Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study.

BACKGROUND: Although treatment of Crohn's disease has improved with development of tumour necrosis factor antagonists, fewer than 50% of patients have sustained benefit. Durable maintenance therapy with orally administered alternative treatments remains an unmet need. We aimed to evaluate the effects of ozanimod, an oral agent selectively targeting sphingosine-1-phosphate receptor subtypes 1 and 5, on endoscopic disease activity in Crohn's disease. METHODS: STEPSTONE was a phase 2, uncontrolled, multicentre trial in adults with moderately to severely active Crohn's disease recruited at 28 hospital and community research centres in Canada, the USA, Hungary, Poland, and Ukraine. All patients began treatment with a 7-day dose escalation (4 days on ozanimod 0·25 mg daily followed by 3 days at 0·5 mg daily). Patients then received ozanimod 1·0 mg oral capsule daily for a further 11 weeks, for a 12-week induction period, followed by a 100-week extension. The primary endpoint was change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline to week 12, as determined by a blinded central reader. Data are reported for the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02531113 and EudraCT, number 2015-002025-19, and is completed. FINDINGS: 69 patients were enrolled between Nov 17, 2015, and Aug 18, 2016. At week 12, the mean change from baseline in SES-CD was -2·2 (SD 6·0); 16 (23·2%, 95% CI 13·9-34·9) patients experienced endoscopic response. A reduction from baseline in Crohn's Disease Activity Index (CDAI) score also was observed (mean change -130·4 [SD 103·9]). Clinical remission (CDAI <150 points) was shown in 27 (39·1%, 95% CI 27·6-51·6) patients and response (CDAI decrease from baseline ≥100) in 39 (56·5%, 95% CI 44·0-68·4) of patients. The mean change from baseline in two-item patient-reported outcome (PRO2, stool frequency, abdominal pain scores) score was -66·1 (SD 65·4). Mean change from baseline in Geboes Histology Activity Score (GHAS) was -5·9 (SD 11·0) and in Robart's Histopathology Index (RHI) -10·6 (25·1). Adverse events were most frequently those attributed to Crohn's disease, most commonly Crohn's disease (flare) in 18 (26%) patients. The most commonly reported serious treatment-related adverse events were Crohn's disease (six [9%]) and abdominal abscess (two [3%]). INTERPRETATION: Endoscopic, histological, and clinical improvements were seen within 12 weeks of initiating ozanimod therapy in patients with moderately to severely active Crohn's disease. Phase 3 placebo-controlled trials have been initiated. FUNDING: Celgene Corporation.

Strategies in the prevention of the formation of postoperative adhesions in digestive surgery: a systematic review of the literature.

BACKGROUND: Postoperative intra-abdominal adhesions after GI surgery constitute a major burden for health care provision globally, causing chronic abdominal symptoms and necessitating repeated surgical intervention. OBJECTIVE: This systematic review examines safety and efficacy data for current anti-adhesion strategies after GI surgery. DATA SOURCES: PubMed, Medline, and Embase databases were searched for randomized control trials and nonrandomized clinical studies of anti-adhesion products from January 1980 to October 2013. STUDY SELECTION: A list of predefined search terms was combined with the Cochrane Highly Sensitive Search Strategy to identify studies. INTERVENTION: The use of an anti-adhesion strategy was investigated. MAIN OUTCOME MEASURES: The primary outcome was the safety profile of anti-adhesion products. Secondary outcomes included the analysis of the reduction in the incidence, extent, and severity of adhesions; incidence of bowel obstruction; quality-of-life data; and oncological outcomes. RESULTS: In total, 24 articles were included in the qualitative analysis: 17 randomized controlled trials and 7 nonrandomized studies, reporting on 5 anti-adhesion products. Data suggest that anti-adhesive products may be used safely; however, hyaluronic acid-based products should not be placed in contact with an anastomosis. The most studied product, a hyaluronic acid/carboxymethylcellulose membrane, reduces the incidence, extent, and severity of adhesions but without strong evidence of prevention of bowel obstruction. LIMITATIONS: The size and quality of available studies varied greatly, reflected by the Jadad and MINORS scores. The majority of studies reported the use of a single product, hyaluronic acid/carboxymethylcellulose membrane. CONCLUSIONS: Limiting adhesion formation after GI surgery is feasible. More evidence is needed regarding the efficacy in reducing chronic abdominal symptoms, repeated operative intervention, and improving quality of life.

Abscess formation mimicking disease progression, in a patient with metastatic renal cell carcinoma during sunitinib treatment.

