Real-world safety and effectiveness of iGlarLixi in people with type 2 diabetes who fast during Ramadan: The SoliRam observational study.

BACKGROUND AND AIMS: To evaluate the safety and effectiveness of iGlarLixi in adults with type 2 diabetes (T2D) fasting during Ramadan. METHODS: SoliRam was a multinational, prospective, single-arm, real-world observational study conducted during Ramadan 2020 and 2021 in adults with T2D treated with iGlarLixi ≥3 months at study entry. The primary endpoint was the percentage of participants experiencing ≥1 episode of severe and/or symptomatic documented hypoglycemia (<70 mg/dL [<3.9 mmol/L]). RESULTS: Among the 409 eligible participants followed during Ramadan, 96.8% fasted for ≥25 days and 92.4% did not break fasting during Ramadan. Four participants broke their fast due to hypoglycemia. Minimal adjustments were seen in antihyperglycemic therapies from pre to during Ramadan. Documented symptomatic hypoglycemia was experienced by 1.0%, 2.3%, and 0.3% of participants, respectively, during the last month of pre-Ramadan, Ramadan, and first month post-Ramadan. Mean change in HbA1c from pre-to post-Ramadan periods was -0.75% (-8.2 mmol/mol), and participants with HbA1c <7% (<53 mmol/mol) increased from 7.9% pre-Ramadan to 28.6% post-Ramadan. CONCLUSIONS: iGlarLixi is an effective and well-tolerated therapy for people with T2D, including those who intend to fast during Ramadan, and is associated with a low risk of hypoglycemia; benefits were observed both during and after Ramadan.

Continuous glucose monitoring-based time-in-range using insulin glargine 300 units/ml versus insulin degludec 100 units/ml in type 1 diabetes: The head-to-head randomized controlled InRange trial.

AIM: To use continuous glucose monitoring (CGM)-based time-in-range (TIR) as a primary efficacy endpoint to compare the second-generation basal insulin (BI) analogues insulin glargine 300 U/ml (Gla-300) and insulin degludec 100 U/ml (IDeg-100) in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: InRange was a 12-week, multicentre, randomized, active-controlled, parallel-group, open-label study comparing glucose TIR and variability between Gla-300 and IDeg-100 using blinded 20-day CGM profiles. The inclusion criteria consisted of adults with T1D treated with multiple daily injections, using BI once daily and rapid-acting insulin analogues for at least 1 year, with an HbA1c of 7% or higher and of 10% or less at screening. RESULTS: Overall, 343 participants were randomized: 172 received Gla-300 and 171 IDeg-100. Non-inferiority (10% relative margin) of Gla-300 versus IDeg-100 was shown for the primary endpoint (percentage TIR ≥ 70 to ≤ 180 mg/dl): least squares (LS) mean (95% confidence interval) 52.74% (51.06%, 54.42%) for Gla-300 and 55.09% (53.34%, 56.84%) for IDeg-100; LS mean difference (non-inferiority): 3.16% (0.88%, 5.44%) (non-inferiority P = .0067). Non-inferiority was shown on glucose total coefficient of variation (main secondary endpoint): LS mean 39.91% (39.20%, 40.61%) and 41.22% (40.49%, 41.95%), respectively; LS mean difference (non-inferiority) -5.44% (-6.50%, -4.38%) (non-inferiority P < .0001). Superiority of Gla-300 over IDeg-100 was not shown on TIR. Occurrences of self-measured and CGM-derived hypoglycaemia were comparable between treatment groups. Safety profiles were consistent with known profiles, with no unexpected findings. CONCLUSIONS: Using clinically relevant CGM metrics, InRange shows that Gla-300 is non-inferior to IDeg-100 in people with T1D, with comparable hypoglycaemia and safety profiles.

iGlarLixi versus basal plus Rapid-Acting insulin in adults with type 2 diabetes advancing from basal insulin therapy: The SoliSimplify Real-World study.

