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Phase II Clinical Trial of First-line Eribulin Plus Trastuzumab for Advanced or Recurrent HER2-positive Breast Cancer.
Sakaguchi, K, Nakatsukasa, K, Koyama, H, Kato, M, Sakuyama, A, Matsuda, T, Tsunoda, N, Fujiwara, I, Yamaguchi, M, Tanaka, H, et al
Anticancer research. 2018;(7):4073-4081
Abstract
BACKGROUND/AIM: Eribulin mesylate has been approved for advanced or metastatic breast cancers subjected to at least two previous chemotherapy regimens. The present multicenter, phase II, single-arm study assessed the efficacy and safety of a first-line regimen of eribulin plus trastuzumab for untreated advanced or metastatic HER2-positive breast cancer. PATIENTS AND METHODS Enrolled patients received eribulin (1.4 mg/m2 intravenously; I.V.) on days 1 and 8 of each 21-day cycle, an initial trastuzumab dose (8 mg/kg I.V.) on day 1, and 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. The primary endpoint was the response rate (RR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Twenty-eight patients (median age: 62.5 years) received a median of 12 (range: 2-53) cycles of eribulin plus trastuzumab. RESULTS The RR was 53.6% [complete response (CR), 4; partial response (PR), 11] with a median PFS of 344 days. The clinical benefit rate was 64.0%. Grade 3/4 adverse events were observed in 12 (42.9%) patients. For details, neutropenia in 8 (28.6%) patients, peripheral neuropathy in 2 (7.1%) patients, interstitial pneumonia in 1 (3.6%) patient, ALT elevation in 1 (3.6%) patient, osteonecrosis of the jaw in 1 (3.6%) patient, and fatigue in 1 (3.6%) patient. The patient with osteonecrosis received denosumab, too. No symptomatic congestive heart failure was observed. CONCLUSION Combination therapy of eribulin plus trastuzumab is acceptable in efficacy and safety, and a capable option for first-line advanced or recurrent HER2-positive breast cancer.
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The Prognostic Significance of Diabetes and Microvascular Complications in Patients With Heart Failure With Preserved Ejection Fraction.
Sandesara, PB, O'Neal, WT, Kelli, HM, Samman-Tahhan, A, Hammadah, M, Quyyumi, AA, Sperling, LS
Diabetes care. 2018;(1):150-155
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OBJECTIVE This study examined the prognostic significance of diabetes and microvascular complications in patients with heart failure with preserved ejection fraction (HFpEF). RESEARCH DESIGN AND METHODS This analysis included 3,385 patients (mean age 69 ± 9.6 years; 49% male; 89% white) with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT). Diabetes and microvascular complications were ascertained by self-reported history and medical record review. Microvascular complications included neuropathy, nephropathy, and retinopathy. Outcomes included hospitalization, hospitalization for heart failure, death, and cardiovascular death. Cox regression was used to examine the risk of each outcome associated with diabetes and microvascular complications. RESULTS Of the 1,109 subjects (32%) with diabetes, 352 (32%) had at least one microvascular complication. Patients with diabetes and microvascular complications had an increased risk for hospitalization (no diabetes: referent; diabetes + no microvascular complication: hazard ratio [HR] 1.18, 95% CI 1.01, 1.37; diabetes + microvascular complications: HR 1.54, 95% CI 1.25, 1.89; P-trend <0.001), hospitalization for heart failure (no diabetes: referent; diabetes + no microvascular complication: HR 1.51, 95% CI 1.14, 1.99; diabetes + microvascular complications: HR 1.97, 95% CI 1.38, 2.80; P-trend <0.001), death (no diabetes: referent; diabetes + no microvascular complication: HR 1.35, 95% CI 1.04, 1.75; diabetes + microvascular complications: HR 1.73, 95% CI 1.22, 2.45; P-trend = 0.0017), and cardiovascular death (no diabetes: referent; diabetes + no microvascular complication: HR 1.34, 95% CI 0.96, 1.86; diabetes + microvascular complications: HR 1.70, 95% CI 1.09, 2.65; P-trend = 0.018). When the analysis was limited to participants who reported prior hospitalization for heart failure (n = 2,449), a higher risk of rehospitalization for heart failure was observed across diabetes categories (no diabetes: referent; diabetes + no microvascular complication: HR 1.40, 95% CI 1.01, 1.96; diabetes + microvascular complications: HR 1.78, 95% CI 1.18, 2.70; P-trend = 0.0036). CONCLUSIONS Diabetes is associated with adverse cardiovascular outcomes in HFpEF, and the inherent risk of adverse outcomes in HFpEF patients with diabetes varies by the presence of microvascular complications.
