Intrarectal injections of botulinum toxin versus placebo for the treatment of urge faecal incontinence in adults (FI-Toxin): a double-blind, multicentre, randomised, controlled phase 3 study.

BACKGROUND: Non-randomised studies assessing intrarectal botulinum toxin type A (BoNTA) injections for faecal incontinence are promising. We aimed to evaluate the efficacy of BoNTA for the treatment of faecal incontinence in a randomised study. METHODS: In this randomised, double-blind, placebo-controlled study, we included adult patients who had at least one urgency or faecal incontinence episode per week for at least 3 months and who had experienced a failure of conservative or surgical treatment from eight French specialist hospital units with the skills to manage patients with faecal incontinence. Patients were randomly assigned (1:1) by a central web form to receive intrarectal submucosal injections of either 200 units of BoNTA (Botox; Allergan, Irvine, CA, USA; BoNTA group) or an equivalent volume of saline (placebo group), stratified by Cleveland Clinic Severity scores (CCS score; ≥12 or <12). Patients, investigators, study site staff, and sponsor personnel were masked to treatment allocation up to the 6-month visit. The primary endpoint was the number of episodes of faecal incontinence and urgency per day assessed using 21-day patient bowel diaries 3 months after the treatment. The primary analysis was performed using a modified intention-to-treat (mITT) approach (ie, in all the randomised patients who had received a treatment) with adjustment for baseline faecal incontinence and urgency episodes. After the final data collection at 6 months after injections, patients were unmasked and offered the BoNTA treatment if they were in the placebo group (rescue therapy) without masking, with an additional 6 months of safety follow-up. This trial is registered with ClinicalTrials.gov, number NCT02414425. FINDINGS: Between Nov 25, 2015, and Nov 25, 2020, we randomly assigned 200 patients to receive either BoNTA (n=100) or placebo (n=100) injections. Due to withdrawals before the injections, 96 patients were included in the BoNTA group and 95 patients were included in the placebo group (mITT analysis). The mean number of faecal incontinence and urgency episodes per day in the BoNTA group decreased from 1·9 (SD 2·2) at baseline to 0·8 (1·8) at 3 months after the injections, and from 1·4 (1·1) to 1·0 (1·0) in the placebo group, with a baseline-adjusted mean group difference at 3 months estimated at -0·51 (95% CI -0·80 to -0·21, p=0·0008). No serious treatment-related adverse events were reported in the trial. The most frequently reported non-serious adverse event (treatment related or not) following the BoNTA or placebo injections was constipation (reported in 68 [40%] of 169 patients who received the BoNTA injections and 38 [40%] of 95 patients who received placebo injections). INTERPRETATION: BoNTA injections are an efficacious treatment for urge faecal incontinence. Further research will define the optimum selection criteria, dose, site of injection, re-injection frequency, and long-term results. FUNDING: General Direction of Healthcare (French Ministry of Health).

The prevalence of proctological symptoms amongst patients who see general practitioners in France.

BACKGROUND: Patients do not often discuss anal symptoms, resulting in late diagnosis of proctological disorders and impacting health. Poor epidemiological knowledge is a contributing factor to this, which can be a significant problem in general medicine. Authors evaluated the role of family doctors in proctological disorders by assessing how many of these are spontaneously diagnosed and how many are diagnosed after questioning the patient. METHODS: Thirty-nine general practitioners completed a targeted questionnaire to assess all patients seen prospectively over 2.5 days of consultations. RESULTS: A total of 1079 questionnaires were completed, 621 (58%) for females and 458 (42%) for males with a median age of 54. Twenty-two patients (2%) were seen primarily for anal symptoms. Following questioning, an anal symptom was found in 153 patients (14%). Symptoms reported were: bleeding (32%), pain (31%), pruritus ani (22%), swelling (22%), oozing (14%), and anal discharge (14%). Physicians' diagnoses were: haemorrhoids, anal fissure, anal discharge, dermatology disease, and functional disorder. In 35% of patients, questioning alone was used to make these diagnoses. Anal incontinence was the only factor associated with referral to a specialist (OR = 5; 95% CI: 1.4-17.8). CONCLUSION: The role of proctology in the general population appears to be significant. In five out of six cases, patients conceal anal symptoms. The high proportion of unexamined patients with anal symptoms is probably multifactorial. Further studies are needed to identify these and put in place the improvement of diagnosis and treatment of anal disorder.

Liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in HFE hemochromatosis.

