Vitamin D supplementation in cutaneous malignant melanoma outcome (ViDMe): a randomized controlled trial.

BACKGROUND: Previous studies have investigated the protective effect of vitamin D serum levels, at diagnosis and during the follow-up period after treatment, on melanoma outcome. In the present study we assess whether vitamin D supplementation, in the follow-up period after diagnosis and surgical resection of the primary tumor, has a protective effect on relapse of cutaneous malignant melanoma and whether this protective effect correlates with vitamin D levels in serum and Vitamin D Receptor immunoreactivity in the primary tumor. METHODS/DESIGN: This study is a multicenter randomized double blind placebo- controlled phase III trial. Patients between the age of 18 and 80 years diagnosed and treated surgically for a melanoma stage IB-III are eligible for randomization in a 1:1 ratio to active treatment or placebo. The study drug is taken each month and consists of either 100,000 International Unit cholecalciferol or arachidis oleum raffinatum used as a placebo. The primary endpoint is relapse free survival. The secondary endpoints are 25 hydroxyvitamin D3 serum levels at diagnosis and at 6 month intervals, melanoma subtype, melanoma site and stage of melanoma at diagnosis according to the 2009 American Joint Committee on Cancer melanoma staging and classification. At randomization a bloodsample is taken for DNA analysis. The study is approved by the local Ethics Committees. DISCUSSION: If we can confirm our hypothesis that vitamin D supplementation after removal of the tumor has a protective effect on relapse of cutaneous malignant melanoma we may reduce the burden of CMM at several levels. Patients, diagnosed with melanoma may have a better clinical outcome and improved quality of life. There will be a decrease in health care costs related to treatment of metastatic disease and there will be a decrease in loss of professional years, which will markedly reduce the economic burden of the disease. TRIAL REGISTRATION: Clinical Trial.gov, NCT01748448 , 05/12/2012.

Effect of baclofen on gastric acid pocket in subjects with gastroesophageal reflux disease symptoms.

Postprandial gastroesophageal reflux (PGER) in the distal esophagus (DE) is associated with a gastric juice 'acid pocket' (AP). Baclofen reduces AP extension into the DE in healthy volunteers, in part through increased lower esophageal sphincter (LES) pressure. We aimed to verify whether baclofen also affects postprandial AP location and extent in gastroesophageal reflux disease (GERD) patients. Thirteen treatment-naive heartburn-prevalent GERD patients underwent two AP studies, after pretreatment with baclofen 40 mg or placebo 30 minutes preprandially. We performed pH-probe stepwise pull-throughs (PT) (1 cm/min, LES -10 to +5 cm) before and every 30 minutes from 30 minutes before up to 150 minutes after a test meal. After the meal, both after placebo and baclofen, gastric pH significantly dropped at 30, 60, 90 minutes postprandially (P: nadir pHs of 3.9 ± 0.6, 2.3 ± 0.6, 2.1 ± 0.4; B: nadir pHs of 2.5 ± 0.4, 2.8 ± 0.4, 2.5 ± 0.3; all P < 0.05). After placebo, LES pressure decreased at 60, 90 and 120 minutes postprandially (32.7 ± 6.1 vs. 24.5 ± 3.1, 27.3 ± 5.9, 27.3 ± 6.0 mmHg; analysis of variance [ANOVA], P = 0.037), but this was prevented by baclofen (25.4 ± 3.4 vs. 29.4 ± 2, 32.2 ± 1.4, 35.5 ± 1.7 mmHg, ANOVA, P = not significant (NS)). Baclofen did not significantly decrease the postprandial AP extent above the LES but prevented the postprandial increase in transient lower esophageal sphincter relaxations (TLESRs) (preprandial vs. postprandial, placebo: 1.1 ± 0.3 vs. 3.7 ± 0.7, P < 0.05; baclofen: 1.4 ± 0.4 vs. 2 ± 0.5, P = NS). In GERD patients, baclofen significantly increases postprandial LES pressure, prevents the increase TLESRs but, unlike in healthy volunteers, does not affect AP extension into the DE.

Effect of baclofen on the acid pocket at the gastroesophageal junction.

