Irritable Bowel Syndrome Patient Experience: A Survey of Patient-Reported Symptoms by Irritable Bowel Syndrome Subtype and Impact on Quality of Life.

Objectives: Irritable bowel syndrome (IBS) is a chronic, debilitating, functional gastrointestinal disorder with symptoms of abdominal pain, bloating, and altered bowel behaviours of constipation (IBS-C), diarrhea (IBS-D), or a mixture of both (IBS-M). There is limited information published on the impact of symptoms on everyday life in the Canadian population. Methods: An online survey was conducted with individuals diagnosed with IBS to capture the severity and frequency of patient-reported symptoms, including impact on productivity, quality of life, healthcare utilization, treatment access, and corresponding symptom relief. Responses from the three subtypes of IBS were categorized to illustrate differences among these. Results: There were 2,470 qualified respondents (filtered from 2,981, which included nonspecific IBS). IBS-M was the most common subtype, at 44 percent. Most individuals from all three IBS subtypes reported experiencing moderate to severe abdominal pain (63-70 percent) and bloating (59-75 percent) over the previous 3 months. Persons living with IBS-C reported severe bloating (32 percent), straining (72 percent), and tenesmus (78 percent) whereas those with IBS-D experienced severe urgency (63 percent) and incontinence (29 percent). Symptoms interfered in daily life, sometimes in 46 percent and often in 23 percent of respondents. Patients reported mood and anxiety disorders as common comorbidities with IBS (mood disorders: 30-34 percent; anxiety disorders: 25-30 percent). Conclusions: This study focuses on the differences among the IBS subtypes. IBS impacts productivity and healthcare utilization, which requires further investigation on approaches to improve treatment. The frequency and severity of symptoms in IBS are high and only a few respondents reported that their symptoms are under control.

High Dose "HDR-Like" Prostate SBRT: PSA 10-Year Results From a Mature, Multi-Institutional Clinical Trial.

Purpose/Objectives: Although ample intermediate-term prostate stereotactic body radiotherapy (SBRT) outcomes have been reported, 10-year results remain relatively sparse. Materials/Methods: Eighteen institutions enrolled 259 low- and intermediate-risk patients. Median follow-up is 5.5 years, with 66 patients followed ≥ 10 years. This SBRT regimen specifically emulated an existing HDR brachytherapy dose schedule and isodose morphology, prescribed to 38 Gy/4 fractions, delivered daily by robotic SBRT, mandating > 150% dose escalation in the peripheral zone. Androgen deprivation therapy was not allowed, and a hydrogel spacer was not available at that time. Results: Median pre-SBRT PSA 5.12 ng/mL decreased to 0.1 ng/mL by 3.5 years, with further decrease to a nadir of < 0.1 ng/mL by 7 years, maintained through 10 years. Ten-year freedom from biochemical recurrence measured 100% for low-risk, 84.3% for favorable intermediate risk (FIR), and 68.4% for unfavorable intermediate (UIR) cases. Multivariable analysis revealed that the UIR group bifurcated into two distinct prognostic subgroups. Those so classified by having Gleason score 4 + 3 and/or clinical stage T2 (versus T1b/T1c) had a significantly poorer 10 year freedom from biochemical recurrence rate, 54.8% if either or both factors were present, while UIR patients without these specific factors had a 94.4% 10-year freedom from biochemical recurrence rate. The cumulative incidence of grade 2 GU toxicity modestly increased over time - 16.3% at 5 years increased to 19.2% at 10 years-- while the incidence of grade 3+ GU and GI toxicity remained low and stable to 10 years - 2.6% and 0%, respectively. The grade 2 GI toxicity incidence also remained low and stable to 10 years - 4.1% with no further events after year 5. Conclusion: This HDR-like SBRT regimen prescribing 38 Gy/4 fractions but delivering much higher intraprostatic doses on a daily basis is safe and effective. This treatment achieves a median PSA nadir of <0.1 ng/mL and provides high long-term disease control rates without ADT except for a subgroup of unfavorable intermediate-risk patients.

Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression.

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.

Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins.

Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.

Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors.

The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.

Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit.

Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.

Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors.

A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).

GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family.

Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.

Design and Synthesis of a Highly Selective and In Vivo-Capable Inhibitor of the Second Bromodomain of the Bromodomain and Extra Terminal Domain Family of Proteins.

Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of in vitro phenotypic assays and in vivo pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical in vitro and in vivo characterization.

The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.

The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, 20 (GSK620) and 56 (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.

Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.

The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.

BILATERAL UVEAL METASTASES SECONDARY TO PROSTATE ADENOCARCINOMA.

