Jesper Bach Hansen

Budesonide treatment of collagenous colitis: a randomised, double blind, placebo controlled trial with morphometric analysis

Background: Collagenous colitis is characterised by diarrhoea, lymphocytic inflammation, and a thickened subepithelial collagen layer in the colorectal mucosa. No standard treatment of the disease is established. Aims: To investigate the clinical and histological effect of oral budesonide (Entocort, AstraZeneca) in the treatment of collagenous colitis. Patients: Twenty patients with collagenous colitis (collagen layer >10 μm) and diarrhoea (>4 stools/day and/or stool weight >200 g/day). Methods: A randomised, double blind, placebo controlled trial of budesonide treatment. Patients were randomised to placebo or budesonide for eight weeks. Stool frequency and stool weight were registered before and after treatment. Sigmoidoscopy was performed before and after treatment, and biopsies at fixed locations were obtained for morphometric analysis. Results: Ten patients were randomised to budesonide and 10 to placebo. All 10 patients receiving budesonide had a clinical response compared with two in the placebo group (p<0.001). In the budesonide group, stool weight was reduced from 574 g/day to 200 g/day and stool frequency was reduced from 6.2/day to 1.9/day (p<0.01). The histological inflammation grade in the sigmoid mucosa and the thickness of the collagen layer were significantly reduced. A correlation between the grade of inflammation as well as collagen layer thickness and stool weight was found. No side effects were reported. Eight of 10 patients had relapse of symptoms within eight weeks after stopping treatment. Conclusions: Budesonide is a highly effective and well tolerated treatment of collagenous colitis. There is a high risk of relapse after stopping eight weeks of treatment.

Risk and Patterns of Bacteraemia After Splenectomy: a Population-Based Study

During a period in which vaccination of splenectomized patients has been recommended, we analysed the patterns of severe post-splenectomy infections (i.e. bacteraemia or meningitis) in a defined population-based cohort. A total of 561 patients undergoing splenectomy were identified during 1984-93 in a Danish county, and the 538 eligible patients were followed for 1731 person-years. After splenectomy, 38 patients contracted a bacteraemia, of which 45% occurred within 30 d (i.e. during the postoperative period). No cases of meningitis were found. Among splenectomized patients the incidence rate of bacteraemia was 2.3 per 100 person-years at risk. Beyond the postoperative period we found an 8-fold increased risk of bacteraemia. Enterobacteria were the predominant cause (45%), and only 1 case due to Streptococcus pneumoniae was recorded. 89 (17%) died during the postoperative period, and the overall mortality rate was 18.4 per 100 person-years at risk. In all, 60% of the patients had been given a pneumococcal vaccination, and a Cox proportional hazard regression model showed that vaccination significantly reduced the risk of bacteraemia of any cause beyond the postoperative period. We conclude that splenectomy increases the risk of severe infections, and that vaccinated patients carry a lower risk of infection than non-vaccinated ones.During a period in which vaccination of splenectomized patients has been recommended, we analysed the patterns of severe post-splenectomy infections (i.e. bacteraemia or meningitis) in a defined population-based cohort. A total of 561 patients undergoing splenectomy were identified during 1984-93 in a Danish county, and the 538 eligible patients were followed for 1731 person-years. After splenectomy, 38 patients contracted a bacteraemia, of which 45% occurred within 30 d (i.e. during the postoperative period). No cases of meningitis were found. Among splenectomized patients the incidence rate of bacteraemia was 2.3 per 100 person-years at risk. Beyond the postoperative period we found an 8-fold increased risk of bacteraemia. Enterobacteria were the predominant cause (45%), and only 1 case due to Streptococcus pneumoniae was recorded. 89 (17%) died during the postoperative period, and the overall mortality rate was 18.4 per 100 person-years at risk. In all, 60% of the patients had been given a pneumococcal vaccination, and a Cox proportional hazard regression model showed that vaccination significantly reduced the risk of bacteraemia of any cause beyond the postoperative period. We conclude that splenectomy increases the risk of severe infections, and that vaccinated patients carry a lower risk of infection than non-vaccinated ones.

