Idiopathic myointimal hyperplasia is a distinct cause of chronic colon ischaemia.

AIM: Colon ischaemia (CI) is most commonly an acute and reversible manifestation of a transient, non-occlusive decrease of blood flow in the colonic microvasculature. Irreversible complications are uncommon and the progression to chronic CI remains controversial. Our objective was to identify cases of chronic CI and assess for distinct clinicopathological features. METHOD: A retrospective review was performed of CI patients having symptom chronicity of ≥ 1 month and ischaemic histology at our institution from 1994 to 2015. Demographic, clinical, endoscopic, radiological, pathological and outcome variables were abstracted. Histological evaluation was performed by two gastrointestinal pathologists. RESULTS: Fifteen patients (n = 9; 67% men) with a median age of 65 years (range 22-88) were identified. The most common presenting symptoms were diarrhoea and abdominal pain (n = 6, 86%; n = 5, 71%, respectively). The typical endoscopic appearance was segmental ulceration of the sigmoid colon (n = 6, 75%). Vascular imaging showed patent mesenteric vessels in all patients. Histopathological evaluation revealed venous intimal hyperplasia consistent with idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) in eight patients; the remainder showed non-specific ulceration and fibrosis. Surgical resection was performed in seven IMHMV patients, resulting in symptom resolution. On re-review of pre-resection biopsies, all IMHMV patients had characteristic changes of hyperplastic, thick-walled, hyalinized vessels in the lamina propria. CONCLUSIONS: IMHMV is a unique histopathological entity causing chronic CI. The small vessel histological changes in IMHMV are distinctive in colonic resections and undetectable by routine vascular imaging. Preoperative diagnosis of IMHMV is possible with endoscopic biopsy and segmental colon resection is curative.

Pseudoachalasia secondary to bariatric surgery.

Secondary achalasia may result from diseases that either infiltrate or compress the lower esophageal sphincter to create an increased high-pressure zone and subsequent esophageal body changes. With bariatric surgery, a potential high-pressure zone is created by a sleeve, band, or bypass just distal to the esophagus. We report four patients who years after a bariatric procedure developed dysphagia followed by esophageal body radiographic and/or manometric features of achalasia. In addition, each of these patients responded symptomatically to endoscopic or surgical therapy either which lowered this high-pressure zone. Furthermore, review of prior cases in the literature suggests this has occurred before. Physicians should be aware of this association but further study is needed on its true prevalence.

Endoscopic diagnosis and treatment of esophageal verrucous squamous cell cancer.

Verrucous squamous cell cancer (VSCC) of the esophagus is a variant of squamous cell carcinoma. This rare entity has been described in only a handful of case reports in the literature. We sought to evaluate the endoscopic features, treatment, and outcomes related to esophageal VSCC. The medical records of all patients with esophageal VSCC seen at our institution from January 1995 to December 2010 were reviewed retrospectively. A total of 11 patients (6 men; mean age 66 years [range 57-75 years]) were identified, with a mean follow up of 4 years (range 0.5-10 years) available in nine patients after diagnosis. About half the patients smoked or consumed alcohol on a regular basis. The median time interval from onset of symptoms to diagnosis of esophageal VSCC was 2.5 years (range 1-20 years), with dysphagia being present in all patients. The majority of tumors (8 of 11) exhibited a white, warty, plaque-like appearance with superimposed Candida at endoscopy, which led solely to a diagnosis of Candida esophagitis on initial presentation. The disease was either extensive (n = 5) throughout the esophagus or localized (n = 6) often by tumor nodules or projections, with the lower third of the esophagus being most commonly involved. Initial pinch biopsies were nondiagnostic in eight (73%) of the patients. Six patients underwent esophagectomy; neoadjuvant chemoradiation therapy was provided in two. In patients treated solely with surgery and who had a preoperative endoscopic ultrasound, the latter tended to overestimate staging of the lesion relative to surgical pathologic staging. Two patients were deemed to be poor operative candidates and received only chemoradiation treatment. One patient with a T2N0 tumor by endoscopic ultrasound staging was managed symptomatically with intermittent endoscopic dilation because of significant comorbidities that precluded surgery and oncologic therapy. There has been no evidence for residual or recurrent neoplastic disease in the eight patients who received treatment with surgery and/or chemoradiation therapy. Five of six patients who underwent surgery have required intermittent endoscopic dilation of anastomotic strictures during follow up. One of the two patients who received only chemoradiation therapy has required periodic endoscopic dilation for radiation-induced esophageal stricture. Two of the nine (22%) patients have died of causes unrelated to VSCC or its treatment at last follow up. In conclusion, a high index of suspicion for esophageal VSCC should be raised by the presence of long-standing symptoms coupled with white, warty esophageal lesions seen on endoscopic evaluation. Candida overgrowth can be expected to confound the diagnosis. Despite the long duration of symptoms, surgical resection typically shows relatively low-grade tumors, consistent with the rare propensity of this variant of esophageal squamous cell carcinoma to metastasize.

Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation.