AIM: For people with suboptimally controlled type 2 diabetes (T2D) on basal insulin (BI), guidelines recommend several treatment advancement options. This study compared the clinical effectiveness of once-daily iGlarLixi versus a multiple-injection BI + rapid acting insulin (RAI) regimen in adults with T2D advancing from BI therapy in real-world clinical practice. MATERIALS AND METHODS: Electronic medical records from the Observational Medical Outcomes Partnership (OMOP) database were analysed retrospectively using propensity score matching to compare therapy advancement with iGlarLixi or BI + RAI in US adults ≥18 years with T2D on BI who had ≥1 valid glycated haemoglobin (HbA1c) value at baseline and at the 6-month follow-up. The primary objective was non-inferiority of iGlarLixi to BI + RAI in HbA1c change from baseline to 6 months (margin 0.3%). RESULTS: Propensity score matching generated cohorts with balanced baseline characteristics (N = 814 in each group). HbA1c reduction from baseline to 6 months with iGlarLixi was non-inferior to BI + RAI [mean difference (95% confidence interval): 0.1 (-0.1, 0.2)%; one-sided p = .0032]. At 6 months, weight gain was significantly lower with iGlarLixi than with BI + RAI [-0.8 (-1.3, -0.2) kg; two-sided p = .0069]. Achievement of HbA1c <7% without hypoglycaemia and weight gain were similar between groups [odds ratio (95% confidence interval): 1.15 (0.81, 1.63); p = .4280]. Hypoglycaemia was low in both groups, probably because of underreporting. CONCLUSIONS: In real-world clinical practice, glycaemic outcomes 6 months after treatment advancement from BI are similar for people with T2D using iGlarLixi versus BI + RAI, with iGlarLixi leading to less weight gain.

Improved patient-reported outcomes with iGlarLixi versus premix BIAsp 30 in people with type 2 diabetes in the SoliMix trial.

AIM: To assess patient-reported outcomes (PROs) in the SoliMix trial, which compared the efficacy and safety of iGlarLixi versus BIAsp 30 in people with type 2 diabetes (T2D). MATERIALS AND METHODS: SoliMix (EudraCT: 2017-003370-13), a 26-week, open-label study, randomized (1:1) 887 adults with T2D and HbA1c ≥7.5%-≤10.0% (≥58-≤86 mmol/mol) on basal insulin plus oral antihyperglycaemic drugs (OADs) to once-daily iGlarLixi or twice-daily premix insulin, BIAsp 30. PROs were assessed using the Treatment-Related Impact Measure Diabetes (TRIM-D) and Global Treatment Effectiveness Evaluation (GTEE) questionnaires. RESULTS: Over 26 weeks, iGlarLixi showed greater improvement from baseline versus BIAsp 30 in total TRIM-D score (least squares mean difference [95% confidence interval]: 5.08 [3.69, 6.47]; effect size: 0.32) and in each TRIM-D domain, with the greatest differences seen in diabetes management (8.47 [6.11, 10.84]) and treatment burden (6.95 [4.83, 9.07]). GTEE scores showed a greater proportion of participants and physicians rated a complete or marked improvement of diabetes control with iGlarLixi (80.5%, 82.8%) versus BIAsp 30 (63.3%, 65.1%) at week 26. Post hoc analyses showed that after adjusting for HbA1c, body weight and hypoglycaemia outcomes, iGlarLixi continued to show greater improvements in TRIM-D total scores versus BIAsp 30. CONCLUSIONS: In addition to better glycaemic control, weight benefit and less hypoglycaemia, once-daily iGlarLixi provided improved diabetes management, treatment burden and perceived effectiveness versus twice-daily premix BIAsp 30, further supporting iGlarLixi as an advanced treatment option in people with suboptimally controlled T2D on basal insulin plus OADs.

Real-World Effectiveness and Safety of Insulin Glargine 300 U/mL in Insulin-Naïve People with Type 2 Diabetes: the ATOS Study.

INTRODUCTION: The clinical benefits of insulin glargine 300 U/mL (Gla-300) have been confirmed in randomised clinical trials (EDITION programme and BRIGHT) and real-world studies in the USA and Western Europe. ATOS evaluated the real-world effectiveness and safety of Gla-300 in wider geographic regions (Asia, the Middle East, North Africa, Latin America and Eastern Europe). METHODS: This prospective observational, international study enrolled adults (≥ 18 years) with type 2 diabetes mellitus (T2DM) uncontrolled [haemoglobin A1c (HbA1c) > 7% to ≤ 11%] on one or more oral anti-hyperglycaemic drugs (OADs) who had been advised by their treating physician to add Gla-300 to their existing treatment. The primary endpoint was achievement of a pre-defined individualised HbA1c target at month 6. RESULTS: Of the 4550 participants included, 4422 (51.8% female) were eligible for assessment. The mean ± standard deviation (SD) age was 57.2 ± 10.8 years, duration of diabetes was 10.2 ± 6.2 years and baseline HbA1c was 9.28 ± 1.0%. The proportion of participants reaching their individualised glycaemic target was 25.2% [95% confidence interval (CI) 23.8-26.6%] at month 6 and 44.5% (95% CI 42.9-46.1%) at month 12. At months 6 and 12, reductions were observed in HbA1c (-1.50% and -1.87%) and fasting plasma glucose (-3.42 and -3.94 mmol/L). Hypoglycaemia incidence was low, and body weight change was minimal. Adverse events were reported in 283 (6.4%) participants, with 57 (1.3%) experiencing serious adverse events. CONCLUSION: In a real-world setting, initiation of Gla-300 in people with T2DM uncontrolled on OADs resulted in improved glycaemic control and low rates of hypoglycaemia with minimal weight change. TRIAL REGISTRATION: Clinicaltrials.gov number NCT03703869.