Long-term budesonide treatment of collagenous colitis: a randomised, double-blind, placebo-controlled trial

Objective: To evaluate the efficacy and safety of long-term budesonide therapy for the maintenance of clinical remission in patients with collagenous colitis. Design: Randomised, placebo-controlled study with a 24-week, blinded follow-up period without any treatment. Setting: Three gastroenterology clinics in Denmark. Patients: Forty-two patients with histologically confirmed collagenous colitis and diarrhoea (more than three stools/day). Interventions: Patients in clinical remission after 6 weeks’ open-label therapy with oral budesonide (Entocort CIR capsules, 9 mg/day) received 24 weeks’ double-blind maintenance therapy with budesonide 6 mg/day or placebo. Thereafter, patients entered the 24-week, blinded follow-up period. Main Outcome Measure: The proportion of patients in clinical remission (three or fewer stools/day) at the end of maintenance therapy. Findings: A total of 34 patients in remission at week 6 were randomly assigned to budesonide 6 mg/day (n  =  17) or placebo (n  =  17). After 24 weeks’ maintenance treatment, the proportions of patients in clinical remission were 76.5% (13 of 17) with budesonide and 12% (2 of 17) with placebo (p<0.001). At 48 weeks (the end of the follow-up period, without any treatment) these values were 23.5% (4 of 17) and 12% (2 of 17), respectively (p = 0.6). The median times to relapse after stopping active treatment (6 plus 24 weeks in the budesonide group; 6 weeks in the placebo group) were 39 and 38 days, respectively. Long-term treatment with budesonide was well tolerated. Conclusions: Long-term maintenance therapy with oral budesonide is efficacious and well tolerated for preventing relapse in patients with collagenous colitis. The risk of relapse after 24 weeks’ maintenance treatment is similar to that observed after 6 weeks’ induction therapy.

Gut pain reactions in man: an experimental investigation using short and long duration transmucosal electrical stimulation.

Abstract Visceral pain is a substantial, clinical problem but unfortunately few experimental models are available to study this phenomenon in man. In the present study we inserted a stimulation catheter 5–10 cm into the ileo‐sigmoidostomy of nine patients. The catheter contained six small, flexible electrodes separated by 4 mm. The gut was stimulated by single burst, repeated burst (five stimuli delivered at 2 Hz), or continuous burst stimuli (4 Hz for 30, 60, 90, and 120 s). The sensation (ST), pain detection (PDT), and pain tolerance (PTT) thresholds to single/repeated burst stimuli were determined. The location/size/sensitivity of referred pain after repeated/continuous stimulation were characterized. The brain potentials to single burst stimuli and to increasing stimulus intensity were measured. ST to single burst stimuli was easy to determine (8 mA) and to reproduce. The patients found it difficult to determine the PDT and PTT to single burst stimuli, however both thresholds were easily determined for repeated burst stimuli. The pain thresholds to single burst stimuli were twice as high as the thresholds to repeated burst stimuli, indicating the importance of central temporal summation for visceral pain. Minor changes in the stimulus location resulted in changes of the referred pain projection site. The words most frequently selected (78%) from the McGill Pain Questionnaire to describe repeated burst stimulations were shooting, pricking, flashing, and boring. The amplitude of the brain potentials increased at increasing stimulus intensity. A stimulus intensity giving an initial pain rating of around 5 on a 0–10 visual analog scale (VAS) was used for continuous stimulation. A general increase of the pain intensity and the area of referred pain was found during this stimulation. It was concluded that electrical stimulation of the human gut provokes pain and especially long sequences of visceral stimuli are adequate to evoke referred pain mimicking pain profiles of pathologic origin.