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Aspiration Therapy As a Tool to Treat Obesity: 1- to 4-Year Results in a 201-Patient Multi-Center Post-Market European Registry Study.
Nyström, M, Machytka, E, Norén, E, Testoni, PA, Janssen, I, Turró Homedes, J, Espinos Perez, JC, Turro Arau, R
Obesity surgery. 2018;(7):1860-1868
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PURPOSE The objective of this post-market study was to evaluate long-term safety and efficacy of aspiration therapy (AT) in a clinical setting in five European clinics. MATERIALS AND METHODS The AspireAssist® System (Aspire Bariatrics, Inc. King of Prussia, PA) is an endoscopic weight loss therapy utilizing a customized percutaneous endoscopic gastrostomy tube and an external device to aspirate approximately 30% of ingested calories after a meal, in conjunction with lifestyle counseling. A total of 201 participants, with body mass index (BMI) of 35.0-70.0 kg/m2, were enrolled in this study from June 2012 to December 2016. Mean baseline BMI was 43.6 ± 7.2 kg/m2. RESULTS Mean percent total weight loss at 1, 2, 3, and 4 years, respectively, was 18.2% ± 9.4% (n/N = 155/173), 19.8% ± 11.3% (n/N = 82/114), 21.3% ± 9.6% (n/N = 24/43), and 19.2% ± 13.1% (n/N = 12/30), where n is the number of measured participants and N is the number of participants in the absence of withdrawals or lost to follow-up. Clinically significant reductions in glycated hemoglobin (HbA1C), triglycerides, and blood pressure were observed. For participants with diabetes, HbA1C decreased by 1% (P < 0.0001) from 7.8% at baseline to 6.8% at 1 year. The only serious complications were buried bumpers, experienced by seven participants and resolved by removal/replacement of the A-Tube, and a single case of peritonitis, resolved with a 2-day course of intravenous antibiotics. CONCLUSION This study establishes that aspiration therapy is a safe, effective, and durable weight loss therapy in people with classes II and III obesity in a clinical setting. TRIAL REGISTRATION ISRCTN 49958132.
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Effectiveness of clinical practice change strategies in improving dietitian care for head and neck cancer patients according to evidence-based clinical guidelines: a stepped-wedge, randomized controlled trial.
McCarter, K, Baker, AL, Britton, B, Beck, AK, Carter, G, Bauer, J, Wratten, C, Halpin, SA, Holliday, E, Oldmeadow, C, et al
Translational behavioral medicine. 2018;(2):166-174
Abstract
Best practice guidelines make a number of recommendations regarding dietitian management of head and neck cancer (HNC) patients. Randomized trials assessing the effectiveness of clinical practice change strategies for improving the nutritional management of HNC patients have not previously been conducted. The purpose of this study was to evaluate the effect of practice change strategies on improving the implementation of best practice guideline recommendations for the nutritional management of HNC patients. Four Australian radiotherapy departments participated in a stepped-wedge, randomized controlled trial. Baseline data were collected across all sites simultaneously, and the intervention was then introduced to each site sequentially, in a randomly determined order. During the intervention phase, sites received a range of supportive clinical practice change strategies to facilitate dietitian adherence to clinical practice guidelines. To assess the associated practice change by dietetic staff, we evaluated the change in implementation of six guideline recommendations for dietitians from preintervention to postintervention periods. Adherence to the clinical practice guidelines during the preintervention period was generally very low. The clinical practice change strategies significantly improved the odds of provision of four of the six guideline recommendations. The study found the intervention significantly enhanced dietitian provision of recommended care for HNC patients during the postintervention period. This finding holds clinical importance for clinician and health service effective implementation of guideline recommendations as well as HNC patient treatment outcomes. Trial registration number ACTRN12613000320752, https://www.anzctr.org.au.
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Efficacy and safety of sacubitril/valsartan in patients with essential hypertension uncontrolled by olmesartan: A randomized, double-blind, 8-week study.
