Primary Sclerosing Cholangitis-Associated Pouchitis: A Distinct Clinical Phenotype.

BACKGROUND & AIMS: Patients with primary sclerosing cholangitis (PSC) commonly undergo ileal pouch-anal anastomosis (IPAA) for medically-refractory ulcerative colitis (UC) or colorectal dysplasia. Pouchitis develops more frequently in patients with PSC, potentially leading to increased morbidity. We aimed to assess clinical characteristics and treatment outcomes for pouchitis in patients with PSC compared to a matched, non-PSC cohort. METHODS: All patients with PSC who underwent IPAA and were diagnosed with pouchitis (PSC-pouchitis) were identified. A matched cohort composed of non-PSC patients who underwent IPAA for UC and subsequently developed pouchitis (UC-pouchitis) was developed. Relevant demographic, clinical, endoscopic, histologic, and treatment data were collected and compared between groups. RESULTS: Of those with PSC-pouchitis (n=182), 53.9% and 46.1% underwent IPAA for medically-refractory disease and dysplasia, respectively, compared to 88.7% and 11.3% in the UC-pouchitis group (P < .001). Patients with PSC-pouchitis were more likely to develop chronic pouchitis (68.1% vs 34.1%; P < .001), have moderate-to-severe pouch inflammation (54.9% vs 32.4%; P < .001), and prepouch ileitis (34.1% vs 11.5%; P < .001) compared to UC-pouchitis. Of those with PSC-pouchitis, 50.6% and 17.6% developed chronic antibiotic-dependent or antibiotic-refractory pouchitis, respectively, compared to 25.8% and 7.7% with UC-pouchitis. There was no difference in treatment response between the two groups with use of thiopurines, anti-tumor necrosis factor agents, and newer biologics. CONCLUSIONS: PSC-associated pouchitis presents with a unique clinical phenotype, characterized by increased risk of chronic pouchitis, moderate-to-severe pouch inflammation, prepouch ileitis, and less response to conventional antimicrobial therapy.

An Update on the Medical Management of Inflammatory Pouch Complications.

Total proctocolectomy with ileal pouch-anal anastomosis is the surgical procedure of choice for patients with medically-refractory ulcerative colitis or ulcerative colitis with associated dysplasia. Although most patients after ileal pouch-anal anastomosis experience good functional outcomes, a number of complications may develop. Of the long-term complications, pouchitis is most common. Although most respond to antibiotic treatment, some patients develop chronic pouchitis, leading to substantial morbidity and occasionally pouch failure. In patients with pouchitis who are not responsive to conventional antimicrobial therapy, secondary causes of chronic pouchitis need to be considered, including Crohn's disease of the pouch. In recent years, more literature has become available regarding the medical management of chronic pouchitis and Crohn's disease of the pouch, including the use of newer biologic agents. We herein provide a concise review on inflammatory complications involving the ileal pouch, including a focused approach to diagnosis and medical management.

De Novo Colitis Associated With Rituximab in 21 Patients at a Tertiary Center.

Rituximab, a monoclonal antibody directed against the CD20 antigen on B lymphocytes, is commonly used in the treatment of hematologic malignancies and rheumatologic disorders.1,2 It acts to rapidly deplete the B lymphocyte population through multiple mechanisms, leading to dysregulation of the immune system.3 Rituximab has been associated with numerous adverse gastrointestinal effects including diarrhea and bowel perforation, and recent reports have associated rituximab with the development of de novo inflammatory bowel disease (IBD).4,5 To our knowledge, there have been no reports of microscopic colitis (MC) associated with rituximab therapy. We aimed to identify patients with rituximab-associated colitis, and to better characterize the clinical features and disease course of these patients.

A Comprehensive Approach to Pouch Disorders.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure of choice for patients with medically refractory ulcerative colitis (UC) or indeterminate colitis, UC with colonic dysplasia or neoplasia, and familial adenomatous polyposis. In general, patients experience good function outcomes and quality of life with an IPAA. Although pouchitis is the most well-recognized and frequent complication after IPAA, a number of additional inflammatory, postsurgical, structural, neoplastic, and functional complications may occur, resulting in pouch dysfunction. We herein provide a comprehensive review of pouch function and an approach to diagnosis and management of pouch complications.

Dual Inhibition of Bruton's Tyrosine Kinase and Phosphoinositide-3-Kinase p110δ as a Therapeutic Approach to Treat Non-Hodgkin's B Cell Malignancies.

Although new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance. Early clinical trials have tested this approach by dosing two drugs in combination in NHL patients. We discovered a single molecule, MDVN1003 (1-(5-amino-2,3-dihydro-1H-inden-2-yl)-3-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), that inhibits Bruton's tyrosine kinase and phosphatidylinositol-3-kinase δ, two proteins regulated by the B cell receptor that drive the growth of many NHLs. In this report, we show that this dual inhibitor prevents the activation of B cells and inhibits the phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two downstream mediators that are important for this process. Additionally, MDVN1003 induces cell death in a B cell lymphoma cell line but not in an irrelevant erythroblast cell line. Importantly, we found that this orally bioavailable dual inhibitor reduced tumor growth in a B cell lymphoma xenograft model more effectively than either ibrutinib or idelalisib. Taken together, these results suggest that dual inhibition of these two key pathways by a single molecule could be a viable approach for treatment of NHL patients.

