Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab in early HER2-positive breast cancer in the APHINITY trial.

BACKGROUND: Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial. PATIENTS AND METHODS: Left ventricular ejection fraction (LVEF) ≥ 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as ≥10% from baseline and to <50%), or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF, or CEs confirmed by the cardiac advisory board. RESULTS: The safety analysis population consisted of 4769 patients. With 74 months of median follow-up, CEs were observed in 159 patients (3.3%): 83 (3.5%) in P + T and 76 (3.2%) in T arms, respectively. Most CEs occurred during anti-HER2 therapy (123; 77.4%) and were asymptomatic or mildly symptomatic decreases in LVEF (133; 83.6%). There were two cardiac deaths in each arm (0.1%). Cardiac risk factors indicated were age > 65 years, body mass index ≥ 25 kg/m2, baseline LVEF between 55% and <60%, and use of an anthracycline-containing chemotherapy regimen. Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 patients (81.9%). CONCLUSIONS: Dual blockade with P + T does not increase the risk of CEs compared with T alone. The use of anthracycline-based chemotherapy increases the risk of a CE; hence, non-anthracycline chemotherapy may be considered, particularly in patients with cardiovascular risk factors.

Diagnostic of hepatic fibrosis with the XL probe of the Fibroscan versus biopsies in patients candidates to bariatric surgery.

BACKGROUND AND AIMS: The risks of the histological evaluation for metabolic liver disease in severe obese subjects led to the development of the Fibroscan® device. The main objective of our study is to evaluate the diagnostic performance of XL probe for the measurement of hepatic fibrosis compared to histological examination, in obese subjects operated from bariatric surgery. METHODS: We included patients free from chronic liver diseases. Liver measurement and controlled attenuation parameter (CAP) were carried out using the Fibroscan®. Liver biopsies were performed during bariatric surgery and evaluated by two pathologists. Correlation between vibration-controlled transient elastography (VCTE) and fibrosis stage was assessed using the Kendall correlation coefficient. Diagnosis performance was assessed using receiver-operating-characteristic curve analysis together with its 95% confidence interval. Cut-off value maximizing the Youden index was computed together with specificity, sensitivity, positive and negative predictive values. RESULTS: The average age and body mass index were 41 years and 43 kg/m2, respectively (n = 108). Forty-one percent of patients presented fibrosis on the histological results. The Kendall correlation coefficient between fibrosis stage and liver stiffness measurement (LSM) was κ = 0.33, p<10-5. ROC analysis for the detection of fibrosis indicated the following values: 0.70 [0.60-0.79] for F≥1, 0.83 [0.72-0.92] for F≥2, 0.90 [0.83-0.97] for F≥3. Optimal cut-offs maximizing the Youden index were 7.0 kPa for F≥1, 8.1 kPa for F≥2 and 8.7 kPa for F≥3. CONCLUSION: Fibroscan® appears to be reliable for detection of significant and severe fibrosis in severe obese patients such as candidates for bariatric surgery. CLINICAL TRIAL NUMBER: NCT03548597.

Olmesartan-associated enteropathy: results of a national survey.

BACKGROUND: Recently, a new enteropathy has been described: olmesartan-associated enteropathy. However, the association has been questioned: a phase 3 trial and a cohort study found no association between gastrointestinal events and olmesartan. AIM: To collect French cases of sartan-associated enteropathy to describe further this entity, confirm or refute causality, and determine if the association exists with other sartans. METHODS: French gastroenterologists were invited to report cases of sartan-associated enteropathy and collect clinical, biological and histological data. Patients with diarrhoea and histological duodenal abnormalities were included. RESULTS: Thirty-six patients with olmesartan-associated enteropathy were reported, including 32 with villous atrophy and four without. There was only one patient with irbesartan-associated enteropathy. None of the patients died. Patients with villous atrophy had diarrhoea, vomiting, renal failure, hypokalaemia, body weight loss and hypoalbuminaemia. Thirty-one patients were hospitalised; four required intensive care. Anti-transglutaminase and anti-enterocyte antibodies were negative; anti-nuclear antibodies were positive (9/11). Endoscopic duodenal biopsies showed villous atrophy (32/32) and polyclonal intra-epithelial CD3+CD8+ lymphocytosis (11/11). Exactly, 14/15 patients responded to steroids and/or immunosuppressants, prescribed because of suspected autoimmune enteropathy. Ten olmesartan interruptions were followed by reintroductions before steroids or immunosuppressants. Interruptions were followed by remissions (9/10), but reintroductions were followed by relapses (9/9). Twenty-nine patients were in remission since olmesartan interruption, including 26 without immunosuppressants. Patients with normal villi had similar clinical characteristics, but mild histological abnormalities (intra-epithelial lymphocytosis and lamina propria lymphocytic infiltration). CONCLUSIONS: Olmesartan causes a severe and immune-mediated enteropathy, with or without villous atrophy. Enteropathy associated with other sartans seems to be very rare.

Quality control of colonoscopy procedures: a prospective validated method for the evaluation of professional practices applicable to all endoscopic units.