PURPOSE: To report a patient with bilateral uveal metastases secondary to previously quiescent prostate adenocarcinoma with a 22-month follow-up. METHODS: Retrospective chart review was performed for this patient. RESULTS: Androgen deprivation therapy and external beam radiation therapy were shown to manage ocular symptoms in a sixty-nine-year-old man previously diagnosed with adenocarcinoma of the prostate. CONCLUSION: Uveal metastases can be the first site of systemic metastasis even long after initial diagnosis and treatment of prostate adenocarcinoma; the 17 years between this patient's treatment for adenocarcinoma and commencement of his ocular symptoms is the longest interval reported. Hormonal therapy, in conjunction with radiation therapy, can successfully reduce tumor burden in these patients and improve visual symptoms over time.

Patient and Dosimetric Predictors of Genitourinary and Bowel Quality of Life After Prostate SBRT: Secondary Analysis of a Multi-institutional Trial.

PURPOSE: Stereotactic body radiation therapy (SBRT) is an emerging option for localized prostate cancer. However, there are no standard dosimetric guidelines, and normal tissue tolerances for extreme hypofractionation are not well defined. We analyzed dosimetric correlations with patient-reported urinary and bowel quality of life (QOL) on a prospective trial. METHODS AND MATERIALS: Patients with low- or intermediate-risk prostate cancer from 18 institutions were enrolled on a phase 2 trial from 2007 to 2012 and treated using robotic SBRT to 38 Gy in 4 fractions on consecutive days. No androgen deprivation was used. Patients received simulation with Foley catheter for urethral delineation. The clinical target volume was prostate (low-risk patients) or prostate plus 1 cm of proximal seminal vesicles (intermediate-risk patients). Multiple dosimetric measures for urethra, bladder, and rectum were prospectively recorded. QOL using the Expanded Prostate Cancer Index Composite was assessed before and after treatment at protocol-specific time points. Linear regression was used to assess factors associated with QOL at 1 month and 2 years. RESULTS: A total of 259 patients were enrolled. QOL data were available for 98%, 96%, and 84% at baseline, 1 month, and 2 years, respectively. Median age was 69 years. Prior transurethral resection of the prostate and clinical target volume size were associated with 2-year urinary incontinence. There was a trend toward worse 2-year obstruction/irritation in older patients on multivariable analysis. Bladder and urethral doses were not associated with either 1-month or 2-year urinary QOL. In contrast, rectum maximum dose was associated with both 1-month and 2-year bowel QOL. At 2 years, the proportion with moderate or big overall bowel problems (as defined by Expanded Prostate Cancer Index Composite-26) was significantly higher in patients with rectum maximum dose greater than versus less than the median 37.4 Gy (11% vs 2%, Fisher's exact test P = .008). CONCLUSIONS: These results provide novel data that contribute to a better understanding of patient and dosimetric factors associated with adverse QOL effects from prostate SBRT.

Phase 2 Multicenter Trial of Heterogeneous-dosing Stereotactic Body Radiotherapy for Low- and Intermediate-risk Prostate Cancer: 5-year Outcomes.

BACKGROUND: Stereotactic body radiation therapy is an emerging treatment for prostate cancer (PC), with potential biological and oncologic advantages. A well-established radiation dosing schedule (38Gy in 4 fractions) has shown excellent long-term efficacy in high-dose-rate (HDR) brachytherapy. OBJECTIVE: To report 5-yr efficacy, toxicity, and quality-of-life (QOL) outcomes of a novel 4-d SBRT regimen. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm prospective phase 2 trial involving 259 patients with low- or intermediate-risk PC treated at 18 US centers from December 2007 to February 2012. The median follow-up was 5yr (interquartile range 37-85mo). INTERVENTION: SBRT with 38Gy in four fractions; radiation plans mimicked HDR brachytherapy dosimetry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured freedom from biochemical recurrence (BCR) and assessed toxicities using the Common Terminology Criteria for Adverse Events v3.0 and QOL using the Expanded Prostate Cancer Index Composite. RESULTS AND LIMITATIONS: The 5-yr BCR-free rates were 100% and 88.5% for patients with low- and intermediate-risk PC, respectively. The cumulative 5-yr grade 2, 3, and 4 toxicity rates were 12.4%, 1.9%, and 0.4% for urinary, and 3.4%, 0%, and 0% for gastrointestinal toxicities, respectively. The median baseline prostate-specific antigen (PSA) level of 5.12ng/ml decreased to 0.1ng/ml by ≥42mo. QOL scores decreased at 1mo but returned to baseline by 6mo, with a later decline (≥24mo) in the urinary continence domain (pad use was 2% at baseline and 10% at 5yr), and lower sexual potency over time. Comparative outcomes versus other types of radiotherapy are difficult because the trial was not randomized. CONCLUSIONS: This regimen yields a high rate of BCR-free survival, with a very low median PSA nadir suggesting prostate ablation. For properly selected patients with low- or intermediate-risk PC who choose SBRT, this treatment regimen is effective. PATIENT SUMMARY: This potent four-treatment stereotactic body radiotherapy regimen appears to be effective for patients with early prostate cancer.

Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses.

FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines.

Clinical and endoscopic significance of bowel-wall thickening reported on abdominal computed tomographies in symptomatic patients with no history of gastrointestinal disease.

