Changes in regional brain volumes in social anxiety disorder following 12 weeks of treatment with escitalopram

It has been suggested that antidepressants, including the selective serotonin reuptake inhibitors have neurotrophic effects. Nevertheless, the impact of treatment with a selective serotonin re-uptake inhibitor on regional brain volumes in social anxiety disorder has not been studied. 11 subjects with social anxiety disorder completed magnetic resonance imaging both before and after 12-weeks of treatment with 20 mg/day escitalopram. No increases in structural grey matter were found, but there were decreases in bilateral superior temporal cortex, vermis and the left cerebellum volumes following 12 weeks of treatment with escitalopram. These preliminary findings require replication to determine their reliability, and extension to determine whether or not they are disorder specific.     

Treatment with daclatasvir and sofosbuvir for 24 weeks without ribavirin in cirrhotic patients who failed first-generation protease inhibitors

Background

Treatment of patients with chronic hepatitis C who failed the triple therapy with first generation of protease inhibitors is not still defined. The combined use of sofosbuvir (SOF) and daclatasvir (DCV) seems to be promising due to higher genetic barrier, good tolerance and effectiveness.

Methods

We described the treatment with this drug combination in a real-life cohort of 20 cirrhotic patients with genotype 1 who failed the triple therapy.

Results

18 of them (90%) with Child–Pugh A, 11 (55%) with genotype 1a, 17 (85%) with more than 1 and 8 (40%) with more than 2 previous failed treatment; all patients had at baseline NS3 resistance-associated variants related to triple therapy failure. RBV was not administered due to anemia in previous treatments. The sustained virological response was 100%.

Conclusion

Treatment with SOF + DCV without RBV for 24 weeks is safe and effective in cirrhotic patients who failed triple therapy with the first generation of protease inhibitors.

     

Marked increase in serum KL-6 and surfactant protein D levels during the first 4 weeks after treatment predicts poor prognosis in patients with active interstitial pneumonia associated with polymyositis/dermatomyositis

Objective

The aim of this study is to determine whether serum KL-6 and surfactant protein D (SP-D) levels predict the prognosis of patients with interstitial pneumonia (IP) in cases of polymyositis (PM) and dermatomyositis (DM).

Patients and methods

Fifty consecutive patients with PM (n = 17) or DM (n = 33) and active IP, 6 of whom died of respiratory failure, were enrolled in this study. Serum KL-6 and SP-D levels were measured every 2–4 weeks. Medical records were reviewed retrospectively. Univariate analyses and multivariate analyses with a logistic regression model were conducted.

Results

Serum KL-6 and SP-D levels were elevated in patients with active IP. At the time of diagnosis of active IP, the serum KL-6 level was within the normal range in 28 % of patients and the SP-D level was within the normal range in 46 % of patients. Serum KL-6 level increased up to 3 months after starting treatment and then decreased gradually to baseline, whereas SP-D level peaked within the first 4 weeks after treatment and decreased rapidly to normal levels. Patients with poor prognosis showed increases in KL-6 and SP-D levels during the first 4 weeks after treatment, which was confirmed by uni- and multivariate analyses. Comparing the marker levels at 2–4 weeks after treatment with those at 0 weeks, an increase in the ratio over 1.70 for KL-6 and over 1.75 for SP-D, and an increase in KL-6 over 850 U/ml during the first 4 weeks after treatment, were poor prognostic factors.

Conclusions

Increases in serum KL-6 and SP-D levels during the first 4 weeks after starting therapy, but not their levels at any one time point, predict poor prognosis in patients with PM/DM. When marked increases of KL-6 and SP-D levels during the first 4 weeks are found or are predicted by serial measurement of the markers, patients have risks of poor prognosis and additional therapy should be considered.     

Bevacizumab every 4?weeks is as effective as every 2?weeks in combination with biweekly FOLFIRI in metastatic colorectal cancer

Purpose

The efficacy and tolerability of bevacizumab every 2 or 4?weeks using the same dosage in combination with biweekly FOLFIRI were retrospectively evaluated in metastatic colorectal cancer (mCRC) patients in the first-line and second-line therapy.

Patients and methods

A total of 332 patients from six centers were evaluated. The patients had received biweekly FOLFIRI in combination with bevacizumab 5?mg/kg every 2?weeks or every 4?weeks schedule for various reasons in individual patients.

