Ian Kronborg

Crohn's disease management after intestinal resection: a randomised trial.

BACKGROUND Most patients with Crohns disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohns disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patients study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohns disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohns Colitis Australia, and the National Health and Medical Research Council.

Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression

H. pylori infection accounts for most cases of gastric cancer, but the initiating events remain unclear. The principal H. pylori pathogenicity‐associated CagA protein disrupts intracellular SHP‐2 signalling pathways including those used by the IL‐6 family cytokines, IL‐6 and IL‐11. Imbalanced IL‐6 family cytokine signalling in the gp130757FF mouse model of gastric cancer arising from hyperactivation of oncogenic STAT3 after altered SHP‐2 : ERK1/2 signalling produces dysplastic antral tumours preceded by gastritis and metaplasia. In a cohort of patient gastric biopsies with known H. pylori and CagA status, we investigated whether (i) STAT3 and ERK1/2 activation is altered in H. pylori‐dependent gastritis; (ii) these profiles are more pronounced in CagA+ H. pylori infection; and (iii) the expression of pro‐inflammatory cytokines that activate STAT3 and ERK 1/2 pathways is associated with progression to gastric cancer. IL‐6, IL‐11, and activated STAT3 and ERK1/2 were quantified in antral biopsies from gastritic stomach, metaplastic tissue, and resected gastric cancer tissues. We observed significantly increased STAT3 and ERK1/2 activation (p = 0.001) in H. pylori‐dependent gastritis, which was further enhanced in the presence of CagA+ H. pylori strains. Of known gastric ligands that drive STAT3 activation, IL‐6 expression was increased after H. pylori infection and both IL‐6 and IL‐11 were strongly up‐regulated in the gastric cancer biopsies. This suggests a mechanism by which IL‐11 drives STAT3 activation and proliferation during gastric cancer progression. We addressed this using an in vitro approach, demonstrating that recombinant human IL‐11 activates STAT3 and concomitantly increases proliferation of MKN28 gastric epithelial cells. In summary, we show increased STAT3 and ERK1/2 activation in H. pylori‐dependent gastritis that is likely driven in an IL‐6‐dependent fashion. IL‐11 expression is associated with adenocarcinoma development, but not gastritic lesions, and we identify a novel mechanism for IL‐11 as a potent inducer of proliferation in the human gastric cancer setting. Copyright

Effects of Sulindac and Ibuprofen in Patients With Cirrhosis and Ascites

Nonsteroidal antiinflammatory drugs impair renal function in susceptible patients with cirrhosis and ascites. A new antiinflammatory drug, sulindac, is reported not to affect renal function. To evaluate its renal-sparing mechanism, sulindac was administered for 5 days and ibuprofen for 1 day to 10 patients and paraaminohippurate and inulin clearances, serum and urine eicosanoids, and serum and urine sulindac metabolites were monitored. Ibuprofen reduced renal clearances in the 5 subjects with greatest sodium retention, whereas sulindac had no effect. Plasma concentration of the active sulfide metabolite was markedly increased in liver patients, and this concentration correlated with the inhibition of serum thromboxane (r = 0.75, p = 0.01). The percent inhibition of serum thromboxane with sulindac administration correlated with the inhibition of urinary eicosanoids (r = 0.68-0.81, all p less than 0.02). Ibuprofen was generally a more potent inhibitor of serum and urine eicosanoids. Thus, a major factor in the renal-sparing effect of sulindac appears to be its less potent inhibition of renal and extrarenal cyclooxygenase systems.

Treatment for Hepatitis C Virus Infection among Current Injection Drug Users in Australia

An estimated 210,000 people were living with hepatitis C virus (HCV) infection in Australia at the end of 2001, and the number of people developing cirrhosis was projected to increase 4-fold by 2020. Eighty percent of prevalent and 90% of incident HCV infections are related to injection drug use. Current injection drug use was an exclusion criterion for access to government-funded treatment for HCV infection until May 2001. Despite the removal of this barrier to treatment access for current injection drug users (IDUs), the number of IDUs receiving treatment remains extremely low. Treatment outcomes among IDUs with chronic HCV infection treated at 2 public hospital-based hepatitis clinics are presented. These data demonstrate that IDUs who continue to inject infrequently during treatment for HCV infection can achieve a sustained virological response. Further studies are under way to examine outcomes of treatment for HCV among clients undergoing treatment for drug dependency who have chronic HCV infection and among current IDUs with acute and newly acquired HCV infection.

Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high‐risk patients – a POCER study analysis

Crohns disease recurs in the majority of patients after intestinal resection.

Clinical experience with the treatment of hepatitis C infection in patients on opioid pharmacotherapy

AIMS To evaluate the efficacy, safety and adherence to hepatitis C (HCV) therapy in patients attending tertiary hepatitis clinics who are receiving opioid replacement therapy. DESIGN A non-randomized, open-label study. Participants were treated with pegylated interferon alpha-2a and weight-based ribavirin for 24 weeks (genotype non-1, n = 31) or 48 weeks (genotype 1, n = 22). SETTING Four tertiary hospital hepatitis clinics in Australia. PARTICIPANTS Fifty-three patients with chronic HCV who were receiving opioid replacement therapy. MEASUREMENTS Patients were monitored for virological response, adverse events and adherence. They were also screened for psychiatric illness prior to and throughout the study utilizing two validated instruments: the Mini International Neuropsychiatric Interview (MINI) and Beck Depression Interview (BDI)-II. FINDINGS The overall sustained virological response (SVR) rate was 57% (71% genotype non-1 versus 36% genotype 1), and was similar in active injectors (63%) and non-injectors (53%). The psychological profile of patients based on validated instruments did not change on therapy. The pattern and frequency of adverse effects were comparable to non-opioid replacement patients. Eighty-five per cent of patients were adherent to therapy by 80/80/80 criteria and only two patients who had an end-of-treatment response relapsed, one of whom was not an active injector. CONCLUSIONS Patients on opioid replacement therapy, even if they continue to inject actively, can achieve comparable sustained virological response rates to other populations with pegylated interferon alpha-2a and ribavirin therapy, suffer no excess rates of adverse effects or psychological complications and have good adherence to therapy.

Novel population-based study finding higher than reported hepatocellular carcinoma incidence suggests an updated approach is needed

Hepatocellular carcinoma (HCC) incidence is rising rapidly in many developed countries. Primary epidemiological data have invariably been derived from cancer registries that are heterogeneous in data quality and registration methodology; many registries have not adopted current clinical diagnostic criteria for HCC and still rely on histology for classification. We performed the first population‐based study in Australia using current diagnostic criteria, hypothesizing that HCC incidence may be higher than reported. Incident cases of HCC (defined by American Association for the Study of Liver Diseases diagnostic criteria or histology) were prospectively identified over a 12‐month period (2012‐2013) from the population of Melbourne, Australia. Cases were captured from multiple sources: admissions to any of Melbournes seven tertiary hospitals; attendances at outpatients; and radiology, pathology, and pharmacy services. Our cohort was compared to the Victorian Cancer Registry (VCR) cohort (mandatory notified cases) for the same population and period, and incidence rates were compared for both cohorts. There were 272 incident cases (79% male; median age: 65 years) identified. Cirrhosis was present in 83% of patients, with hepatitis C virus infection (41%), alcohol (39%), and hepatitis B virus infection (22%) the commonest etiologies present. Age‐standardized HCC incidence (per 100,000, Australian Standard Population) was 10.3 (95% confidence interval [CI]: 9.0‐11.7) for males and 2.3 (95% CI: 1.8 to 3.0) for females. The VCR reported significantly lower rates of HCC: 5.3 (95% CI: 4.4 to 6.4) and 1.0 (95% CI: 0.7 to 1.5) per 100,000 males and females respectively (P < 0.0001). Conclusions: HCC incidence in Melbourne is 2‐fold higher than reported by cancer registry data owing to under‐reporting of clinical diagnoses. Adoption of current diagnostic criteria and additional capture sources will improve registry completeness. Chronic viral hepatitis and alcohol remain leading causes of cirrhosis and HCC. (Hepatology 2016;63:1205–1212)

Hepatic macrophage activation predicts clinical decompensation in chronic liver disease