Advancing therapy with iGlarLixi versus premix BIAsp 30 in basal insulin-treated type 2 diabetes: Design and baseline characteristics of the SoliMix randomized controlled trial.

AIM: Premix insulin is commonly used in some regions of the world, despite the higher risk of hypoglycaemia and weight gain compared with basal insulin, based on the premise that it offers a simplified insulin regimen. iGlarLixi is a once-daily titratable fixed-ratio formulation that combines basal insulin glargine 100 units/mL (iGlar) and the GLP-1 RA, lixisenatide, which offers a single-injection option for treatment intensification, with improved HbA1c reductions, similar hypoglycaemia risk and more favourable bodyweight profiles over iGlar alone. This randomized controlled study directly compares, for the first time, treatment intensification with iGlarLixi versus premix insulin analogue biphasic insulin aspart 30 (BIAsp 30) in adults with T2D inadequately controlled on basal insulin in combination with one or two oral antihyperglycaemic drugs. MATERIALS AND METHODS: This was an open-label, active-controlled, comparative, parallel-group, multicentre, phase 3b study. In total, 887 adults with T2D uncontrolled on basal insulin were randomized to switch to either iGlarLixi once daily, or BIAsp 30 twice daily, for 26 weeks. RESULTS: Overall, 887 participants were enrolled (mean age 59.8 years, 50.2% female) from 89 centres in 17 countries. At baseline, 65.6% had a duration of T2D of 10 years or longer, and the mean HbA1c at baseline was 8.6%. CONCLUSIONS: The study directly compared the efficacy and safety of iGlarLixi versus BIAsp 30 in people with T2D uncontrolled on basal insulin and one or more oral antihyperglycaemic agents. These results provide robust clinical data that may inform clinicians in their therapeutic management of people with T2D uncontrolled on basal insulin requiring additional therapy.

Target attainment in insulin-naive patients at high risk for hypoglycemia: Results from ACHIEVE Control.

AIMS: To better understand outcomes in people with type 2 diabetes at high risk of hypoglycemia, we conducted post hoc analyses in subgroups of participants from the real-world ACHIEVE Control study (NCT02451137) with ≥1 hypoglycemia risk factor. METHODS: Insulin-naive adults with type 2 diabetes and A1c ≥8% were randomized 1:1 to insulin glargine 300 U/mL (Gla-300) or standard-of-care basal insulin (SOC-BI). Participants had documented history of ≥1 risk factors for hypoglycemia: chronic kidney disease, cardiovascular disease, dementia or blindness, age ≥65 years, or history of hypoglycemia. Outcomes included individualized A1c target attainment without documented symptomatic hypoglycemia (blood glucose [BG] ≤3.9 mmol/L or <3.0 mmol/L) or severe hypoglycemia, A1c target attainment, and absence of documented symptomatic or severe hypoglycemia at 6 and 12 months. RESULTS: Within subgroups, odds ratios generally showed trends favoring Gla-300 versus SOC-BI, particularly for hypoglycemia avoidance in participants ≥65 years of age (BG ≤3.9 mmol/L; odds ratio, 1.52; 95% confidence interval, 1.14-2.03) and those with chronic kidney disease (BG ≤3.9 mmol/L; odds ratio, 2.28; 95% confidence interval, 1.26-4.12). Results were consistent with the overall population. CONCLUSIONS: These data suggest potential benefit of Gla-300 versus SOC-BI for avoiding hypoglycemia in participants with ≥1 hypoglycemia risk factor.