Velusetrag (TD-5108) is a potent, selective high intrinsic activity serotonin 5-HT(4) receptor agonist. We assessed effects of Velusetrag on gastrointestinal transit and compared its pharmacokinetics in healthy volunteers (HV) and chronic constipation (CC) patients. Sixty HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg Velusetrag (single and 6-day dosing). Primary endpoints were colonic transit (geometric centre at 24 h, GC24) and ascending colon emptying (ACE) T(1/2) after first dose. Secondary endpoints included gastric emptying (GE) T(1/2) and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T(1/2), and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T(1/2) at 15-50 mg. Pharmacokinetics studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of Velusetrag. Stimulation of bowel function after15 mg Velusetrag was similar in CC and controls. There were no serious adverse events; notable adverse events were the predictable gastrointestinal effects such as diarrhoea or altered bowel movements. Velusetrag significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted.

Understanding measurements of intestinal permeability in healthy humans with urine lactulose and mannitol excretion.

Our aim was to understand the information from differential two-sugar excretion (2-SE) in measuring intestinal permeability. In a crossover study in 12 healthy volunteers, we compared urinary excretion ratios of lactulose (L) to mannitol [(M) LMR] after ingestion in liquid formulation (LF) or in delayed-release, methacrylate-coated capsules (CAP). Both formulations were radiolabelled. Urine was collected every 2 h from 0 to 8 h, and from 8 to 24 h. Two hours after LF, gastric residual was 15.9 +/- 6.2% (SEM), and the percentage in colon was 49.6 +/- 7.8%; in 11/12 participants, liquid had entered colon within 2 h. Average CAP arrival time in colon was 5.16 +/- 0.46 h (mode 6 h). After LF, mannitol was extensively absorbed in the first 8 h; lactulose absorption was low throughout the 24 h. After the LF, the LMR (geometric mean, 95% CI per h) in the 0-2 h urine was [0.08 (0.05, 0.11)], which was lower than in 8-24 h urine [0.32 (0.16, 0.46); P < 0.05]. Urine LMRs at 8-24 h were similar after LF or CAP. We concluded that, after LF, sugar excretion in 0-2 h urine may reflect both SI and colon permeability. Colonic permeability is reflected by urine sugar excretion between 6 and 24 h. CAP delivery reduces mannitol excreted at 0-6 h, compared with LF. The 0-5 or 6 h 2-SE urine likely reflects both SI and colon permeability; the higher LMR in the 8-24 h urine relative to 0-2 h urine should be interpreted with caution and does not mean that colon is more permeable than SI.

Measurement of serum 7alpha-hydroxy-4-cholesten-3-one (or 7alphaC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry.

Bile acid malabsorption (BAM) is reported in up to 50% of patients with functional diarrhoea and irritable bowel syndrome with diarrhoea (IBS-D). Serum 7alpha-hydroxy-4-cholesten-3-one (7alphaHCO or 7alphaC4), an indirect measurement of hepatic bile acid synthesis, has been validated as a measurement of BAM relative to the (75)SeHCAT retention test. Our aim was to develop a serum 7alphaC4 assay, normal values, and compare results from healthy controls, patients with ileal Crohn's disease or resection, and patients with IBS-D or IBS with constipation (IBS-C). Stored serum samples were used from adult men and women in the following groups: 111 normal healthy controls, 15 IBS-D, 15 IBS-C, 24 with distal ileal Crohn's disease and 20 with distal ileal resection for Crohn's disease. We adapted a published high pressure liquid chromatography, tandem mass spectrometry (HPLC-MS/MS) assay. The HPLC-MS/MS assay showed good linearity in concentration range 0-200 ng mL(-1), sensitivity (lowest limit of detection 0.04 ng mL(-1)), and high analytical recovery (average 99%, range 93-107%). The 5th to 95th percentile for 111 normal healthy controls was 6-60.7 ng mL(-1). There were significant overall group differences (anovaon ranks, P < 0.001), with significantly higher values for terminal ileal disease or resection. There were significant differences between health and IBS (anova, P = 0.043) with higher mean values in IBS-D relative to controls (rank sum test, P = 0.027). We have established a sensitive non-isotopic assay based on HPLC-MS/MS, determined normal 7alphaC4 values, and identified increased 7alphaC4 in IBS-D and in distal ileal resection and disease. This assay has potential as a non-invasive test for BAM in IBS.

Effect of a kappa-opioid agonist, i.v. JNJ-38488502, on sensation of colonic distensions in healthy male volunteers.

Kappa-opioid receptors are located on visceral pain fibres. JNJ-38488502 is a highly selective tetrapeptide kappa-opioid agonist with little access to the central nervous system and low risk of central nervous system side effects. The aim of the study was to evaluate the effects of i.v. JNJ-38488502 on sensations, including pain, during colonic distension. In a single-centre study, 23 healthy adult males underwent a single-dose, randomized, double-blind crossover study of JNJ-38488502 (0.42 mg kg(-1) i.v. infusion) vs placebo on left colon compliance, sensory thresholds and ratings during standard distensions. One participant could not undergo sensation studies. In the other 22, JNJ-38488502 increased colonic compliance (pressure at half-maximum volume 17.9 +/- 0.8 mmHg) compared to placebo (21.6 +/- 0.9 mmHg, P = 0.007). There was no significant effect on sensory thresholds which, however, were not reached by 44 mmHg in >50% of participants in both treatment phases. There were no significant treatment effects on sensory ratings to distensions at 8, 16, 24, 32 and 36 mmHg above baseline operating pressure. JNJ-38488502 was associated with increased urine output and plasma prolactin, consistent with kappa-opioid receptor activation. This study concluded that i.v. JNJ-38488502 induced kappa-opioid effects, but did not attenuate colonic sensations following random order colonic distension. Further studies of effects on pain sensations in health and disease are required.