Previous studies established that a pocket of highly acidic gastric juice is present postprandially at the gastroesophageal junction in man. The GABA-B agonist baclofen inhibits postprandial reflux events through its effects on the lower esophageal sphincter (LES). The aim of the current study was to investigate whether baclofen would affect the location and the extent of the postprandial acid pocket in healthy volunteers. Twelve healthy volunteers underwent acid pocket studies on two different occasions, at least 1 week apart. LES position was determined preprandially with pull-through manometry. Dual pH electrode and manometry probe stepwise pull-through (1 cm/minute, LES-10 to +5 cm) was performed at 30-minute intervals for 150 minutes, with administration of placebo or baclofen 40 mg after the first and ingestion of a liquid meal after the second pull-through. After placebo, a significant drop in intragastric gastric pH was present at the gastroesophageal junction after the meal, reflecting the acid pocket, and this was associated with a drop in LES pressure. Baclofen did not affect the presence of the acid pocket, but prevented the postprandial drop in LES pressure, and the extent of the acid pocket above the upper margin of the manometrically located LES was significantly decreased by baclofen (1.6 ± 0.7 vs. 0.3 ± 0.4 cm at 60 minutes, 2.2 ± 0.6 vs. 0.2 ± 0.6 at 90 minutes, and 1.5 ± 0.5 vs. 0.7 ± 0.7 cm at 120 minutes, all P < 0.05). Baclofen does not alter the intragastric acid pocket, but limits its extension into the distal esophagus, probably through an increase in postprandial LES pressure.

Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers.

There are limited data concerning the effects of 5-HT(1A) receptor activation on esophageal motility. Sumatriptan, a 5-HT(1A) receptor agonist, was recently reported to enhance esophageal peristalsis after intravenous administration. Buspirone, an orally available 5-HT(1A) receptor agonist, was shown to modulate gastroduodenal motor function. Our aim was to evaluate the effect of buspirone on esophageal motility of healthy volunteers. On two separate visits, 20 healthy volunteers aged 21-29 years (nine women) underwent esophageal manometry before and 10, 30, and 60 minutes after the administration of buspirone 20-mg or placebo capsule, according to a double-blind crossover design. At each time point, we compared buspirone and placebo effects on: resting pressure of the lower esophageal sphincter (LES); residual pressure and duration of LES relaxation; amplitude, duration, and onset velocity of esophageal body contractions, during 10 swallows of 5 mL of water. Significant analysis of variance differences (P < 0.05) are presented as mean ± standard deviation. Buspirone significantly increased mean distal esophageal wave amplitude (151 vs. 87 mmHg, P < 0.05) and duration (6.1 vs. 4.2 seconds, P < 0.05). Similarly, buspirone significantly increased mean LES resting pressure (26 vs. 21 mmHg, P < 0.05) and mean residual LES pressure (7.9 vs. 2 mmHg, P < 0.05), whereas reduced mean LES relaxation duration (7.2 vs. 8.0 seconds, P < 0.05) and mean distal onset velocity (7.6 vs. 14.7 cm/second, P < 0.05). Buspirone enhances esophageal peristalsis and LES function in healthy volunteers. Further study is warranted on the effects of buspirone on esophageal function and symptoms in patients with ineffective esophageal motility.

The symptoms of varicose veins: difficult to determine and difficult to study.

OBJECTIVES: To investigate the activities which may exacerbate symptoms in patients with varicose veins. METHODS: Questionnaires sent to patients before clinics and at least six months later. RESULTS: Both questionnaires were returned by 149 of 203 patients (74%) but only 124 contained adequate data for comparison--55 from patients who had surgical treatment and 69 who had no surgery. At initial presentation, worsening of discomfort attributed to varicose veins was common during (58%) or after (48%) standing and in hot weather (44%), but less when sitting with the feet down (31%), and after (31%) or when walking (19%). Surgery significantly reduced the total number of symptoms reported by patients at follow-up (p<0.02). However, none of the symptoms reported during specific activities was significantly lessened by surgery compared with no treatment--possibly because the attrition of patients during the study resulted in small numbers for analysis. CONCLUSIONS: Symptoms are a common indication for treating varicose veins and it is therefore important to be sure that they are due to the veins, rather than other causes. This report highlights traditional and logical questions which may help to identify symptoms caused by varicose veins but illustrates the difficulty of validating them.

Severely impaired gastric accommodation is a hallmark of post-Nissen functional dyspepsia symptoms.

BACKGROUND: Laparoscopic Nissen fundoplication is a commonly performed antireflux surgery, after which reflux symptoms are well controlled, however, complications such as inability to belch or dyspeptic symptoms (mimicking those of functional dyspepsia [FD]) might occur. The aim of the study was to prospectively evaluate symptom pattern and underlying pathophysiological mechanisms in patients with post-Nissen dyspepsia. METHODS: Twenty-four patients (12 f, mean age 44.5±2.8 years) with post-Nissen dyspepsia symptoms, five patients (3 f, mean age 38.8±3.2 years) with post-Nissen dysphagia symptoms and 14 pre-fundoplication patients (3 f, mean age 42.1±2.5 years) were evaluated. Patients filled out a Rome II-based dyspepsia symptom severity score, performed a gastric emptying test, and a gastric barostat study was used to evaluate the function of the proximal stomach. KEY RESULTS: Upper abdominal bloating scores were higher in post-Nissen dyspepsia patients (P=.016) and symptoms of postprandial distress syndrome (PDS) were more present in post-Nissen dyspepsia patients compared to the other two groups (P=.07). Weight loss was significantly higher in the post-Nissen groups compared to the pre-fundoplication (P=.02). Gastric emptying rates were similar in the three groups. Gastric accommodation (GA) was significantly impaired in the post-Nissen dyspepsia group (dyspepsia -30[-86-83] vs dysphagia 163[148-203] vs pre-fundoplication 147[75-174] mL, P=.004) and the prevalence of patients with impaired GA was higher in the post-Nissen group (P=.007). Postprandial fullness was more prevalent in patients with impaired GA compared to those with normal GA (P=.01). CONCLUSIONS AND INTERFERENCES: Patients with post-Nissen dyspepsia show a symptom pattern similar to that in FD patients with PDS, and the main underlying mechanism seems to be impaired gastric accommodation to a meal.