Safety of lixisenatide plus basal insulin treatment regimen in Indian people with type 2 diabetes mellitus during Ramadan fast: A post hoc analysis of the LixiRam randomized trial.

AIMS: Hypoglycemia is one of the most important complications associated with Ramadan fasting in people with type 2 diabetes. LixiRam (NCT02941367) was the first randomized trial comparing safety and efficacy of lixisenatide + basal insulin (BI) vs. sulphonylurea + BI in people with type 2 diabetes who fast during Ramadan. This post hoc analysis focuses on the LixiRam study population from India. METHODS: Adults with type 2 diabetes insufficiently controlled with sulphonylurea + BI ± another oral anti-hyperglycemic drug were randomized 1:1 to receive lixisenatide + BI or to continue sulphonylurea + BI treatment. RESULTS: In total, 150 participants were randomized in India. One participant (1.3%) with lixisenatide + BI vs. 5 participants (6.8%) with sulphonylurea + BI experienced ≥1 documented symptomatic hypoglycemic event during the Ramadan fast (odds ratio [OR]: 0.22; 95% confidence interval [CI]: 0.02-1.93). Incidence of any hypoglycemia was numerically lower with lixisenatide + BI vs. sulphonylurea + BI during Ramadan fasting (1.3% [1/75] vs. 14.7% [11/75], respectively; OR: 0.09; 95% CI: 0.01-0.69). No new safety signals were identified. CONCLUSIONS: A combination of lixisenatide prandial GLP1-RA + BI may be a suitable treatment option for people with type 2 diabetes who elect to fast during Ramadan. Clinical Trial Registry: clinicaltrials.gov (NCT02941367).

Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in MRI-Defined Locally Advanced T3 Resectable Rectal Cancer: Final Results of a Randomized, Noncomparative Phase 2 INOVA Study.

BACKGROUND: Recurrence and distant metastases remain a significant issue in locally advanced rectal cancer (LARC). Several multimodal strategies are assessed in clinical trials. PATIENTS AND METHODS: Patients with mid/low magnetic resonance imaging-defined high-risk LARC were randomized to arm A (12-week bevacizumab + FOLFOX-4 then bevacizumab-5-fluorouracil [5-FU]-radiotherapy [RT] before total mesorectal excision [TME]) or arm B (bevacizumab-5-FU-RT then TME). Long-term efficacy and safety up to 5 years' follow-up are reported. No comparison between arms was planned. RESULTS: Overall, 91 patients (46 in arm A and 45 in arm B) were included. Main results have been presented previously. During the late follow-up period (> 4 weeks after surgery), 4 patients (8.7%) in arm A and 4 (8.9%) in arm B experienced grade 3/4 adverse events related to bevacizumab; the most frequent were 2 anastomotic fistulas (both in arm A) and abscesses (1 in arm A and 2 in arm B). At 5 years' follow-up, 9 (19.6%) and 11 (24.4%) patients in arms A and B developed a fistula in the year after surgery, and 2 (4.3%) in arm A at > 1 year after surgery. Most resolved before study end. Five-year disease-free survival was 70% and 64.3% in arms A and B, respectively. Five-year overall survival was 90.5% (95% confidence interval, 76.7, 96.3) in arm A and 72.7% (95% confidence interval, 56.0, 83.9) in arm B. CONCLUSION: Neoadjuvant bevacizumab + FOLFOX-4 may have the potential to increase survival outcomes when followed by bevacizumab-5-FU-RT and TME in LARC. Bevacizumab-5-FU-RT then TME was associated with a higher-than-projected rate of anastomotic fistulas. Further research of neoadjuvant strategies in LARC is encouraged.

Real-world anaplastic lymphoma kinase (ALK) rearrangement testing patterns, treatment sequences, and survival of ALK inhibitor-treated patients.

