Eran Goldin

Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial

BACKGROUNDnComplex perianal fistulas in Crohns disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohns disease.nnnMETHODSnWe did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (≥18 years) with Crohns disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579.nnnFINDINGSn212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15·2%, 97·5% CI 0·2-30·3; p=0·024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15·8%, 0·5-31·2; p=0·021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine).nnnINTERPRETATIONnCx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohns disease who did not respond to conventional or biological treatments, or both.nnnFUNDINGnTiGenix.

Colonic substance P levels are increased in ulcerative colitis and decreased in chronic severe constipation

Substance P content was determined by radioimmunoassay in colonic mucosa from 24 patients with chronic severe constipation, 16 with active ulcerative colitis, and 28 normal controls. In patients with chronic severe constipation, the mean concentration of substance P (19.9±8.2 pg/mg) was significantly lower than in normal subjects (71±18 pg/mg). In patients with ulcerative colitis, colonic substance P concentration in inflamed mucosa (170±46 pg/mg) was significantly higher than its levels in normal subjects. Substance P may therefore have a role in the pathogenesis of clinical conditions associated with diarrhea and constipation.

Mutant KRAS is a druggable target for pancreatic cancer

Significance Pancreatic cancer is still one of the major challenges in clinical oncology. Mutant KRAS is a driving oncogene in the majority of human pancreatic cancer cases. We have made an effort to meet this challenge by developing a therapeutic platform for local and prolonged delivery of siRNA. Our results show that the siRNA targeted against KRAS mutations with a local prolonged release system knocks down KRAS expression in vitro and in vivo, leading to an antitumor effect. Our report describes an applicable and efficient delivery method of siRNA that overcomes the major obstacles of toxicity and organ accessibility. Notably our approach enabled the conversion of KRAS from a nondruggable to a potentially druggable cancer target. Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial–mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.

Relationships between hypoglycaemia and gastric emptying abnormalities in insulin-treated diabetic patients1

Abstractu2002 We hypothesize that hypoglycaemia in insulin‐treated diabetic patients may result from gastric emptying abnormalities causing insulin and food absorption mismatching. We tested gastric emptying in insulin‐treated diabetic patients with unexplained hypoglycaemia and without dyspepsia and in diabetic patients without hypoglycaemia, prospectively. Thirty‐one diabetic patients with unexplained hypoglycaemic events within 2u2003h of insulin injection and 18 insulin‐treated diabetic patients without hypoglycaemic events underwent gastric emptying breath tests, glycaemic control and autonomic nerve function. Gastric emptying tests were abnormal in 26 (83.9%) and in four (22.2%) patients with and without hypoglycaemia, respectively (Pu2003<u20030.001). Gastric emptying was significantly slower in hypoglycaemic diabetic patients (t1/2 139.9u2003±u200374.1 vs 77.8u2003±u200323.3 and tlag 95.8u2003±u200380.3 vs 32.84u2003±u200316.95u2003min, Pu2003<u20030.001 for both comparisons; t‐tests). A significant association between hypoglycaemic patients and abnormal values of t1/2 and tlag was found (Pu2003<u20030.001). Gastric emptying abnormalities were more frequent in hypoglycaemic patients. We suggest gastric emptying tests for diabetic patients with unexplained hypoglycaemic events.

Cost effectiveness of mass screening for coeliac disease is determined by time-delay to diagnosis and quality of life on a gluten-free diet

Aliment Pharmacol Theru200231, 901–910

Role of Endogenous Gastric Prostanoids in the Pathogenesis and Therapy of Duodenal Ulcer

Synthesis of prostaglandin E2 and 6-keto prostaglandin F1 alpha by cultured antral and fundic gastric mucosa obtained from 86 patients with active duodenal ulcer who were not receiving medication was 50% lower (p less than 0.01) than their respective synthesis by cultured gastric mucosa in normal subjects. Antral and fundic prostanoid synthesis in patients receiving chronic therapy with nonsteroidal antiinflammatory drugs was almost completely inhibited. The decreased synthesis of antral and fundic prostaglandin E2 and 6-keto prostaglandin F1 alpha in duodenal ulcer patients was not affected following ulcer healing achieved after 4 wk of therapy with placebo, arbacet, misoprostol, sucralfate, and pirenzepine. In contrast, following 4 wk of therapy with ranitidine, both antral and fundic prostaglandin E2 synthesis were significantly increased when compared with their respective synthesis before therapy. These results confirm that gastric prostanoid synthesis is decreased in patients with active duodenal ulcer and in subjects treated with nonsteroidal antiinflammatory drugs, suggesting that decreased endogenous prostanoid synthesis may contribute to the pathogenesis of mucosal damage. The induction of endogenous prostanoids by ranitidine may contribute to its therapeutic effect.

Effects of guided imagery with relaxation training on anxiety and quality of life among patients with inflammatory bowel disease.