UNLABELLED: Defects in human hemochromatosis protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential complications from HFE-related hereditary hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Patients (n=18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (± 99) µg/L. Magnetic resonance imaging showed that iron overload was absent in nine patients, mild in one patient with metabolic syndrome, and high (180 µmol/g) in one patient with hereditary spherocytosis discovered after LT. At the end of follow-up, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; P<0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at 1 and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. CONCLUSION: In HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients who received LTs for other liver diseases.

[Haemorrhoidal disease in pregnancy]. / Pathologie hémorroïdaire de la parturiente.

External hemorrhoids thrombosis affects 8% of women during last trimester pregnancy and 20% of women immediately after delivery. Their treatment is medical with local treatment (with corticoid and anesthetic), defecation regulation and paracetamol. NSAID can be used after delivery in absence of breath-feeding. Local excision is not possible in most of the cases because of inflammation. Surgery has to be an exception because medical treatment is sufficient in almost all cases. Anal fissure is the most frequent differential diagnosis, encountered in 15% after all deliveries. Symptoms associate anal pain during and after defecation with blood on toilet paper. The only identified risk factor for hemorrhoids thrombosis (and anal fissure) is dyschesia. We have to think about it.

The positive predictive value of guaiac faecal occult blood test in relation to the number of positive squares in two consecutive rounds of colorectal cancer screening.

The aim of this study was to define the positive predictive values of a positive guaiac faecal occult blood test according to the number of positive squares, in two consecutive rounds of colorectal cancer mass screening in a French region. A total of 4172 colonoscopies were analyzed. Sex, age, number of positive squares, and colonoscopic and histopathologic findings were studied. In the results obtained, 76.6% of positive tests were positive with one or two squares. The number of positive squares was not related to sex, age and rank of participation. The positive predictive value for cancers and adenomas increased significantly with age, sex (male) and number of positive squares from 6.6% (one to two squares) to 27.6% (five to six squares) and from 15.2% to 22.2%, respectively. Cancer was diagnosed 211 times (54.1%) and advanced neoplasia was diagnosed 696 times (65.3%) following positive tests with one to two squares. The TNM stage of cancer increased significantly with the number of positive squares: 85.8% of stages 0-1-2 for one to two positive squares and 66.3% for five to six positive squares (P<0.001). Multivariate analysis showed an increased risk of cancer and advanced neoplasia for male patients and aged persons. The number of positive squares significantly increased the risk of cancer (odds ratio=4.6 for five to six positive squares) and the risk of advanced neoplasia (odds ratio=2.9). Age, sex and number of positive squares were independent predictive factors of positive guaiac faecal occult blood test. The proportion of TNM stages 3-4 was significantly higher in those with five to six positive squares. Performing a complete colonoscopy in every individual having a positive test, especially aged men with a high number of positive squares, should be a priority in any screening programme.

Increased incidence of life-threatening ventricular arrhythmias in implantable defibrillator patients after the World Trade Center attack.

OBJECTIVES: This study was designed to evaluate whether the destruction of the World Trade Center (WTC) on September 11, 2001 (9/11), led to an increased frequency of ventricular arrhythmias among patients fitted with an implantable cardioverter-defibrillator (ICD). BACKGROUND: The WTC attack induced psychological distress. Because ICDs store all serious arrhythmias for months, the attack provided a unique opportunity to compare pre- and post-9/11 frequencies of potentially lethal arrhythmias among ICD patients. METHODS: Two hundred consecutive ICD patients who presented for regularly scheduled follow-up to six affiliated clinics were recruited into this observational study. The electrograms stored in the ICDs for the three months before 9/11 and 13 months thereafter were scrutinized in a blinded manner (relative to date) for all ventricular tachyarrhythmias (tachycardia or fibrillation) triggering ICD therapy. RESULTS: The frequency of tachyarrhythmias increased significantly for the 30 days post-9/11 (p = 0.004) relative to all other months between May 2001 and October 2002. In the 30 days post-9/11, 16 patients (8%) demonstrated tachyarrhythmias, compared with only seven (3.5%) in the preceding 30 days, representing a 2.3-fold increase in risk (95% confidence interval 1.1 to 4.9; p = 0.03). The first arrhythmic event did not occur for three days following 9/11, with events accumulating in a progressive non-clustered pattern. CONCLUSIONS: Ventricular arrhythmias increased by more than twofold among ICD patients following the WTC attack. The delay in onset and the non-clustered pattern of these events differ sharply from effects following other disasters, suggesting that subacute stress may have served to promote this arrhythmogenesis.