BACKGROUND: The anaplastic lymphoma kinase (ALK) treatment landscape is crowded following recent ALK inhibitor approvals, and updated information on real-world treatment patterns in advanced non-small-cell lung cancer (aNSCLC) with ALK rearrangement (ALK+) is needed. METHODS: This retrospective US cohort study used Flatiron Health's longitudinal electronic health record (EHR)-derived database. Patients (≥ 18 years old) diagnosed with stage IIIB/IV aNSCLC, with documented ALK rearrangement and ≥2 visits after January 1, 2011 were followed until February 28, 2016. Patients enrolled on a clinical trial or exposed to ALK inhibitors other than crizotinib or ceritinib were excluded. Treatment patterns, time and type of biomarker testing, and overall survival (OS) were analyzed. RESULTS: Median age (n = 300) was 62.5 years; 55% female; 48% non-smokers; 8.7% central nervous system (CNS) metastases at diagnosis. Overall, 73% and 86% received their first ALK biomarker test before/at diagnosis, or before/during first-line treatment, respectively. In total, 90.0%, 78.1%, and 74.7% received first-, second-, and third-line therapy, respectively. Most patients received ALK-targeted treatment; 62% received crizotinib, of which 21% reported a dose reduction. Progression was the most common reason for crizotinib (78%) and ceritinib (41%) discontinuation. Median OS was 29.4 months (95% CI =24.7-39.6) overall; 27.1 months (95% CI =22.0-35.0) in patients with CNS metastases, and 36.9 months (95% CI =25.1-not reached) without. CONCLUSIONS: Despite widespread crizotinib use in patients with ALK+ aNSCLC, a high proportion of patients progressed. Ongoing analyses of EHR-derived cohorts are valuable in assessing real-world testing rates and therapeutic use of ALK inhibitors.

Comparative effectiveness from a single-arm trial and real-world data: alectinib versus ceritinib.

AIM: To compare the overall survival of anaplastic lymphoma kinase-positive non-small-cell lung cancer patients who received alectinib with those who received ceritinib. MATERIALS & METHODS: Two treatment arms (alectinib [n = 183] and ceritinib [n = 67]) were extracted from clinical trials and an electronic health record database, respectively. Propensity scores were applied to balance baseline characteristics. Kaplan-Meier and multivariate Cox regression were conducted. RESULTS: After propensity score adjustment, baseline characteristics were balanced. Alectinib had a prolonged median overall survival (alectinib = 24.3 months and ceritinib = 15.6 months) and lower risk of death (hazard ratio: 0.65; 95% CI: 0.48-0.88). CONCLUSION: Alectinib was associated with prolonged overall survival versus ceritinib, which is consistent with efficacy evidence from clinical trials.

Bevacizumab in Combination with Platinum-Based Chemotherapy in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer with or without Brain Metastases: A French Cohort Study (EOLE).

OBJECTIVES: The aim of this study was to describe the characteristics of patients receiving bevacizumab plus first-line metastatic chemotherapy for non-squamous advanced non-small cell lung cancer (aNSCLC), with or without brain metastases, in routine clinical practice. Other objectives were to describe treatment efficacy, modalities of use, and safety. METHODS: For this non-interventional, prospective, national, multicentre study, data were collected every 3 months over 18 months. RESULTS: Of the 407 patients analysed, 84 (21%) with brain metastases at bevacizumab initiation had poorer general health than patients with no brain metastases (Eastern Cooperative Oncology Group [ECOG] performance status score = 2: 16 vs. 11%). All but 2 patients received bevacizumab (7.5 or 15 mg/kg/3 weeks in 99% of patients) in combination with doublet chemotherapy. Median progression-free survival and overall survival did not differ significantly between patients with or without brain metastases (6.5 months, 95% CI 5.7-8.1 vs. 6.9 months, 95% CI 5.9-7.6, p = 0.57; 14.5 months, 95% CI 10.0 vs. 12.5 months, 95% CI 10.1-14.7, p = 0.33). In 30 and 32% of the patients, respectively, at least one serious adverse event was reported, with a causal relationship to bevacizumab in 20 and 21% of the patients. CONCLUSION: This study confirmed in a real-life setting the safety profile and survival benefits of first-line chemotherapy with bevacizumab in aNSCLC patients with brain metastases.

Factors influencing the use of tocilizumab as monotherapy in patients with rheumatoid arthritis in a real-life setting: results at 1†year of the ACT-SOLO study.