Cheung, DG, Aizenberg, D, Gorbunov, V, Hafeez, K, Chen, CW, Zhang, J
Journal of clinical hypertension (Greenwich, Conn.). 2018;(1):150-158
Abstract
A majority of patients with hypertension fail to achieve blood pressure (BP) control despite treatment with commonly prescribed drugs. This randomized, double-blind phase III trial assessed the superiority of sacubitril/valsartan 200 mg (97/103 mg) to continued olmesartan 20 mg in reducing ambulatory systolic BP after 8-week treatment in patients with mild to moderate essential hypertension uncontrolled with olmesartan 20 mg alone. A total of 376 patients were randomized to receive either sacubitril/valsartan (n = 188) or olmesartan (n = 188). Superior reductions in 24-hour mean ambulatory systolic BP were observed in the sacubitril/valsartan group vs the olmesartan group (-4.3 mm Hg vs -1.1 mm Hg, P < .001). Reductions in 24-hour mean ambulatory diastolic BP and pulse pressure and office systolic BP and diastolic BP were significantly greater with sacubitril/valsartan vs olmesartan (P < .014). A greater proportion of patients achieved BP control with sacubitril/valsartan vs olmesartan. The overall incidence of adverse events was comparable between the groups. Compared with continued olmesartan, sacubitril/valsartan was more effective and generally safe in patients with hypertension uncontrolled with olmesartan 20 mg.
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Intestinal anti-transglutaminase 2 immunoglobulin A deposits in children at risk for coeliac disease (CD): data from the PreventCD study.
Borrelli, M, Maglio, M, Korponay-Szabó, IR, Vass, V, Mearin, ML, Meijer, C, Niv-Drori, H, Ribes-Koninckx, C, Roca, M, Shamir, R, et al
Clinical and experimental immunology. 2018;(3):311-317
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In coeliac disease (CD), anti-tissue transglutaminase 2 immunoglobulin (Ig)A antibodies (anti-TG2) are produced and deposited in the intestine. PreventCD (www.preventcd.com) is a European multi-centre study, which investigates the influence of infant nutrition and that of genetic, immunological and other environmental factors on the risk of developing CD. The aim of the current study was to evaluate the appearance of intestinal anti-TG2 deposits in very early intestinal biopsies from at-risk infants and their predictive value for villous atrophy. Sixty-five small bowel biopsies, performed in 62 children, were investigated for the presence of intestinal anti-TG2 extracellular IgA deposits by using double immunofluorescence. The biopsies were performed in the presence of elevated serum levels of CD-associated antibodies and/or symptoms suggesting disease. Deposits of anti-TG2 IgA were present in 53 of 53 CD patients and three of three potential CD patients. In potential CD patients, mucosal deposits showed a patchy distribution characterized by some areas completely negative, whereas active CD patients had uniformly present and evident mucosal deposits. Only one of six patients without CD (negative for serum anti-TG2 and with normal mucosa) had intestinal deposits with a patchy distribution and a weak staining. Two of the 53 CD patients received a definitive diagnosis of CD after a second or third biopsy; mucosal deposits of anti-TG2 IgA were evaluated in all samples. Before developing villous atrophy, both patients had anti-TG2 deposits in normal mucosal architecture, antibodies in one patient being absent in serum. We demonstrated that in CD the intestinal deposits of anti-TG2 are a constant presence and appear very early in the natural history of disease.
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Evaluation of the Pooled Cohort Risk Equations for Cardiovascular Risk Prediction in a Multiethnic Cohort From the Women's Health Initiative.