Eradication of Helicobacter pylori Compared with Long-Term Acid Suppression in Duodenal Ulcer Disease: A Randomized Trial with 2-Year Follow-up

Background: Trials evaluating long-term management of duodenal ulcer disease have mainly been focused on recurrence of ulcers, disregarding effects on dyspeptic and reflux symptoms. Profound acid inhibition with a proton pump inhibitor is the gold standard therapy in acid-related diseases. We aimed to compare the symptomatic effects of eradication therapy with those of long-term omeprazole treatment in a design with periods both with and without acid inhibition. Methods: Patients with active duodenal ulcer were randomized either to omeprazole, 20 mg twice daily until healing, followed by omeprazole, 20 mg/day for 1 year, or to eradication therapy (metronidazole, amoxicillin, and omeprazole for 2 weeks) followed by placebo for 1 year. All patients were followed up passively for an additional year. Clinical controls were performed every 2 months the 1st year (maintenance phase) and every 6 months during the passive follow-up phase. The study was multicentric and double-blind. The primary end-point was discontinuation of treatment, irrespective of reason. Results: Two hundred and seventy-six patients were randomized (139 in the eradication treatment group). In the maintenance phase there were no differences in the reporting of dyspeptic symptoms or in premature withdrawal. In the passive follow-up phase only five patients in the eradication therapy group discontinued owing to relapse of dyspeptic symptoms or ulcer, compared with 51 patients initially randomized to long-term omeprazole. There were no differences in reflux symptoms or in the development of reflux oesophagitis. Conclusions: Eradication therapy and long-term omeprazole are equally effective in controlling dyspeptic symptoms and reflux in duodenal ulcer patients with healed ulcers. One-quarter of the duodenal ulcer patients who start eradication therapy continue to be symptomatic or fail therapy for other reasons over a 2-year period. Eradication therapy does not increase the risk of reflux in ulcer patients.Background: Trials evaluating long-term management of duodenal ulcer disease have mainly been focused on recurrence of ulcers, disregarding effects on dyspeptic and reflux symptoms. Profound acid inhibition with a proton pump inhibitor is the gold standard therapy in acid-related diseases. We aimed to compare the symptomatic effects of eradication therapy with those of long-term omeprazole treatment in a design with periods both with and without acid inhibition. Methods: Patients with active duodenal ulcer were randomized either to omeprazole, 20 mg twice daily until healing, followed by omeprazole, 20 mg/day for 1 year, or to eradication therapy (metronidazole, amoxicillin, and omeprazole for 2 weeks) followed by placebo for 1 year. All patients were followed up passively for an additional year. Clinical controls were performed every 2 months the 1st year (maintenance phase) and every 6 months during the passive follow-up phase. The study was multicentric and double-blind. The primary end-point was disco...

Pain evoked by electrical stimulation of the prepyloric region of the stomach: Cutaneous sensibility changes in the referred pain area

OBJECTIVE: To investigate the pain threshold and the referred pain areas to electrical stimulation of the prepyloric region of the stomach, and the cutaneous sensibility in the referred pain areas.

Risk Factors for Symptom Relapse in Collagenous Colitis After Withdrawal of Short-term Budesonide Therapy

Background:Oral budesonide has been proven effective in short- and long-term treatment of collagenous colitis; however, symptom relapse frequently occurs after drug withdrawal. The aim of this study was to identify the risk factors for symptom relapse in patients with collagenous colitis after withdrawal of short-term budesonide therapy. Methods:One hundred twenty-three patients from 4 randomized controlled studies who achieved clinical remission after short-term treatment with budesonide (9 mg/d) were analyzed, including 40 patients receiving subsequent budesonide maintenance therapy (6 mg/d) for 6 months and 83 patients without active maintenance treatment. Variables available for analysis were age, sex, baseline stool frequency, duration of diarrhea, collagenous band thickness, and lamina propria inflammation. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated by Cox proportional hazard model. Results:The overall symptom relapse rate was 61%. By multivariate analysis, a baseline stool frequency >5 per day (HR, 3.95; 95% CI, 1.08–14.39), history of diarrhea >12 months (HR, 1.77; 95% CI, 1.04–3.03), and the absence of budesonide maintenance therapy (HR, 2.71; 95% CI, 1.37–5.38) were associated with symptom relapse. The time to relapse was shorter in patients with a baseline stool frequency >5 per day (56 versus 199 d, P = 0.024), as in those with history of diarrhea >12 months (56 versus 220 d, P = 0.009). Budesonide maintenance therapy delayed the time to relapse (56 versus 207 d, P = 0.005). Conclusions:Our data demonstrate that a high stool frequency at baseline and a long duration of diarrhea are risk factors for symptom relapse in collagenous colitis, whereas budesonide maintenance therapy is a protective factor against symptom relapse.