Results

Approximately 70?% of all patients had 2-week treatment schedule. In the first-line therapy (n?=?240), the overall response rate (ORR) was 34.1?% in 2-week and 36.3?% in 4-week groups. Median progression-free survival (PFS) was 8?months (95?%CI, 6.8–9.2) and 9?months (95?%CI, 6.6–11.4) (p?=?0.074), and median overall survival (OS) was 22?months (95?%CI, 15.8–28.2) and 20?months (95?%CI, 8.1–31.9) (p?=?0.612) in 2- and 4-week groups, respectively. One-year survival rate was 76.2?% for 2-week group and 73.2?% for 4-week group. In the second-line therapy (n?=?92), the ORR was similar between the groups (24.5 vs 25.9?% in 2- and 4-week groups, respectively). Median PFS was 6?months (95?%CI, 4.7–7.3) and 11?months (95?%CI, 6.3–15.7) (p?=?0.074), and median OS was 15?months (95?%CI, 9.6–20.4) and 17?months (95?%CI, 13.7–20.3) (p?=?0.456) for 2-week and for 4-week groups, respectively. One-year survival rate was 61.3?% for 2-week and 71.3?% for 4-week groups. Toxicity profile was similar in 2- and 4-week groups and included neutropenia, febrile neutropenia, nausea and vomiting, diarrhea, mucositis, bleeding, hypertension, thromboembolism and fistulization.

Conclusion

Bevacizumab 5?mg/kg every 2?weeks or every 4?weeks in combination with biweekly FOLFIRI had similar efficacy and tolerability in mCRC. Because of the retrospective nature of our study, the data should be examined cautiously. However, our study clearly points out the need for determination of optimum biological dosing interval of bevacizumab in well-designed, prospective, randomized trials.     

Usefulness of underwater endoscopic submucosal dissection in saline solution with a monopolar knife for colorectal tumors (with videos)

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Predictive factors for 24 weeks sustained virologic response (SVR24) and viral relapse in patients treated with simeprevir plus peginterferon and ribavirin

Background

Simeprevir with peginterferon and ribavirin has been used for the treatment of chronic hepatitis caused by genotype 1 hepatitis C virus (HCV). We explored the predictive factors for sustained virological response (SVR) and viral relapse using datasets from four Japanese phase 3 studies (CONCERTO).

Methods

We used a multiple logistic regression model. First, an integrated dataset comprising 357 patients was analyzed. Subsequently, prior treatment-naïve and relapser (223 patients) and nonresponder (134 patients) of interferon-based treatment subsets were analyzed to identify predictors of SVR. A subset of nonresponders (106 patients) who were treated ≥24 weeks was also analyzed to identify predictors for viral relapse.

Results

In the integrated dataset, prior treatment response was significantly associated with SVR. In subset analyses, interleukin-28B (IL28B) TT genotype and undetectable plasma HCV RNA level at week 4 were associated in treatment-naïve patients and relapsers [odds ratio (OR); 4.106 and 3.701, respectively]. In the nonresponders, the IL28B TT genotype population was very small, and inosine triphosphatase (ITPA) and undetectable plasma HCV RNA at week 4 were associated (OR; 2.506 and 3.333, respectively). Furthermore, ribavirin dose intensity (RBV-DI) and detectable plasma HCV RNA at week 4 were significantly associated with viral relapse (OR; 0.327 and 2.922, respectively).

Conclusion

IL28B and plasma HCV RNA level at week 4 were clinically relevant predictive factors for SVR in treatment-naïve patients and relapsers. Moreover, RBV-DI and plasma HCV level at week 4 were identified as relevant predictive factors for viral relapse in nonresponders.

     

Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes mellitus inadequately controlled on metformin: a randomised clinical trial

Aims/hypothesis

The aim of this work was to compare treatment intensification strategies based on orally administered vs injectable incretin-based antihyperglycaemic agents in patients with type 2 diabetes mellitus on metformin monotherapy.