INTRODUCTION: Using a biologic disease-modifying antirheumatic drug (bDMARD) as monotherapy in clinical practice for patients with rheumatoid arthritis (RA) is common and recognised by health authorities although current guidelines recommend to combine them with conventional synthetic (cs)DMARDs. This study mainly aimed to search for real-life factors influencing the use of tocilizumab as MONO or in combination (COMBO). METHODS: In this non-interventional, prospective, national, multicentre study, data were collected every 3 months over a 12-month period in RA patients starting tocilizumab. The proportion of monotherapy patients was described, together with significant explicative factors. RESULTS: Among the 577 analysed patients recruited from January 2012 to August 2013 (228 monotherapy patients; 40%), 79% were women, mean RA duration was 11±9 years, previous RA treatments included bDMARDs and csDMARDs in 75% of cases and mean Disease Activity Score 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR) was 5.2±1.3 at inclusion. Explicative factors for monotherapy were at least 65 years (OR=1.47, p=0.0485), no methotrexate within the two last years (OR=5.96, p<0.0001), past severe infection (OR=1.99, p=0.0272) and higher baseline DAS28-ESR (OR=1.22, p=0.0086). Regarding clinical results (DAS28-ESR, Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) low disease activity and remission; ACR20/50/70 and European League Against Rheumatism (EULAR) response; Health Assessment Questionnaire Disability Index (HAQ-DI) score), no relevant differences between monotherapy and combination patients were observed at 1 year. A total of 23 tocilizumab-treated patients (4%) experienced serious infections; no new safety signals were noted with no differences between groups. CONCLUSIONS: ACT-SOLO confirms the high proportion of RA patients receiving tocilizumab as MONO in clinical practice. The study also showed that clinical results at 1 year were similar between MONO and COMBO patients in a real-life setting. TRIAL REGISTRATION NUMBER: NCT01474291.

Use of [(18)F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [(18)F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial.

BACKGROUND: An effective and well tolerated treatment is needed for patients with early HER2-positive breast cancer who do not achieve a pathological complete response after neoadjuvant therapy. The AVATAXHER trial aimed to predict pathological complete response early with the use of PET and to investigate whether the addition of bevacizumab could improve the proportion of patients achieving a pathological complete response in patients unlikely to respond to treatment. METHODS: AVATAXHER was a randomised, open-label, non-comparative, multicentre phase 2 study that enrolled women (≥18 years of age) with early-stage HER2-positive breast cancer from 26 oncology centres in France. Patients initially received two cycles of neoadjuvant docetaxel (100 mg/m(2) intravenously every 3 weeks) plus trastuzumab (8 mg/kg intravenously every 3 weeks then 6 mg/kg intravenously every 3 weeks for the second course). Before the first and second cycles, [(18)F]-fluorodeoxyglucose (FDG) PET was done and the change in standardised uptake value was used to predict pathological complete response in each patient. Patients who were predicted to be responders on PET continued to receive standard therapy. Predicted non-responders were randomly assigned (2:1) to receive four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) and trastuzumab (6 mg/kg intravenously every 3 weeks) plus bevacizumab (15 mg/kg intravenously every 3 weeks; group A) or continue on docetaxel plus trastuzumab alone (group B). Randomisation was open label and was done by an adaptive minimisation method. Although investigators and patients were aware of group assignment, the anatomo-pathologist in charge of centralised review of surgical samples and lymph nodes was masked to treatment assignment. The primary endpoint was centrally assessed pathological complete response according to the Chevallier classification. Efficacy analyses were done in the intention-to-treat population. Safety analyses in this Article were done on all patients who received at least one dose of treatment starting from cycle 3. Survival outcomes are not yet mature. This study is registered with ClinicalTrials.gov (NCT01142778) and EUDRACT (2009-013410-26). FINDINGS: Between May 19, 2010, and Oct 1, 2012, 152 patients were recruited for the study. Ten patients were subsequently excluded, leaving 142 patients in the intention-to-treat population. Of these 142 patients, 69 were predicted by [(18)F]-FDG PET to be treatment responders after two cycles of treatment. The 73 predicted non-responders were randomly assigned to group A (n=48) and group B (n=25). Pathological complete responses were noted in 37 (53·6%, 95% CI 41·2-65·7) of the PET responders, 21 (43·8%, 29·5-58·8) of those in group A, and six (24·0%, 9·4-45·1) of those in group B. Incidences of grade 3-4 adverse events were similar in all three groups. The most common grade 3-4 adverse events were neutropenia (four in PET responders, five in group A, and three in group B), febrile neutropenia (one, three, and one, respectively), and myalgia (four, none, and one, respectively). Overall, 24 serious adverse events were reported in 15 patients (PET responders: nine events in four [6%] of 67 patients; group A: 14 events in ten [21%] of 47 patients; group B: one event in one [4%] of 25 patients). No deaths occurred during the study. INTERPRETATION: In patients with HER2-positive breast cancer, early PET assessment can help to identify non-responders to neoadjuvant docetaxel plus trastuzumab therapy. In these patients, the addition of bevacizumab can increase the proportion of patients achieving a pathological complete response. This potential new role for PET and the activity of bevacizumab in this setting need to be confirmed in larger phase 3 trials. FUNDING: Roche France.