BACKGROUND: Bowel-wall thickening (BWT) is a commonly reported finding on diagnostic abdominal pelvic computed tomographies (CT) in patients with no history of gastroenterologic disease. The significance of this nonspecific finding is not clear. METHODS: Medical records from the Vancouver General Hospital were reviewed from October 27, 1999, to October 27, 2009. The initial search yielded 5696 cases, of which 76 cases met the inclusion criteria for review. Inclusion criteria were the following: age older than 18 years, symptoms without a diagnosis of gastrointestinal disease before CT, the reported finding of terminal ileal and/or colonic BWT, colonoscopy after CT, and/or microbiologic investigations. Exclusion criteria included known gastrointestinal disease before CT. The primary objective was to determine if BWT could be associated with a significant endoscopic pathology. The secondary objective was to determine whether the pattern of abnormality on the CT was associated with a specific endoscopic finding. RESULTS: A total of 76 patients met the inclusion criteria of our study. Of those, 76% had various identifiable pathologies on colonoscopy. Only 24% had normal colonoscopic findings. Inflammatory bowel disease (IBD) and infectious colitis were the most common causes of BWT. A report of "skip lesions" on the CT (5%) was always associated with IBD. "Pancolitis" reported on the CT (11%) was associated with endoscopic findings of IBD in 25% of cases, infection in 50% of cases, and normal findings in 25% of cases. The report of "stranding" (36%) on CT in the presence of BWT was associated with many non-neoplastic endoscopic pathologic processes, including infectious colitis (22%), IBD (19%), and ischemia (15%), but also was associated with normal endoscopic findings in 26% of the cases. "Lymphadenopathy" was reported in 17% of the CTs and was associated with infectious colitis (30%), IBD (38%), or neoplastic processes (15%) but also normal endoscopic findings in 15%. CONCLUSION: Symptomatic patients who are found to have nonspecific BWT on CT should undergo definitive endoscopic investigation because the majority will have significant gastroenterologic disease, and only a minority will have a normal colonoscopy.

The utility of pharmacokinetic-pharmacodynamic modeling in the discovery and optimization of selective S1P(1) agonists.

Sphingosine-1-phosphate (S1P(1)) receptor agonists such as Fingolimod (FTY-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. This class of compound act by inducing peripheral lymphopenia. Using an integrated pharmacokinetic/pharmacodynamic (PK-PD) approach based on an in vivo rat model, novel S1P(1) agonists were identified with a predicted more rapid rate of reversibility of lymphocyte reduction in human compared to Fingolimod. The in vivo potency of 15 compounds based on PK-PD modelling of the rat lymphocyte reduction model was correlated with in vitro measures of potency at the S1P(1) receptor using ß arrestin recruitment and G-protein signalling. A structurally novel S1P(1) agonist was identified and predictions of human pharmacokinetics and clinical dose are presented.

What is chronic constipation? Definition and diagnosis.

Although chronic constipation is a common complaint, there are no ideal biological markers for its diagnosis. Diagnosis rests on individual patient perception or clinical criteria developed by expert consensus. Investigation options are multiple but often not necessary. When selected, investigations are directed at confirming the absence of a primary underlying disease, differentiating or defining an alteration in colonic motility or identifying an anorectal evacuation disorder.

Gastric polyps in patients with portal hypertension.

OBJECTIVES: Gastric hyperplastic polyps are usually associated with chronic gastritis including Helicobacter pylori gastritis and postantrectomy stomachs. Here, we report on a series of 12 patients with portal hypertension secondary to liver cirrhosis, who were found to have a unique histological type of gastric polyp on endoscopy. METHODS: Retrospective chart review of 12 patients with portal hypertension, who presented with histologically diagnosed gastric hyperplastic polyps. These polyps were reviewed and compared with hyperplastic polyps from 21 patients who did not have portal hypertension. RESULTS: The endoscopic appearances of portal hypertension-associated polyps varied considerably, with sizes ranging up to 18 mm. They were sessile or pedunculated, singular or multiple, found in the antrum or body of the stomach, and endoscopically appeared to be typical hyperplastic polyps. Histopathological examination, however, showed mucosal hyperplasia and extensive vascular proliferation and granulation tissue formation. CONCLUSION: The unique histological appearance of gastric hyperplastic polyps in patients with portal hypertension polyps is described. The exact pathogenetic mechanism of polyp formation is unclear although it seems possible that the underlying cause is mucosal injury that is vascular in nature rather than being secondary to surface inflammation. Although there is an emerging evidence of the neoplastic potential of usual hyperplastic polyps, the natural history of portal hypertension-associated polyps is unknown. Identification and management of portal hypertension-associated gastric polyps present a particular dilemma, as these patients often have coagulopathies and vascular ectasias. Therefore, the natural history and endoscopic features of gastric polyps arising in portal hypertensive patients warrants further exploration.