OBJECTIVES: To produce valid information, an evaluation of professional practices has to assess the quality of all practices before, during and after the procedure under study. Several auditing techniques have been proposed for colonoscopy. The purpose of this work is to describe a straightforward original validated method for the prospective evaluation of professional practices in the field of colonoscopy applicable in all endoscopy units without increasing the staff work load. METHODS: Pertinent quality-control criteria (14 items) were identified by the endoscopists at the Cochin Hospital and were compatible with: findings in the available literature; guidelines proposed by the Superior Health Authority; and application in any endoscopy unit. Prospective routine data were collected and the methodology validated by evaluating 50 colonoscopies every quarter for one year. RESULTS: The relevance of the criteria was assessed using data collected during four separate periods. The standard checklist was complete for 57% of the colonoscopy procedures. The colonoscopy procedure was appropriate according to national guidelines in 94% of cases. These observations were particularly noteworthy: the quality of the colonic preparation was insufficient for 9% of the procedures; complete colonoscopy was achieved for 93% of patients; and 0.38 adenomas and 0.045 carcinomas were identified per colonoscopy. CONCLUSION: This simple and reproducible method can be used for valid quality-control audits in all endoscopy units. In France, unit-wide application of this method enables endoscopists to validate 100 of the 250 points required for continuous medical training. This is a quality-control tool that can be applied annually, using a random month to evaluate any changes in routine practices.

Fas/CD95 pathway induces mouse liver regeneration and allows for highly efficient retrovirus-mediated gene transfer.

Stable gene transfer into hepatocytes has been proposed to compensate for genetic deficiencies that affect liver function, or to deliver diffusible factors into the circulation. This strategy can be achieved using retroviral vectors; however, cell division must occur. We describe a simple and reproductive method that enables the induction of hepatocyte replication in a controlled fashion, thus allowing an efficient in vivo retroviral liver transduction that is applicable to mouse models of human genetic disorders. The approach is based on liver susceptibility to apoptosis via the Fas/CD95 pathway. We show that, 4 days following a single Fas agonist antibody (JO2) injection, hepatocyte replication occurs, the intensity of which is correlated with the level of the induced hepatic cytolysis. This treatment enables in vivo liver transduction, and its efficiency also correlates with the level of hepatic cytolysis. When recombinant retroviral vectors were infused intravenously during the period of hepatocyte replication, 15.4% +/- 1.7% of the hepatocytes were transduced, reaching up to 32.5%.

Therapeutic liver repopulation in a mouse model of hypercholesterolemia.

Liver repopulation constitutes an attractive approach for the treatment of liver disorders or of diseases requiring abundant secretion of an active protein. We have described previously a model of selective repopulation of a normal liver by Fas/CD95-resistant hepatocytes, in which we achieved up to 16% hepatocyte repopulation. In the present study, we investigated the therapeutic efficacy of this strategy. With this aim, apolipoprotein E (ApoE) knockout mice were transplanted with Fas/CD95-resistant hepatocytes which constitutively express ApoE. Transplanted mice were submitted to weekly injections of non-lethal doses of the Fas agonist antibody Jo2. After 8 weeks of treatment, we obtained up to 30% of the normal level of plasma ApoE. ApoE secretion was accompanied by a drastic and significant decrease in total plasma cholesterol, which even fell to normal levels. Moreover, this secretion was sufficient to markedly reduce the progression of atherosclerosis. These results demonstrate the efficacy of this repopulation approach for correcting a deficiency in a protein secreted by the liver.

Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment.

To examine the effects of interferon (IFN) therapy on clinical, biochemical, and histological features in patients with compensated hepatitis C virus (HCV)-related cirrhosis, we have conducted a randomized, controlled trial of IFN therapy versus observation. Eight centers included a total of 99 patients with biopsy-proven cirrhosis. IFN-alpha2b, 3 million units three times per week, or no antiviral therapy was given for 48 weeks. Twenty-three patients dropped out. End-of-treatment biochemical response was not observed in any of the 39 controls but was observed in 6 of the 47 treated patients (P <.02); sustained biochemical response was obtained in only 2 treated patients. Controls and treated patients did not significantly differ with regard to the changes in serum level of albumin, bilirubin, alpha-fetoprotein, in plasma prothrombin, in histological activity, or liver collagen content. During trial or follow-up (160 +/- 57 weeks), hepatocellular carcinoma developed in 9 controls and 5 treated patients (NS); decompensation of cirrhosis occurred in 5 controls and 7 treated patients. Seven controls and 10 treated patients died. In conclusion, in patients with compensated HCV-related cirrhosis, a 48-week course of IFN therapy is safe and is able to induce end-of-treatment biochemical response in a significant proportion of patients. However, a 48-week course of IFN therapy usually fails to achieve sustained response and, within the limit of this study, did not significantly improve the 3-year outcome. Therefore, a longer course of IFN therapy or combination therapy with ribavirin should be evaluated in patients with HCV-related cirrhosis.