) discontinued treatment: 3 due to adverse events (2.8%), 7 due to a lack of response, and 1 who was lost to follow-up. Following 24 weeks of treatment, 15 patients reported minor adverse events. CONCLUSIONS: In a large real-world Israeli cohort of non-naïve-to-biological-treatment CD patients, ustekinumab was effective and safe in induction of clinical remission with a significant reduction in the number of patients requiring steroid treatment.

Clinical and Radiologic Characteristics of Intra-Abdominal Fistulizing Crohn's Disease.

BACKGROUND: Few studies describe the radiological and laboratory characteristics of patients with Crohn's disease (CD) with intra-abdominal fistulae. OBJECTIVES: We aimed to describe a cohort of CD patients with intra-abdominal fistulae and determine characteristics associated with complex fistulae. METHODS: Data were gathered from medical records and imaging studies of patients. Evaluation included type of fistula, number of fistulae, and radiological characteristics. RESULTS: A total of 205 fistulae in 132 patients were identified with an average patient age of 31 (±12) years. The average time from CD diagnosis to fistula development was 7 years. The most common type of fistula was entero-enteric (53%). Patients with an extra-intestinal fistula presented with an average of 1.96 fistulae, compared with an average of 1.28 fistulae for those with a fistula limited to the bowel (p =0.01). Except for the number of fistula no other significant differences were observed in radiological characteristics of patients who were diagnosed with a fistula at time of CD diagnosis compared to those diagnosed with a fistula later. CONCLUSIONS: The most common CD-associated intra-abdominal fistulae are entero-enteric and entero-colonic fistulae. An extra-intestinal fistula and diagnosis of a fistula subsequent to diagnosis of CD were associated with an increased number of fistulae per patient.

Inflammatory bowel disease patient profiles are related to specific information needs: A nationwide survey.

BACKGROUND: Inflammatory bowel diseases (IBD) is a heterogenous, lifelong disease, with an unpredictable and potentially progressive course, that may impose negative psychosocial impact on patients. While informed patients with chronic illness have improved adherence and outcomes, previous research showed that the majority of IBD patients receive insufficient information regarding their disease. The large heterogeneity of IBD and the wide range of information topics makes a one-size fits all knowledge resource overwhelming and cumbersome. We hypothesized that different patient profiles may have different and specific information needs, the identification of which will allow building personalized computer-based information resources in the future. AIM: To evaluate the scope of disease-related knowledge among IBD patients and determine whether different patient profiles drive unique information needs. METHODS: We conducted a nationwide survey addressing hospital-based IBD clinics. A Total of 571 patients completed a 28-item questionnaire, rating the amount of information received at time of diagnosis and the importance of information, as perceived by participants, for a newly diagnosed patient, and for the participants themselves, at current time. We performed an exploratory factor analysis of the crude responses aiming to create a number of representative knowledge domains (factors), and analyzed the responses of a set of 15 real-life patient profiles generated by the study team. RESULTS: Participants gave low ratings for the amount of information received at disease onset (averaging 0.9/5) and high ratings for importance, both for the newly diagnosed patients (mean 4.2/5) and for the participants themselves at current time (mean 3.5/5). Factor analysis grouped responses into six information-domains. The responses of selected profiles, compared with the rest of the participants, yielded significant associations (defined as a difference in rating of > 0.5 points with a P < 0.05). Patients with active disease showed a higher interest in work-disability, stress-coping, and therapy-complications. Patients newly diagnosed at age > 50, and patients with long-standing disease (> 10 years) showed less interest in work-disability. Patients in remission with mesalamine or no therapy showed less interest in all domains except for nutrition and long-term complications. CONCLUSION: We demonstrate unmet patient information needs. Analysis of various patient profiles revealed associations with specific information topics, paving the way for building patient-tailored information resources.

Isolation and expansion of high yield of pure mesenchymal stromal cells from fresh and cryopreserved placental tissues.