BACKGROUND: Renal cell carcinoma (RCC) represents approximately 3% of all adult cancers and is more common in males. Systemic treatment for RCC has improved following the introduction of tyrosine kinase inhibitors, such as sunitinib. The molecular targets of sunitinib are receptor tyrosine kinases (RTKs). Moreover, sunitinib has an additional anti-angiogenic effect through its inhibition of the vascular endothelial growth factor receptor activation. CASE PRESENTATION: We present a case of intra-abdominal abscess formation mimicking disease progression, in a patient with metastatic renal cell carcinoma during sunitinib treatment. CONCLUSION: In the advancing era of molecular therapy of solid tumours, sunitinib has demonstrated significant efficacy in the post-cytokine setting treatment of metastatic renal cancer. Concurrently, however, increasing evidence has emerged to indicate that this class of drugs exert profound immunomodulatory effects on T cells and play major roles in immune tumor surveillance.

Intensive care treatment of severe mixed metabolic acidosis.

We report a case of severe metabolic acidosis associated with acute renal failure and septicaemia following treatment with maximal therapeutic doses of metformin and diclofenac. On the second day of intensive care the patient deteriorated with respiratory insufficiency and abdominal pain during continuous renal replacement therapy. A laparoscopy revealed a perforated cholecystitis with abscess formation. The patient regained renal function and recovered. Intake of diclofenac 5 days before this episode could have been the main cause of renal insufficiency and metabolic acidosis in this patient and could also have delayed surgical treatment by masking early clinical signs of perforated cholecystitis. The renal failure may also have caused metformin and lactate to accumulate, contributing to the mixed pattern of metabolic acidosis. This case report describes a mixed organic and non-organic metabolic acidosis associated with acute renal failure, presumably resulting from a combination of drugs and diseases often found in the elderly - metformin for diabetes mellitus and a non-steroidal anti-inflammatory drug for cholecystolithiasis. Acid-base balance and electrolyte changes were rapidly normalized by continuous renal replacement therapy.

Long-term treatment of rectovaginal fistulas in Crohn's disease: response to infliximab in the ACCENT II Study.

BACKGROUND & AIMS: The ACCENT II study (A Crohn's Disease Clinical Trial Evaluating Infiximab in a New Long-term Treatment Regimen in Patients With Fistulizing Crohn's Disease) evaluated the efficacy and safety of infliximab maintenance treatment in patients with fistulizing Crohn's disease. This post hoc analysis was conducted to determine the efficacy and safety of infliximab therapy in women with rectovaginal fistulas. METHODS: All patients received 5 mg/kg infliximab intravenously at weeks 0, 2, and 6. Patients who achieved response at weeks 10 and 14 then were randomized as responders if they had at least 50% of baseline fistulas closed, or as nonresponders, to receive placebo or infliximab 5 mg/kg every 8 weeks through week 54. RESULTS: Of 282 patients in the ACCENT II study, 25 of 138 (18.1%) women had a total of 27 draining rectovaginal fistulas at baseline. After infusions of infliximab at weeks 0, 2, and 6, 60.7% (17 of 28) and 44.8% (13 of 29) of rectovaginal fistulas were closed at weeks 10 and 14, respectively. Among responders, 72.2% (13 of 18) of rectovaginal fistulas were no longer draining at week 14. The duration of rectovaginal fistula closure was longer in the infliximab 5-mg/kg maintenance group (median, 46 wk) than in the placebo group (33 wk). CONCLUSIONS: Infliximab is effective in short-term closure of rectovaginal fistulas and maintenance treatment was more effective than placebo in prolonging rectovaginal fistula closure.

Retroperitoneal abscess after neurolytic celiac plexus block from the anterior approach.

BACKGROUND AND OBJECTIVES: The anterior approach for celiac plexus block has the potential risks of infection, hemorrhage, and fistula formation. We report a case of a patient who developed a retroperitoneal abscess with the formation of a vascular-enteric fistula after a neurolytic celiac plexus block from the anterior approach. CASE REPORT: A 60-year-old female with a history of pain secondary to chronic idiopathic calcifying pancreatitis (VAS 7-8) underwent a subtotal resection of the head of the pancreas with an end-to-side pancreatojejunostomy using a Roux-en-Y loop. Pain continued secondary to chronic pancreatitis. Because of intolerance (vomiting and constipation) of morphine and transdermal fentanyl over a 2-month period, it was decided to perform a neurolytic celiac plexus block using the anterior approach with ultrasound guidance. The patient's pain was completely relieved, enabling withdrawal of oral analgesics. Pain reappeared after 2 years, and the same technique was repeated. Ten days later, she was admitted with diabetic ketoacidosis and lower gastrointestinal bleeding. Computed tomography showed a left paravertebral retroperitoneal abscess; arteriography suggested a fistula between the mesenteric vein and the jejunum. Urgent surgery was undertaken, revealing a leak of the pancreatojejunostomy and a large abscess around the celiac plexus. A distal pancreatectomy and partial resection of the Roux-en-Y loop was performed. The patient was discharged 1 month later in good clinical condition. Because of recurrent pain, she has required repeated neurolytic celiac plexus blocks via a posterior approach without complications. CONCLUSION: The posterior approach for neurolytic celiac plexus block should be considered in particular in patients with previous pancreatic surgery.