[Generic drugs at hospital discharge: assessment in geriatrics]. / Médicaments génériques en sortie d'hospitalisation : évaluation dans un service de gériatrie.

OBJECTIVES: To assess the impact of physician awareness to promote the prescription and the dispensing of generic drugs at hospital discharge. METHODS: The study consisted in a Before/After Study design including the analysis of medical prescriptions at hospital discharge, after a pharmaceutical intervention to physicians in a geriatric ward. Each drug was classified according to its terms of prescribing (International Nonproprietary Name (INN), Generic or Trade Name). The primary endpoint defined is the rate of medication prescribed by INN or generic. Statistical analysis was performed on all medicines and according to the prescribers' status (junior/senior). RESULTS: Three hundred and fifty one drugs were prescribed in the group "before intervention" versus 301 in the group "after". The average number of drugs prescribed per patient was similar between the two groups (9.5 drugs/patient). A generic prescription has been improved by 5% between the two periods (19.7% "before" vs 24.3% "after", p=0.27). Analysis on prescriber status indicates that the pharmaceutical intervention had a significant impact on junior physicians, which resulted in improved prescribing of drug (INN or generic) from 17.6% to 31.4% between the two periods (p=0.006). CONCLUSION: The pharmaceutical intervention to physicians has led to an improvement of drug prescription (INN or generic) at hospital discharge. This awareness has affected mainly junior prescribers hence the need to extend this type of intervention to all prescribers of our establishment.

Brain dynamic neurochemical changes in dystonic patients: a magnetic resonance spectroscopy study.

Measurements of the concentrations of γ-aminobutyric acid (GABA) and glutamate in the motor cortices and lentiform nuclei of dystonic patients using single-voxel (1)H magnetic resonance spectroscopy (MRS) have yielded conflicting results so far. This study aimed to investigate dynamic changes in metabolite concentrations after stimulation of the motor cortices in patients with upper limb dystonia. Using single-voxel MRS at 3 T, the concentrations of GABA, glutamate plus glutamine, and N-acetylaspartate were measured bilaterally in the primary sensorimotor cortex, lentiform nucleus, and occipital region before and after 5-Hz transcranial magnetic stimulation (TMS) over the dominant motor cortex. Data obtained from 15 patients with upper limb primary dystonia were compared with data obtained from 14 healthy volunteers. At baseline, there was no group difference in concentration of metabolites in any region. rTMS induced a local (in the stimulated motor cortex) decrease of N-acetylaspartate (P < .006) to the same extent in healthy volunteers and patients. GABA concentrations were modulated differently, however, decreasing mildly in patients and increasing mildly in healthy volunteers (P = .05). There were no remote effects in the lentiform nucleus in either group. The stimulation-induced changes in metabolite concentrations have been interpreted in view of the increased energy demand induced by rTMS. The dynamics of the GABA concentration were specifically impaired in dystonic patients. Whether these changes reflect changes in the extrasynaptic or synaptic GABA component is discussed.

Accuracy of high resolution (1.5 tesla) pelvic phased array magnetic resonance imaging (MRI) in staging prostate cancer in candidates for radical prostatectomy: results from a prospective study.

OBJECTIVE: To evaluate the role of pelvic phased array MRI in staging prostate cancer (CaP). MATERIALS AND METHODS: We prospectively collected data over 12 months on CaP patients who underwent preoperative MR imaging with a pelvic phased array before radical prostatectomy. MR images were analyzed prospectively by 2 radiologists. MR imaging findings were then correlated with pathologic findings. RESULTS: Overall, 101 patients were included with a mean PSA level of 8 (range 1.8-30). Reader 1 (AUC 0.895, 95% CI 0.791-0.999) had a higher performance than reader 2 (AUC 0.687, 95% CI, 0.555-0.819) and than DRE (AUC 0.728, 95% CI, 0.599-0.857) in discriminating T2 from T3 CaP (P = 0.01). The κ-index of inter-observer agreement was 0.56. A model that combines MRI findings, DRE, PSA, and Gleason score was the most competitive for staging (AUC 0.895, 95% CI, 0.791-0.999). For the multivariate analysis, 3 criteria were significantly associated with extracapsular extension: asymmetry of the neuro-vascular bundles (P = 0.001), asymmetric enhancement of neurovascular bundles (P = 0.02), and bulging of the capsule (P = 0.0003). CONCLUSION: Pelvic phased array MRI presented satisfying results in its ability to adequately stage CaP and notably in detecting the extracapsular extension of tumors. It is likely to provide reliable information but rather in the hands of an experienced radiologist.