The injection of placental stromal cells isolated from fetal human tissues (f-hPSC) was reported to indirectly induce tissue regeneration in different animal models. A procedure of f-hPSC isolation from fragments of both selected fresh or cryopreserved bulk placental neonate tissues is proposed, based on their high migratory potential,. The fragments of the desired fetal placental tissues are adhered to a culture dish by traces of diluted fibrin and covered with culture medium. Spontaneous migration of pure f-hPSC from the tissue fragments to the cell culture dishes is followed by their rapid expansion by numerous passages. The isolated f-hPSC express typical mesenchymal surface antigens, including CD29, CD105, CD166 and CD146, with negative expression of white blood cell lineage and endothelial cells markers. Optimal yields of f-hPSC cultures can also be obtained from tissue samples cryopreserved in medium composed of 10% dimethyl sulfoxide (M2SO) and 50% fetal calf serum. Slightly better yields are obtained with media supplemented with 1% human albumin. Medium with 5% M2SO and/or 0.25 mg/ml PEG yielded inferior results. The f-hPSC from fresh or cryopreserved tissues express similar cell markers and growth kinetics. The proposed isolation protocol may also be applied for high yield isolation of stromal cells from fresh and cryopreserved tissue of other organs.

A Validated Score Assessing the Risk of an Intra-Abdominal Abscess in Patients with Crohn's Disease Presenting at the Emergency Department.

BACKGROUND AND AIMS: A majority of acutely ill Crohn's disease [CD] patients who present to Emergency Department [ED] will undergo an abdominal CT to rule out disease complications. We aimed to generate a simple non-invasive scoring model to predict the presence of an intra-abdominal abscess in CD patients in the ED. METHODS: We performed a retrospective case-control study at four Israeli hospitals from January 1, 2010 to May 30, 2018. Inclusion criteria included patients with an established diagnosis of CD that had cross-sectional abdominal imaging performed. A total of 322 patients were included, and 81 [25%] were diagnosed with an intra-abdominal abscess. RESULTS: In univariate analysis, ileo-colonic location (odds ratio [OR] 1.88, p = 0.0148), perianal CD [OR 7.01, p = 0.0004], fever [OR 1.88, p = 0.0247], neutrophil-to-lymphocyte ratio [OR 1.12, p < 0.0001], and C-reactive protein [OR 1.10, p < 0.0001] were significantly associated with abscess formation, whereas current use of corticosteroids was negatively associated with abscess formation [OR 0.46, 95% CI, 0.2-0.88, p = 0.0192]. We developed a diagnostic score that included five parameters that were significant on multivariate regression analysis, with assignment of weights for each variable according to the coefficient estimate. A low cut-off score of ≤7 was associated with a negative predictive value [NPV] of 93% for abscess formation, whereas a high cut-off score of >9 was associated with a positive predictive value of 65%. We validated this score with an independent cohort [area under the curve of 0.881 and NPV of 98.5%]. CONCLUSION: We recommend incorporating this score as an aid for stratifying acutely ill CD patients in the ED with low or high probability of the presence of an intra-abdominal abscess.

G-EYE colonoscopy is superior to standard colonoscopy for increasing adenoma detection rate: an international randomized controlled trial (with videos).

BACKGROUND AND AIMS: Colorectal cancer (CRC) is largely preventable with routine screening and surveillance colonoscopy; however, interval cancers arising from precancerous lesions missed by standard colonoscopy still occur. An increased adenoma detection rate (ADR) has been found to be inversely associated with interval cancers. The G-EYE device includes a reusable balloon integrated at the distal tip of a standard colonoscope, which flattens haustral folds, centralizes the colonoscope's optics, and reduces bowel slippage. The insufflated balloon also aims to enhance visualization of the colon during withdrawal, thereby increasing the ADR. METHODS: In this randomized, controlled, international, multicenter study (11 centers), patients (aged ≥50 years) referred to colonoscopy for screening, surveillance, or changes in bowel habits were randomized to undergo either balloon-assisted colonoscopy by using an insufflated balloon during withdrawal or standard high-definition colonoscopy. The primary endpoint was the ADR. RESULTS: One thousand patients were enrolled between May 2014 and September 2016 to undergo colonoscopy by experienced endoscopists; 803 were finally analyzed (standard colonoscopy n = 396; balloon-assisted colonoscopy n = 407). Baseline parameters were similar in both groups. Balloon-assisted colonoscopy provided a 48.0% ADR compared with 37.5% in the standard colonoscopy group (28% increase; P = .0027). Additionally, balloon-assisted colonoscopy provided for a significant increase in detection of advanced (P = .0033) flat adenomas (P < .0001) and sessile serrated adenomas/polyps (P = .0026). CONCLUSION: Balloon-assisted colonoscopy yielded a higher ADR and increased the detection of advanced, flat, and sessile serrated adenomas/polyps when compared with standard colonoscopy. Improved detection by the G-EYE device could impact the quality of CRC screening by reducing miss rates and consequently reducing interval cancer incidence. (Clinical trial registration number: NCT01917513.).