Background: Inflammatory Bowel Disease (IBD) impacts quality of life (QoL). Psychological factors influence the course of the disease and should be targeted for intervention. Methods: Our study was a prospective, randomised control trial. Fifty-six outpatients were randomly chosen and allocated to a treatment group or a waiting-list control group. Treatment group patients attended three relaxation-training sessions and received an audio disc for home practice. Evaluations performed pre and post-treatment: state anxiety was assessed with the State-Trait Anxiety Inventory, QoL with the IBD Questionnaire. The Visual Analogue Scale assessed pain, depression, stress and mood. Patients completed a symptom monitoring diary. The control groups symptoms were monitored without study-related treatment. Results: Thirty-nine subjects completed the study and were included in the data analysis. Following the relaxation-training intervention, the treatment groups (nu2009=u200918) measured results showed a statistically significant improvement as compared to the control group (nu2009=u200921) (time by treatment interaction): anxiety levels decreased (pu2009<u20090.01), QoL and mood improved (pu2009<u20090.05), while levels of pain and stress decreased (pu2009<u20090.01). Conclusions: Findings indicate IBD patients may benefit from relaxation training in their holistic care. New studies as well as further investigation of the subject are warranted.

Long-Term Results of “Chemical Sphincterotomy” for Chronic Anal Fissure: A Prospective Study

IntroductionPharmacologic anal sphincter relaxants promote fissure healing; however, their effect is transient and the risk of late recurrence remains uncertain.MethodsFrom August 1997 to August 2002, patients with chronic anal fissure attending our outpatient clinic were treated with a protocol that included: topical isosorbide dinitrate, 2.5xa0mg, or nifedipine, 0.2 percent t.i.d., or the combination of both. Botulinum toxin 20 units was injected to the internal anal sphincter to those who failed. All the patients were contacted and interviewed during November to December 2002.ResultsFollow-up was a median of 47.43 ± 13 (range, 4.7–60) months. A total of 455 patients completed the study; 323 patients (71 percent) healed at follow-up ending: 170 of the healed patients had one or more recurrences that responded to further treatment (37.4 percent), whereas 153 patients (33.6 percent) healed and had no recurrences. One hundred thirty-two patients (29 percent) did not heal and were referred to lateral sphincterotomy. Long intervals between symptoms appearance and treatment initiation decreased healing and increased recurrence rates (P = 0.03 and 0.01 respectively).ConclusionsTopical treatment is effective for patients with chronic anal fissure, at short-term and long-term periods. Because for many patients it is not a definitive treatment, it can be offered to those who are ready to receive repeated treatments. Longer intervals between symptom appearance and treatment initiation negatively affects fissure healing and recurrence rate.

Prophylactic administration of topical glutamine enhances the capability of the rat colon to resist inflammatory damage

Glutamine is an important nutrient for the GI tract and has been shown to exert a protective effect on the bowel. Nonetheless, in the context of IBD, data demonstrating a therapeutic role for glutamine has been inconclusive. IBD is associated with oxidative stress caused by reactive oxygen species. We aimed to investigate the effect of topical glutamine administration in rats before or after induction of colitis by trinitrobenzenosulfonic acid. In study I glutamine enemas were given beginning 2 days before or on the same day of induction of colitis. Inflammation severity was assessed by macroscopic and microscopic score and tissue myeloperoxidase activity. In study II glutamine enemas were given for 3 days without induction of colitis: mitotic index and colonic crypt length were measured, as well as water-soluble low molecular weight antioxidants and energy-rich phosphate levels (by HPLC). Results showed that glutamine significantly decreased indexes of inflammation when administered before induction of colitis. Glutamine caused an increase in the mitotic index and the levels of water-soluble low molecular weight antioxidants and energy-rich phosphates. We conclude that glutamine exerts a beneficial effect only when administered before induction of colitis, by increasing the resistance of the colonic tissue to inflammatory injury. This effect is probably mediated by increasing the antioxidant capacity and energy level of the tissue.

Effect of substance P on Rat gastrointestinal transit

Thein vivo effect of substance P and related peptide analogs on gastrointestinal transit in unanesthetized rats was studied. Fasted male rats were given intragastrically 0.5 ml of a powdered charcoal (BaSo4·H2O) meal and were concomitantly injected intraperitoneally with 8 Μg/kg of substance P or a related peptide. In control rats, the percentage of small intestine traversed by the meal 15 min after feeding was 44.9±1.4 (N = 12). Substance P, [Glu6]SP6–11, [pGlu6, gPhe6, mGly9]SP6–11 and [pGlu5,N-MePhe8,N-MeGly9SP6–11, significantly accelerated intestinal transit: 59.5±3.1% (N=7); 66.0±3.8% (N=14), 66.8±2.4% (N=25), and 58.4±4.4% (N=4), respectively. Concomitant injection of [pGlu6SP6–11 and BOC-Phe-Phe-Gly-NHOH, an inhibitor of enzyme degradation at a dose of 800 Μg/kg lowered by 10-fold the dose of [pGlu6]SP6–11 needed to induce the same degree of intestinal transit acceleration. These results indicate that in rats, substance P and related peptides accelerate gastrointestinal transit.