Validation of a short food frequency questionnaire to evaluate nutritional lifestyles in hypercholesterolemic patients.

OBJECTIVES: The purpose of our study was to develop and validate a short food frequency questionnaire which could assess the nutritional lifestyles of hypercholesterolemic patients consulting in daily practice. MATERIAL AND METHODS: The questionnaire explores 11 nutrient categories. Hundred and thirty-one patients were recruited for the construct validity and 58 patients for the external validity in La Pitié Hospital, Paris. The reference method used was the diet history. To measure the internal consistency and to test the sensibility to change on a large scale, the questionnaire was used in an observational study conducted in Spain in 1048 moderate hypercholesterolemic patients. Psychometric analyses included construct validity, internal consistency, test-retest reliability, external validity and sensibility to change. RESULTS: Validation of the questionnaire indicated a good internal consistency (Cronbach Coefficient Alpha at 0.69) and test-retest reliability (intraclass correlation coefficient=0.89). The correlation between the scores of the FFQ and those of the diet history was significant with a Pearson correlation coefficient at 0.3 (P=0.029). The comparison between the ranking of the patients showed an agreement of 72% with a kappa of 0.48 [0.10; 0.69]. The sensibility to change was good with a score evolution improving one and four months after nutrition advices: 28.2% of patients ranked in group 1 at inclusion versus 61.3% (P<0.0001) at one month and 75.2% (P<0.0001) at four months. CONCLUSION: In conclusion, we developed and validated a food questionnaire for hypercholesterolemic patients, which can be used as a therapeutic education tool in daily practice or in clinical research.

L-carnitine treatment in incident hemodialysis patients: the multicenter, randomized, double-blinded, placebo-controlled CARNIDIAL trial.

BACKGROUND: L-carnitine levels decrease rapidly and steadily with duration of hemodialysis, and carnitine depletion can impair response to recombinant human erythropoietin (rHuEPO). The study hypothesis was that L-carnitine supplementation during the first year of hemodialysis would improve this response. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From October 2006 through March 2010, this multicenter, randomized, double-blinded study assigned 92 incident hemodialysis patients to receive placebo or 1 g of intravenous L-carnitine after each dialysis session for 1 year. The primary outcome measure compared the groups for rHuEPO resistance index (EPO-RI), defined as weekly rHuEPO doses (IU/kg body weight divided by hemoglobin level) (g/dl). RESULTS: In the L-carnitine group, carnitine concentration increased from a mean ± SD of 79 ± 51 µmol/L to 258 ± 137 µmol/L; in the placebo group, it declined from 68 ± 25 µmol/L to 53 ± 24 µmol/L (interaction group × time, P<0.001). Carnitine deficiency affected about 30% of the patients in the placebo group during the study period. EPO-RI varied from 15.8 ± 11.3 to 9.5 ± 5.8 IU/kg per g/dl in the placebo group and from 20.6 ± 12.8 to 15.6 ± 15.9 IU/kg per g/dl in the L-carnitine group, for a mean variation of -3.94 ± 12.5 IU/kg per g/dl and -2.98 ± 15.5 IU/kg per g/dl, respectively (P=0.7). After adjustment for baseline characteristics, the EPO-RI course was similar in each group (difference between groups, P=0.10; interaction group × time, P=0.9). CONCLUSIONS: Carnitine levels decrease by about 11% ± 33% during the first year of hemodialysis. Treatment of incident hemodialysis patients with L-carnitine does not improve their response to rHuEPO.

Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia.

OBJECTIVE: Women with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility. DESIGN: Case/control study. METHODS: Sixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28 ± 3 days), were included. LH pulse patterns over 6 h were determined in patients and controls. RESULTS: No differences were observed between patients and controls in terms of mean LH levels, LH pulse amplitude, or LH frequency. In CAH patients, LH pulsatility patterns were heterogeneous, leading us to perform a clustering analysis of LH data, resulting in a two-cluster partition. Patients in cluster 1 had similar LH pulsatility patterns to the controls. Patients in cluster 2 had: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels. CONCLUSIONS: LH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.