Mora, S, Wenger, NK, Cook, NR, Liu, J, Howard, BV, Limacher, MC, Liu, S, Margolis, KL, Martin, LW, Paynter, NP, et al
JAMA internal medicine. 2018;(9):1231-1240
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IMPORTANCE Atherosclerotic cardiovascular disease (ASCVD) kills approximately 1 in every 3 US women. Current cholesterol, hypertension, and aspirin guidelines recommend calculating 10-year risk of ASCVD using the 2013 Pooled Cohort Equations (PCE). However, numerous studies have reported apparent overestimation of risk with the PCE, and reasons for overestimation are unclear. OBJECTIVE We evaluated the predictive accuracy of the PCE in the Women's Health Initiative (WHI), a multiethnic cohort of contemporary US postmenopausal women. We evaluated the effects of time-varying treatments such as aspirin and statins, and ascertainment of additional ASCVD events by linkage with the Centers for Medicare and Medicaid Services (CMS) claims. DESIGN, SETTING, AND PARTICIPANTS The WHI recruited the largest number of US women (n = 161 808) with the racial/ethnic, geographic, and age diversity of the general population (1993-1998). For this study, we included women aged 50 to 79 (n = 19 995) participating in the WHI with data on the risk equation variables at baseline and who met the guideline inclusion and exclusion criteria. Median follow-up was 10 years. MAIN OUTCOMES AND MEASURES For this study, ASCVD was defined as myocardial infarction, stroke, or cardiovascular death. RESULTS Among the 19 995 women (mean [SD] age, 64 [7.3] years; 8305 [41.5%] white, 7688 [38.5%] black, 3491 [17.5%] Hispanic, 103 [0.5%] American Indian, 321 [1.6%] Asian/Pacific Islander, and 87 [0.4%] other/unknown), a total of 1236 ASCVD events occurred in 10 years and were adjudicated through medical record review by WHI investigators. The WHI-adjudicated observed risks were lower than predicted. The observed (predicted) risks for baseline 10-year risk categories less than 5%, 5% to less than 7.5%, 7.5% to less than 10%, and 10% or more were 1.7 (2.8), 4.4 (6.2), 5.3 (8.7), and 12.4 (18.2), respectively. Small changes were noted after adjusting for time-dependent changes in statin and aspirin use. Among women 65 years or older enrolled in Medicare, WHI-adjudicated risks were also lower than predicted, but observed (predicted) risks became aligned after including events ascertained by linkage with CMS for additional surveillance for events: 3.8 (4.3), 7.1 (6.4), 8.3 (8.7), and 18.9 (18.7), respectively. Similar results were seen across ethnic/racial groups. Overall, the equations discriminated risk well (C statistic, 0.726; 95% CI, 0.714-0.738). CONCLUSIONS AND RELEVANCE Without including surveillance for ASCVD events using CMS, observed risks in the WHI were lower than predicted by PCE as noted in several other US cohorts, but risks were better aligned after including CMS events. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00000611.
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Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial.
Pouteau, E, Kabir-Ahmadi, M, Noah, L, Mazur, A, Dye, L, Hellhammer, J, Pickering, G, Dubray, C
PloS one. 2018;13(12):e0208454
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Magnesium (Mg) plays a role in over 600 biochemical reactions. It is depleted during stress, and a lack of Mg increases the release of stress hormones, leading to a vicious cycle of lowered resistance to stress and further Mg depletion. Vitamin B6 influences neurotransmitters involved in depression and anxiety, and may improve the uptake of magnesium into cells. The aim of this randomised control trial was to evaluate the effects of combined magnesium and vitamin B6 supplementation in stressed people with low blood levels of magnesium. 260 adults aged 18-50 completed the 8-week study. At the beginning of the trial, all participants had suboptimal blood serum magnesium (0.45 mmol/L to 0.85 mmol/L) and reported moderate to extremely severe stress levels. Participants were divided into two groups. One group received magnesium supplementation (465mg magnesium lactate dihydrate, equivalent to 300mg elemental magnesium; Mg), whilst the other received a combined magnesium and vitamin B6 supplement (470 mg magnesium lactate dihydrate plus 5 mg pyridoxine hydrochloride; Mg-B6). After 8 weeks, the Mg-B6 group reported a reduction in stress levels of 44.9%, and the Mg group reported a reduction of 42.4%, with no statistical difference between the two groups overall. However, participants who reported severe or extremely severe stress levels at the start of the study experienced 24% greater improvement with Mg-B6 versus Mg. Researchers concluded that in people with low magnesium levels experiencing severe or extremely severe stress, combining vitamin B6 with magnesium appears to be of greater benefit than supplementing Mg alone.