Discovery of pyrazolopyrimidine derivatives as novel inhibitors of ataxia telangiectasia and rad3 related protein (ATR).

The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K.

Clinical implications of serial versus isolated biliary fluorescence in situ hybridization (FISH) polysomy in primary sclerosing cholangitis.

BACKGROUND: Cholangiocarcinoma (CCA) is a leading cause of death in patients with primary sclerosing cholangitis (PSC). Biliary polysomy detected by fluorescence in situ hybridization (FISH) helps to identify patients with early CCA, but not all PSC patients with polysomy develop CCA. Here, we examined the features and clinical outcomes of PSC patients with serial versus isolated polysomy. METHODS: All patients with PSC who underwent ≥1 endoscopic retrograde cholangiography (ERC) with FISH testing at Mayo Clinic, Rochester from 2008-2011 were identified. Patients diagnosed with CCA at the time of initial polysomy were excluded. Serial polysomy was defined as polysomy on ≥2 ERCs; isolated polysomy was defined as polysomy once followed by all nonpolysomy results. The primary outcome was the diagnosis of CCA. RESULTS: Twenty-seven patients with polysomy and ≥1 subsequent ERC with FISH were identified. Of these, 11 (40.7%) had serial polysomy and 16 (59.3%) had isolated polysomy. CCA was more likely to be diagnosed in patients with serial versus isolated polysomy (36.4% vs. 6.3%; p = .046). Overall, four patients (36.4%) with serial polysomy and three (18.8%) with isolated polysomy underwent liver transplantation (LT), with time to LT being significantly shorter for the former (14.0 vs. 65.4 months; p = .0003). CONCLUSIONS: Biliary polysomy reverted in ≥50% of patients with PSC; this group appears to be at decreased risk of CCA compared to those with serial polysomy. Nevertheless, both groups should be followed closely, and those with serial polysomy may benefit from early LT evaluation.

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ.

The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.

Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors.

While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR-HDAC6 inhibitors it should be possible to target patients who don't respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC50=0.0356µM and AR binding IC50=<0.03µM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics.

Pouchitis Is a Common Complication in Patients With Familial Adenomatous Polyposis Following Ileal Pouch-Anal Anastomosis.

BACKGROUND & AIMS: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure most commonly selected for patients with familial adenomatous polyposis (FAP) or ulcerative colitis that is refractive to medical treatment. Pouchitis is the most common complication in patients with ulcerative colitis after IPAA, but is thought to rarely occur in patients with FAP. We investigated the frequency of pouchitis and other pouch-related complications in patients with FAP after IPAA. METHODS: We performed a retrospective cohort study of all patients with FAP who underwent IPAA at a single tertiary institution from 1992 through 2015 (n = 113). Patients were identified using International Classification of Diseases-9 diagnostic and current procedural terminology codes. We obtained relevant demographic and clinical data from patients' electronic medical records. The frequencies of pouchitis and pouch-related complications were determined. RESULTS: Twenty-five patients (22.1%) developed pouchitis (mean time to pouchitis, 4.1 years) and 88 did not (77.9%). Patients with pouchitis showed a trend toward developing late (>90 days after IPAA) pouch-related complications (56.0% of patients with pouchitis developed late complications, compared with 36.4% without). In patients who developed pouchitis, the disease course was acute in 72.0% and chronic in 28.0%. Of those treated, 69.6% responded to antibiotics, 13.0% became dependent on antibiotics, and 13.0% developed antibiotic resistance. CONCLUSIONS: Pouchitis is more prevalent in patients with FAP than previously believed. Although pouchitis seems to occur later in patients with FAP than in patients with ulcerative colitis, and have a milder course, it should be considered a common complication among patients with FAP following IPAA.

Bioactivation of sitaxentan in liver microsomes, hepatocytes, and expressed human P450s with characterization of the glutathione conjugate by liquid chromatography tandem mass spectrometry.

Sitaxentan is a selective endothelin-A receptor antagonist that was marketed as Thelin in several European countries and Canada for pulmonary arterial hypertension. Sitaxentan was undergoing further clinical trials in the United States but due to four deaths and one case of liver transplantation from severe liver toxicity that appeared to be idiosyncratic in nature, it was withdrawn worldwide in December, 2010. Sitaxentan contains a 1,3-benzodioxole ring that undergoes enzymatic demethyleneation to an ortho-catechol metabolite that can further oxidize to a reactive ortho-quinone metabolite. Here, we report the detection and mass spectral characterization of a glutathione conjugate of this sitaxentan quinone reactive metabolite that was trapped in vitro using mouse, rat, dog, and human liver microsomes supplemented with NADPH and glutathione and that was also observed in rat and human hepatocytes. Using human liver microsomes, we also demonstrated that P450 3A4 undergoes time-dependent inhibition. Density functional calculations on the catechol metabolite of sitaxentan indicated that the reaction leading to the quinone was thermodynamically favorable with an enthalpy change of -6.3 kcal/mol. Using density functional methodology, we modeled the attack of glutathione on the quinone with an S-methyl thiolate anion which allowed us to predict, based on the difference in transition state energies, that the 2-position on the phenyl ring was more likely than the 5-position as the site of glutathione conjugation. Overall, our results demonstrated that sitaxentan is capable of facile formation of a reactive ortho-quinone metabolite capable of reacting with glutathione and may rationalize the idiosyncratic nature of the hepatotoxicity that led to its withdrawal.