Five years of fecal microbiota transplantation - an update of the Israeli experience.

AIM: To evaluate and describe the efficacy of fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI) in a national Israeli cohort. METHODS: All patients who received FMT for recurrent (recurrence within 8 wk of the previous treatment) or refractory CDI from 2013 through 2017 in all the five medical centers in Israel currently performing FMT were included. Stool donors were screened according to the Israeli Ministry of Health guidelines. Clinical and laboratory data of patients were collected from patients' medical files, and they included indications for FMT, risk factors for CDI and disease severity. Primary outcome was FMT success (at least 2 mo free of CDI-related diarrhea post-FMT). Secondary outcomes included initial response to FMT (cessation of diarrhea within 7 d) and recurrence at 6 mo. RESULTS: There were 111 FMTs for CDI, with a median age of 70 years [interquartile range (IQR): 53-82], and 42% (47) males. Fifty patients (45%) were treated via the lower gastrointestinal (LGI, represented only by colonoscopy) route, 37 (33%) via capsules, and 24 (22%) via the upper gastrointestinal (UGI) route. The overall success rate was 87.4% (97 patients), with no significant difference between routes of administration (P = 0.338). In the univariant analysis, FMT success correlated with milder disease (P = 0.01), ambulatory setting (P < 0.05) and lower Charlson comorbidity score (P < 0.05). In the multivariant analysis, only severe CDI [odd ratio (OR) = 0.14, P < 0.05] and inpatient FMT (OR = 0.19, P < 0.05) were each independently inversely related to FMT success. There were 35 (32%) patients younger than 60 years of age, and 14 (40%) of them had a background of inflammatory bowel disease. CONCLUSION: FMT is a safe and effective treatment for CDI, with capsules emerging as a successful and well-tolerated route. Severe CDI is less likely to respond to FMT.

Diagnosis of Cytomegalovirus Infection during Exacerbation of Ulcerative Colitis.

BACKGROUND/AIMS: The role of cytomegalovirus (CMV) reactivation during exacerbations of ulcerative colitis (UC) is yet a matter of debate, and assessment of CMV infection in UC patients remains an ongoing challenge. We aimed to identify associated parameters and compare detection methods for CMV infection during UC exacerbation. METHODS: Clinical, pathological and virological parameters were retrospectively analyzed in all patients hospitalized in our institution for UC exacerbation between January 2009 and April 2015, who underwent full evaluation for CMV infection in colonic tissue by histopathology, immunohistochemistry (IHC) and CMV-PCR. RESULTS: Of 28 patients who underwent full examination for tissue CMV-infection, 13 (46.4%) were found to be positive for CMV. Tissue CMV-PCR was more sensitive for the detection of CMV infection than histopathology and IHC. CMV-positive patients had a statistically higher frequency of recent steroid treatment and fever, with higher mean partial Mayo scores and lower mean albumin levels. There were no significant differences between CMV-positive and CMV-negative patients in terms of age, severity of colitis and disease duration. In a multivariable model, only recent steroid treatment and fever were independently associated with colonic CMV infection. CONCLUSIONS: This study provides a clinical model to detect the presence of CMV infection in patients hospitalized with UC exacerbation, which could direct proper investigation and facilitate timely empirical therapy.

Efficacy and Safety of Vedolizumab for Induction of Remission in Inflammatory Bowel Disease-the Israeli Real-World Experience.