Abnormal brain processing in hepatic encephalopathy: evidence of cerebral reorganization?

Background and aim Hepatic encephalopathy (HE) is a severe and frequent complication of liver cirrhosis characterized by abnormal cerebral function. Little is known about the underlying neural mechanisms in HE and human data are sparse. Electrophysiological methods such as evoked brain potentials after somatic stimuli can be combined with inverse modeling of the underlying brain activity. Thereby, information on neuronal dynamics and brain activity can be studied in vivo. The aim of this study was to investigate the sensory brain processing in patients with HE. Patients and methods Twelve patients with minimal or overt HE and 26 healthy volunteers were included in the study. Cerebral sensory processing was investigated as (i) an auditory reaction time task; (ii) visual and somatosensory evoked brain potentials, and (iii) reconstruction of the underlying brain activity. Results Somatosensory evoked potentials were reproducible (all P>0.05), whereas flash evoked potentials were not reproducible (all P<0.05). Compared with healthy volunteers, the patient group had a prolonged reaction time index (P=0.03) along with increasing prolongation of latencies of median nerve evoked potentials (P<0.03). Reconstruction of the underlying brain sources showed a lateral shift in source localization of the P45 (P<0.001) and N60 components (P=0.02). A correlation between the psychometric hepatic encephalopathy score and the dipole shift corresponding to the N60 (P=0.003) component was seen. Conclusion HE patients have evidence of prolonged intracerebral nerve conduction, along with lateralization of brain activity following median nerve stimulation. This possibly represents cortical reorganization and may be important in our understanding of this condition.

Survival of patients with primary liver cancer in central and northern Denmark, 1998–2009

Objective Primary liver cancer (PLC) is a serious disease with high mortality. During the last decade, improvements in the diagnostic procedures and treatment of PLC may have improved survival. However, few updated longitudinal studies examined this issue. In a population-based setting, we studied changes in the prognoses over time. Methods Between 1998 and 2009, we identified all patients with PLC in the central and northern Denmark regions, with a combined population of 1.8 million. We determined age- and period-stratified survival, and computed mortality rate ratios (MRRs) with 95% confidence intervals (CIs), using Cox proportional hazard regression to assess changes over time, while controlling for age and gender. We conducted the analyses for PLC overall and separately for hepatocellular carcinoma (HCC) and cholangiocarcinoma, respectively. Results We included 1064 patients with PLC. Their median age was 69 years (range 17–94 years). The number of patients diagnosed with PLC in the period 2007–2009 was approximately 40% higher than the number in 1998–2000. One-year survival increased from 16% in 1998–2000 to 28% in 2007–2009, corresponding to an adjusted 1-year MRR of 0.65 (95% CI: 0.54–0.79). In patients aged <60 years, we found the most pronounced increase in 1-year survival, from 14% to 49% in women and from 19% to 41% in men. The 3- and 5-year survival in the entire cohort increased from 5% to a predicted 11% and from 2% to a predicted 7% during our study period, respectively. Accordingly, the expected 3- and 5-year adjusted MRRs were 0.68 (95% CI: 0.57–0.82) and 0.68 (95% CI: 0.57–0.81), respectively. One-, 3-, and 5-year survival improved during the study period for both HCC and cholangiocarcinoma. Conclusion PLC survival remains poor in the Danish population, although we observed an increase over the period 1998–2009, particularly in young people.

Grazoprevir, Ruzasvir, and Uprifosbuvir for HCV After NS5A Treatment Failure

People with hepatitis C virus (HCV) infection who have failed treatment with an all‐oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor‐containing regimen. C‐SURGE (PN‐3682‐021) and C‐CREST Part C (PN‐3682‐011 and ‐012) were open‐label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor–containing all‐oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C‐SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24‐week no ribavirin arm and the 16‐week plus ribavirin arm (lost to follow‐up, n = 1), respectively. In C‐CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance‐associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. Conclusion: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor–containing therapy. (Hepatology 2017;66:1794–1804)