Hepatic macrophages (Kupffer cells) play important roles in inflammation and portal hypertension in patients with chronic liver disease (CLD).1 We recently showed that plasma soluble CD163 (sCD163), a specific marker for macrophage activation, is produced within and released from the liver with a direct relationship to the portal venous pressure gradient.2 ,3 We hypothesised that: (1) sCD163 is elevated in patients with CLD with previous clinical decompensation; and (2) sCD163 is a marker for CLD progression and clinical deterioration. We measured sCD163 in 52 controls and 116 consecutive patients with CLD (89% cirrhosis) caused by chronic hepatitis C (36%), alcohol (30%), non-alcoholic fatty liver disease (11%), chronic hepatitis B (10%); other liver diseases (12%) accounted for the remainder of the cases. Cirrhosis was diagnosed by consistent examination and radiological findings, or by liver biopsy. All controls had no history or clinical examination signs of CLD, and normal liver function tests. They were followed for a median of …

Cardiorespiratory function in stable methadone maintenance treatment (MMT) patients.

Patients in methadone maintenance programmes (MMT) often smoke tobacco and cannabis and many have ongoing illicit drug use. There is therefore potential for these patients to have abnormal cardiorespiratory function; however, few studies address this in stable MMT patients. We assessed resting cardiorespiratory function on 50 stable MMT patients (25 males, 25 females). Forty‐six MMT patients were current tobacco smokers, 19 were current cannabis users and none were currently using opioids other than prescribed methadone. We defined abnormalities of respiratory function as those results outside the 95% confidence interval of reference values for normal subjects adjusted for age, weight, height and sex. Thirty‐one (62%) MMT patients had reduced carbon monoxide transfer factor (D L CO); 17 (34%) had elevated single breath alveolar volume (V A) and 43 (86%) had a reduced D L CO/V A ratio. Six patients (12%) had reduced FEV 1; one (2%) had reduced FVC; and nine (18%) had an obstructive ventilatory defect. Ten (20%) patients had PaCO 2 higher than 45 mmHg and 14 (28%) had alveolar to arterial oxygen gradient (A‐aPO 2) higher than 15 mmHg. CXR, Echocardiography and ECG showed no significant abnormalities. We conclude that stable MMT patients have abnormalities of resting respiratory function which may be due to ongoing tobacco cigarette and current or past cannabis smoking.

Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial

BACKGROUND Despite revised guidelines that no longer exclude people who inject drugs (PWID) from treatment for hepatitis C virus (HCV) infection, many clinicians are reluctant to treat recent PWID. This study aimed to evaluate the efficacy of sofosbuvir and velpatasvir therapy in people with chronic HCV infection and recent injection drug use. METHODS In this open-label, single-arm phase 4 trial (SIMPLIFY), we recruited participants with recent injection drug use (past 6 months) and chronic HCV genotype 1-6 infection from seven countries (19 sites). Participants received oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. Therapy was given in 1-week electronic blister packs to record the time and date of each dose. The primary endpoint was the proportion of patients with sustained virological response 12 weeks after completion of treatment (SVR12; defined as HCV RNA <12 IU/mL), analysed in all patients who received at least one dose. This study is registered with ClinicalTrials.gov, number NCT02336139, and follow-up is ongoing to evaluate the secondary endpoint of HCV reinfection. FINDINGS Between March 29, and Oct 31, 2016, we enrolled 103 participants; 29 (28%) of whom were female, nine (9%) had cirrhosis, 36 (35%) had HCV genotype 1, five (5%) had genotype 2, 60 (58%) had genotype 3, and two (2%) had genotype 4. 61 (59%) participants were receiving opioid substitution therapy during the study, 76 (74%) injected in the past month, and 27 (26%) injected at least daily in the past month. 100 (97%) of 103 participants completed treatment; two people were lost to follow-up and one person died from an overdose. There were no virological failures. 97 (94%, 95% CI 88-98) of 103 people achieved SVR12. Three participants with an end-of-treatment response did not have a SVR; two were lost to follow-up and one had reinfection. Drug use before and during treatment did not affect SVR12. Treatment-related adverse events were seen in 48 (47%) patients (one grade 3, no grade 4). Seven (7%) patients had at least one serious adverse event; only one such event (rhabdomyolysis, resolved) was possibly related to the therapy. One case of HCV reinfection was observed. INTERPRETATION HCV treatment should be offered to PWID, irrespective of ongoing drug use. Recent injection drug use should not be used as a reason to withhold reimbursement of HCV therapy. FUNDING Gilead Sciences.