Methods

In a 26 week, open-label study, 653 patients (baseline HbA_1c?=?8.2% [66 mmol/mol]) were randomised at 111 sites in 21 countries in a 1:1 ratio to a strategy using oral agents (starting with sitagliptin 100 mg/day) or a strategy using the injectable drug liraglutide starting at a dose of 0.6 mg/day, up-titrated to 1.2 mg/day after 1 week. The following patients with type 2 diabetes mellitus were recruited for the study: those aged 18–79 years, on a stable dose of metformin monotherapy ≥1,500 mg/day for ≥12 weeks, with an HbA_1c ≥7.0% (53 mmol/mol) and ≤11.0% (97 mmol/mol) and a fasting fingerstick glucose (FFG) <15 mmol/l (<270 mg/dl) at the randomisation visit, deemed capable by the investigator of using a Victoza pen injection device (containing 6 mg/ml liraglutide; Novo Nordisk, Bagsværd, Denmark). Women taking part in the study agreed to remain abstinent or use an acceptable method of birth control during the study. Randomisation was performed via a computer-generated allocation schedule using an interactive voice response system. After 12 weeks, patients on sitagliptin with HbA_1c ?≥?7.0% (53 mmol/mol) and fasting glucose >6.1 mmol/l had their treatment intensified with glimepiride; patients on liraglutide with HbA_1c ?≥?7.0% (53 mmol/mol) had the dose up-titrated to 1.8 mg/day. The primary analysis assessed whether the strategy using oral drugs was non-inferior to that using an injectable drug regarding HbA_1c change from baseline at week 26 using a per-protocol (PP) population and a non-inferiority margin of 0.4%.

Results

In the PP population (522 patients included: oral strategy, n?=?269; injectable strategy, n?=?253) antihyperglycaemic therapy was intensified at week 12 in 50.2% and 28.5%, respectively. HbA_1c decreased over 26 weeks in both treatment strategy groups, with a larger initial reduction at week 12 in the injectable strategy group. The LS mean change in HbA_1c at week 26 was ?1.3% (95% CI ?1.4, ?1.2) in the oral strategy group and ?1.4% (95% CI ?1.5, ?1.3) in the injectable strategy group; the study met the non-inferiority criterion. Both treatment regimens were generally well tolerated; hypoglycaemia was reported more often with the oral strategy, while nausea, vomiting, diarrhoea and abdominal pain were reported more often with the injectable strategy.

Conclusions/interpretation

An oral, incretin-based treatment strategy with sitagliptin and, if needed, glimepiride may be a good approach in many patients with type 2 diabetes mellitus for managing inadequate glycaemic control on metformin monotherapy, as compared with an injectable treatment strategy with liraglutide. The oral and injectable strategies had similar effects on HbA_1c and had good overall tolerability. Trial registration ClinicalTrials.gov NCT01296412 Funding The study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc., Whitehouse Station, NJ, USA.     

Prediction of the therapeutic response to methotrexate at 24 weeks by methotrexate–polyglutamates concentration in erythrocytes at 8 weeks in patients with rheumatoid arthritis

Objectives: The objective of this study is to evaluate the pharmacokinetics and pharmacodynamics of methotrexate–polyglutamates (MTX-PGs) in erythrocytes in patients with rheumatoid arthritis and correlate them with the efficacy.

Methods: MTX-PG concentrations in erythrocytes were measured in 42 MTX-naïve patients repeatedly for 24 weeks by high-performance liquid chromatography. In 56 patients receiving stable MTX doses for at least 12 weeks, the correlation between MTX doses and MTX-PG concentrations was examined. The efficacy was measured by the change of DAS28CRP (ΔDAS28CRP).

Results: There were moderate correlations between MTX dose and MTX-PG 3, 4, and 5. At 24 weeks, MTX-PG2, 3, 4, and 1–5 were higher in patients with ΔDAS28CRP >1.2 than in those with ≤1.2. The cutoff value of MTX-PG1-5 to discriminate ΔDAS28CRP >1.2 from ≤1.2 at 24 weeks was 68.7?nM. Among 20 patients with MTX-PG1-5?>?50.6?nM at 8 weeks, seven already improved at 8 weeks and additional 11 improved at 24 weeks (p?p?=?0.500).

Conclusions: Erythrocyte MTX-PGs might be a potential indicator and predictor of MTX efficacy.     