Spontaneous life-threatening hemobilia during acute liver failure successfully treated with transarterial embolization.

A 28-year-old patient admitted with jaundice, vomiting and deteriorating coagulopathy was diagnosed with acute liver failure. After listing for urgent transplantation, he developed Boerhaave's syndrome and massive hemobilia, two life-threatening complications. Massive hemobilia secondary to a fistula between the right hepatic artery and the right bile duct occurred several days after transjugular biopsy and was controlled with fluid resuscitation, transfusion and arterial embolization. Two days later he was transplanted successfully, and is currently doing well after more than 72 months. Aggressive treatment of potentially reversible complications during acute liver failure whilst awaiting transplantation is mandatory to allow survival of these patients.

Review article: the pathophysiology, differential diagnosis and management of rumination syndrome.

BACKGROUND: Rumination syndrome, characterised by the effortless, often repetitive, regurgitation of recently ingested food into the mouth, was originally described in children and in the developmentally disabled. It is now well-recognised that rumination syndrome occurs in patients of all ages and cognitive abilities. AIM: To review a scholarly review on our current understanding of the rumination syndrome. METHODS: The review was conducted on the basis of a medline search to identify relevant publications pertaining to the pathophysiology, clinical diagnosis and management of rumination syndrome. RESULTS: The Rome III consensus established diagnostic criteria for rumination syndrome in adults, children and infants. A typical history can be highly suggestive but oesophageal (high resolution) manometry/impedance with ingestion of a meal may help to distinguish rumination syndrome from other belching/regurgitation disorders. The pathophysiology is incompletely understood, but involves a rise in intra-gastric pressure, generated by a voluntary, but often unintentional, contraction of the abdominal wall musculature, at a time of low pressure in the lower oesophageal sphincter, causing retrograde movement of gastric contents into the oesophagus. To date, controlled trials in the treatment rumination syndrome are lacking. The mainstay of treatment for rumination syndrome is explanation and behavioural treatment which consists of habit reversal techniques that compete with the urge to regurgitate. Chewing gum, prokinetics, baclofen and even antireflux surgery have been proposed as adjunctive therapies, but high quality studies are generally lacking. CONCLUSIONS: Rumination is an under-recognised condition with incompletely understood pathophysiology. Behavioural therapy seems effective, but controlled treatment trials are lacking.

Increasing body weight enhances prevalence and proximal extent of reflux in GERD patients 'on' and 'off' PPI therapy.

BACKGROUND: Increased body weight is associated with higher intragastric pressure. Proximal extent of reflux is a determinant of symptoms in patients with gastro-esophageal reflux disease (GERD). We aimed to investigate the association between body mass index (BMI) and abdominal circumference on the incidence and proximal extent of reflux. METHODS: A total of 95 patients [37 men, age 51(16-82) years] with typical and/or atypical GERD symptoms underwent 24 h impedance-pH monitoring. Forty-nine patients were studied 'off' and 46 'on' proton pump inhibitors (PPI) treatment. Reflux was classified as acid (pH < 4) or weakly acidic (pH 4-7). Proximal extent was defined as the number of reflux events reaching ≥15 cm above the lower esophageal sphincter. Body mass index and abdominal circumference (cm) were assessed. KEY RESULTS: In patients 'off' PPI, there was a correlation between BMI and esophageal acid exposure (ρ = 0.53, P < 0.001), volume exposure (ρ = 0.48, P < 0.001), total number of reflux events (ρ = 0.47, P < 0.001) and number of acid reflux events (ρ = 0.49, P < 0.001). In patients 'on' PPI there was a correlation between BMI and esophageal acid exposure (ρ = 0.32, P = 0.03), volume exposure (ρ = 0.46, P < 0.01) and total number of reflux events (ρ = 0.33, P = 0.03). Similar correlations were found between abdominal circumference and reflux. A correlation between BMI and proximal extent of reflux was present in patients 'off' PPI (ρ = 0.32, P = 0.03). In patients 'on' PPI, we found a correlation between abdominal circumference and proximal extent (ρ = 0.31, P = 0.03). CONCLUSIONS & INFERENCES: Body mass index and abdominal circumference may contribute to GER and its proximal extent, in patients 'on and 'off' PPI. Further studies investigating the role of weight reduction in the control of GERD symptoms are warranted.