BACKGROUND: Vedolizumab (VDZ) is an anti-integrin monoclonal antibody effective in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to examine the "real world" efficacy and safety of VDZ in a large national patient cohort. METHODS: Patients with inflammatory bowel disease treated with VDZ were prospectively followed for 14 weeks. Patients who completed the induction protocol (week 0/2/6/14) or discontinued the treatment before week 14 for adverse events (AEs) or primary nonresponse were included. The primary outcome was induction of clinical remission at week 14; secondary outcomes included clinical response and corticosteroid-free clinical remission. RESULTS: A total of 204 patients (CD-130, UC-69, inflammatory bowel disease-unclassified-5) from 8 centers in Israel were included. Fifteen (7.4%) of the patients were anti-tumor necrosis factor naive and 46 (35.4%) had a previous surgery. For patients with CD, 69/130 (53.1%) responded to treatment; 45 (34.6%) achieved clinical remission; and 38 (29.2%) achieved corticosteroid-free remission at week 14. Fourteen (10.7%) patients discontinued VDZ before week 14 due to primary nonresponse or AEs. For UC, 32/74 (43.2%) responded to treatment; 20 (28.4%) achieved clinical remission, and 18 (24.3%) achieved corticosteroid-free remission at week 14. Fifteen (20.3%) patients with UC did not complete the induction due to primary nonresponse or AEs. AEs were reported by 29 (14.2%) patients (CD and UC combined), most common being nasopharyngitis and skin eruptions. CONCLUSIONS: In a large real-world Israeli cohort of anti-tumor necrosis factor-experienced patients with inflammatory bowel disease, VDZ was effective and safe in induction of clinical remission and steroid-free clinical remission.

Ameliorating Active Ulcerative Colitis via an Orally Available Toll-Like Receptor-9 Modifier: A Prospective Open-Label, Multicenter Phase II Trial.

BACKGROUND: Treatment of active ulcerative colitis is associated with incomplete efficacy, adverse events, and loss of response. Toll-like receptor-9 mediates innate and adaptive immune response toward intestinal microorganisms. The oral synthetic oligonucleotide toll-like receptor-9 modulator has demonstrated anti-inflammatory properties in colitis murine models and a satisfactory safety profile in humans. AIM: To evaluate the efficacy and safety of BL-7040 (a Toll-like receptor-9 modulator) in patients with moderately active ulcerative colitis. METHODS: Moderately active ulcerative colitis patients were included in this multicenter, open-label phase IIa trial. Concomitant mesalamine and steroids at a stable dose were allowed. Clinical outcome was evaluated using the Mayo score, histology, and mucosal cytokine levels. Side effects were registered. RESULTS: Sixteen out of 22 patients completed a 5-week treatment course and 2-week follow-up. Six patients discontinued the study, three of them due to adverse events. Clinical remission was observed in two patients (12.5 %), and clinical response as well as mucosal healing were achieved in half (50 %) of the patients, while all others remained stable. Furthermore, mucosal neutrophil (p = 0.002) and mucosal interleukin-6 levels (p = 0.046) were significantly reduced in responders compared to non-responders. Toll-like receptor-9 was well tolerated with only one unrelated to study drug serious adverse event (hemoglobin decrease) and 29 mild-to-moderate adverse events. CONCLUSIONS: Oral administration of the Toll-like receptor-9 agonist BL-7040 appeared efficacious, safe and well tolerated in patients with moderately active ulcerative colitis.

Feasibility of Unbiased RNA Profiling of Colorectal Tumors: A Proof of Principle.

Despite recent advances in molecular profiling of colorectal cancer (CRC), as of yet this has not translated into an unbiased molecular liquid biopsy profile which can accurately screen for early CRC. In this study we depict the profile of early stage CRC as well as for advanced adenomas (AA) by combination of current molecular knowledge with microarray technology, using efficient circulating free plasma RNA purification from blood and RNA amplification technologies. We joined literature search with Affymetrix gene chip experimental procedure to draw the circulating free plasma RNA profile of colorectal cancer disease reflected in blood. The RNA panel was tested by two datasets comparing patients with CRC with healthy subjects and patients with AA to healthy subjects. For the CRC patient cohort (28 CRC cases vs. 41 healthy controls), the ROC analysis of the selected biomarker panel generated a sensitivity of 75% and a specificity of 93% for the detection of CRC using 8-gene classification model. For the AA patient cohort (28 subjects vs. 46 healthy controls), a sensitivity of 60% and a specificity of 87% were calculated using a 2-gene classification model. We have identified a panel of 8 plasma RNA markers as a preliminary panel for CRC detection and subset markers suitable for AA detection. Subjected to extensive clinical validation we suggest that this panel represents a feasible approach and a potential strategy for noninvasive early diagnosis, as a first-line screening test for asymptomatic, average-risk population before colonoscopy.