No predictive effect of body mass index on clinical response in patients with rheumatoid arthritis after 24 weeks of biological disease-modifying antirheumatic drugs: a single-center study

The aim of this study was to determine whether body mass index (BMI) is associated with clinical response to biologics in patients with rheumatoid arthritis (RA). We enrolled 68 patients with RA who were treated with biological disease-modifying antirheumatic drugs (bDMARDs). Biologics included abatacept, tocilizumab, and tumor necrosis factor-α (TNF-α) blockers (etanercept and adalimumab). Baseline BMI (kg/m²) was classified as normal (BMI?<?23.0), overweight (23.0?≤?BMI?<?25.0), or obese (BMI?≥?25.0). Improvement of disease activity score 28 (DAS28) and achievement of the European League Against Rheumatism (EULAR) remission and responses between baseline and 24 weeks were our measures of clinical improvement. Mean baseline BMI before treatment with bDMARDs in patients with RA was 22.2 (SD 3.6). DAS28-ESR and DAS28-CRP were significantly reduced from baseline after 24 weeks of treatment with bDMARDs (p?<?0.001 of both). ?DAS28-ESR and ?DAS28-CRP were not found among patients with normal, overweight, or obese BMI (p?=?0.133 and p?=?0.255, respectively) nor were EULAR responses or EULAR remission (p?=?0.540 and p?=?0.957, respectively). Logistic regression analysis showed no relationship of BMI with EULAR clinical responses (p?=?0.093 for good response and p?=?0.878 for EULAR remission). This study reveals that BMI is not a predictive factor of clinical response to bDMARDs in patients with RA.     

Serum level of reactive oxygen metabolites (ROM) at 12 weeks of treatment with biologic agents for rheumatoid arthritis is a novel predictor for 52-week remission

We have shown that serum levels of reactive oxygen metabolites (ROM) were associated with C-reactive protein (CRP) and disease activity score based on the examination of 28 joints (DAS28) in patients with rheumatoid arthritis (RA); however, their clinical significance as biomarkers has not been elucidated. Forty-eight biologic agent (BA)-naïve RA patients were included in this study. Associations between serum levels of ROM, CRP, matrix metalloproteinase-3 (MMP-3), DAS28-erythrocyte sedimentation rate (ESR), and Health Assessment Questionnaire (HAQ) at 12 weeks of treatment and DAS28 (ESR) remission at 52 weeks (52-week remission) were investigated. The ROM serum level at baseline in the remission group (n = 34) was 527 ± 132 Carratelli units (U.Carr) (normal range <300), decreased to 335 ± 79.1 at 4 weeks, and remained low thereafter. In the non-remission group (n = 14), the ROM serum level at baseline was 592 ± 113 U.Carr, decreased to 450 ± 152 at 4 weeks, but gradually increased thereafter. Among significantly different factors at 12 weeks between the remission and non-remission groups, ROM and DAS28 (ESR) were identified as predictors of 52-week remission (p = 0.045, odds ratio 0.985, 95% confidence interval 0.97–1.000 for ROM). The cutoff value of ROM was determined to be 381.5 U.Carr (sensitivity 0.833, specificity 0.871). These results show that serum ROM levels can predict remission with high accuracy and could be a useful biomarker for achieving remission in the current treat-to-target strategy for RA.     

Changes in vascular structure in diabetic patients after 8 weeks aerobic physical exercise: a randomized controlled trial

Diabetes is a highly prevalent metabolic disease with macrovascular and microvascular complications. Insulin resistance plays a major role in the pathogenesis of atherosclerosis in type 2 diabetes patients. The risk of atherosclerosis progress in diabetes is of 2–4 orders of magnitude. Early atherosclerosis can be detected by carotid intima-media thickness (cIMT) ultrasonography. There is an inverse relationship between intima-media thickness and physical activity. The aim of this study was to investigate the effects of an 8-week aerobic exercise program on the vascular structure in different segments of the carotid artery. This study was a randomized control trial. Thirty individuals were selected out of 642 volunteers who fulfilled the inclusion criteria. They were randomly divided into aerobic exercise and control groups by a block randomization method. This study was carried out during May–October 2016 in Iran. The aerobic protocol comprised of 24 sessions of aerobic exercise on a treadmill for 30 min per session, 3 days a week. The intensity of the training protocol was 50–70% of the patient’s max heart rate. Measurements of vascular parameters were evaluated by the same person, before and after the 24-session intervention. There were no significant differences between anthropometric, sex, age, diabetic history, and cardiac ejection fraction, compared to baseline characteristics. Intima-media thickness (0.52 ± 0.12), intima-media/lumen (0.07 ± 0.02) in bulb carotid, common carotid, and internal carotid, as well as bulb wall, were reduced significantly in the training group compared to the control group after 8 weeks (p < 0.05). Twenty-four sessions of aerobic exercise improved vascular parameters in type 2 diabetics.