Effect of rimonabant on oesophageal motor function in man.

BACKGROUND: Cannabinoid type 1 (CB1) receptors are implicated in the control of transient lower oesophageal sphincter relaxations (TLESRs) in animals. In man, it is unclear whether CB1 receptors are involved in the control of oesophageal function. AIM: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. METHODS: Twelve healthy volunteers underwent two oesophageal manometry studies with administration of wet swallows and a meal after 3 days' premedication with placebo or rimonabant 20 mg. RESULTS: Rimonabant did not significantly alter preprandial LES pressure (21.1±4.0 vs. 17.3±3.0 mmHg, N.S.), but postprandial LES pressures were significantly enhanced (9.9±1.9 vs.17.1±2.7 mmHg in the first and 10.0±1.4 vs. 19.3±3.6 mmHg in the second postprandial hour, both P<0.05). Swallow-induced relaxations and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contractions at all time points (e.g. 5.0±0.3 vs. 8.0±0.3s preprandially and 5.0±0.2 vs. 8.2±0.3s at 60 min postprandially, both P<0.01). The number of postprandial TLESRs (3.1±0.5 vs. 1.2±0.5, P<0.05) and acid reflux episodes (1.4±0.2 vs. 0.3±0.1, P<0.05) were significantly lower after rimonabant. CONCLUSION: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and decreases TLESRs in healthy subjects.

Modulation of the postprandial acid and bile pockets at the gastro-oesophageal junction by drugs that affect gastric motility.

BACKGROUND: Previous studies have established the presence of a postprandial acid pocket at the gastro-oesophageal junction. AIMS: To investigate whether altering gastric motility would affect the location and the extent of postprandial acid pockets in healthy volunteers and also to study the presence of bile in this pocket. METHODS: A total of 16 healthy volunteers underwent pH and Bilitec probe stepwise pull-through to measure regional differences in pH and bile absorbance before and 10, 30 and 50 min after a liquid meal. At the start of the meal, saline, erythromycin or sumatriptan was administered. RESULTS: After saline, ingestion of a meal induced an acid pocket, with a mean pH drop of 2.26 (compared to 0.25 before the meal, P < 0.05) and a nadir pH of 2.71. The acid pocket persisted 30 and 50 min postprandially (pH drops 1.59 and 1.68 and nadir pH 3.17 and 2.52 respectively). Compared with saline, erythromycin significantly suppressed the pH drop and nadir pH (on average 0.66 and 3.4 at 10 min; comparable patterns at 30 and 50 min). After sumatriptan a significantly lower nadir pH was observed at 30 and 50 min (respectively 2.02 and 1.74, P < 0.05 compared with saline). A postprandial bile pocket was noted in 50% of pull-throughs after saline, compared to 78% after erythromycin and 31% after sumatriptan. CONCLUSIONS: The presence of a bile pocket in a subset of the subjects confirms the heterogeneity of postprandial intragastric contents. Erythromycin disrupts the acid pocket but increases the presence of bile, while sumatriptan has opposite effects.

The effects of itopride on oesophageal motility and lower oesophageal sphincter function in man.

BACKGROUND: Itopride is a new prokinetic agent that combines antidopaminergic and cholinesterase inhibitory actions. Previous studies suggested that itopride improves heartburn in functional dyspepsia, and decreases oesophageal acid exposure in gastro-oesophageal reflux disease. It remains unclear whether this effect is due to effects of itopride on the lower oesophageal sphincter (LES). AIMS: To study the effects of itopride on fasting and postprandial LES function in healthy subjects. METHODS: Twelve healthy volunteers (five men; 32.6 ± 2.0 years) underwent three oesophageal sleeve manometry studies after 3 days premedication with itopride 50 mg, itopride 100 mg or placebo t.d.s. Drug was administered after 30 min and a standardized meal was administered after 90 min, with measurements continuing to 120 min postprandially. Throughout the study, 10 wet swallows were administered at 30-min intervals, and gastrointestinal symptoms were scored on 100 mm visual analogue scales at 15-min intervals. RESULTS: Lower oesophageal sphincter resting pressures, swallow-induced relaxations and the amplitude or duration of peristaltic contractions were not altered by both doses of itopride, at all time points. Itopride pre-treatment inhibited the meal-induced rise of transient LES relaxations (TLESRs). CONCLUSIONS: Itopride inhibits TLESRs without significantly affecting oesophageal peristaltic function or LES pressure. These observations support further studies with itopride in gastro-oesophageal reflux disease.