Abstract
INTRODUCTION Animal and clinical studies suggest complementary effects of magnesium and high-dose pyridoxine (vitamin B6) on stress reduction. This is the first randomized trial evaluating the effects of combined magnesium and vitamin B6 supplementation on stress in a stressed population with low magnesemia using a validated measure of perceived stress. METHODS In this Phase IV, investigator-blinded trial (EudraCT: 2015-003749-24), healthy adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 and serum magnesium concentration 0.45 mmol/L-0.85 mmol/L, were randomized 1:1 to magnesium-vitamin B6 combination (Magne B6 [Mg-vitamin B6]; daily dose 300 mg and 30 mg, respectively) or magnesium alone (Magnespasmyl [Mg]; daily dose 300 mg). Outcomes included change in DASS-42 stress subscale score from baseline to Week 8 (primary endpoint) and Week 4, and incidence of adverse events (AEs). RESULTS In the modified intention-to-treat analysis (N = 264 subjects), both treatment arms substantially reduced DASS-42 stress subscale score from baseline to Week 8 (Mg-vitamin B6, 44.9%; Mg 42.4%); no statistical difference between arms was observed (p>0.05). An interaction (p = 0.0097) between baseline stress level and treatment warranted subgroup analysis (as per statistical plan); adults with severe/extremely severe stress (DASS-42 stress subscale score ≥25; N = 162) had a 24% greater improvement with Mg-vitamin B6 versus Mg at Week 8 (3.16 points, 95% CI 0.50 to 5.82, p = 0.0203). Consistent results were observed in the per protocol analysis and at Week 4. Overall, 12.1% of Mg-vitamin B6 treated and 17.4% of Mg-treated subjects experienced AEs potentially treatment related. CONCLUSIONS These findings suggest oral Mg supplementation alleviated stress in healthy adults with low magnesemia and the addition of vitamin B6 to Mg was not superior to Mg supplementation alone. With regard to subjects with severe/extremely severe stress, this study provides clinical support for greater benefit of Mg combined with vitamin B6.
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Efficacy of ipragliflozin as monotherapy or as add-on therapy with other oral antidiabetic medications for treating type 2 diabetes in Japanese patients with inadequate glycemic control: A subgroup analysis based on patient characteristics.
Osonoi, T, Nakamoto, S, Saito, M, Tamasawa, A, Ishida, H, Osonoi, Y
Journal of diabetes investigation. 2018;(2):341-353
Abstract
AIMS/INTRODUCTION The aim of the present study was to evaluate the efficacy and safety of ipragliflozin in treating Japanese type 2 diabetes patients with inadequate glycemic control by investigating diurnal variations of blood glucose and body composition. MATERIALS AND METHODS This was an investigator-initiated, multicenter, prospective study with a 6-month treatment period. The primary outcome investigated was change in hemoglobin A1c levels from baseline. Secondary outcomes included changes in fasting plasma glucose, insulin resistance, variations in 24-h glucose levels detected by continuous glucose monitoring, bodyweight, body composition, waist circumference and serum lipids. Adverse events were evaluated throughout the study. RESULTS A total of 98 patients completed the study. Over the 6-month period, ipragliflozin-treated patients showed reduction in hemoglobin A1c levels by 0.3%, fasting plasma glucose levels by 13.0 mg/dL, bodyweight by 2.1 kg, body fat mass by 1.5 kg and extracellular water by 0.3 kg, as well as a decrease in systolic/diastolic blood pressures. Significant reductions from baseline in mean amplitude of glucose excursions and standard deviation, and the reduced frequency of hyperglycemia were confirmed. High-density lipoprotein cholesterol was also significantly improved. Notably, the subgroup analysis of hemoglobin A1c levels, bodyweight, waist circumference, and body composition based on age, sex and body mass index showed similar reductions within each subgroup. The incidences of adverse events and adverse drug reactions were 20.0% and 1.0%, respectively, over the 6-month period. CONCLUSIONS Ipragliflozin is a useful oral antidiabetic medication for patients with a wide range of background characteristics.
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Development of a lifestyle intervention for the metabolic syndrome: Discovery through proof-of-concept.
Powell, LH, Appelhans, BM, Ventrelle, J, Karavolos, K, March, ML, Ong, JC, Fitzpatrick, SL, Normand, P, Dawar, R, Kazlauskaite, R
Health psychology : official journal of the Division of Health Psychology, American Psychological Association. 2018;(10):929-939
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OBJECTIVE The aim was to describe the early phases of the progressive development of a lifestyle treatment for sustained remission of the metabolic syndrome (MetS) using the Obesity-Related Behavioral Intervention Trials (ORBIT) model for behavioral treatment development as a guide. METHODS Early discovery and design phases produced a 3-component (diet, physical activity, stress), group-based lifestyle treatment with an intensive 6-month phase followed by monthly, participant-led maintenance meetings. In the proof-of-concept phase, 26 participants with the MetS (age 53 ± 7 years, 77% female, and 65% ethnic minority) were recruited in a quasi-experimental design to determine if treatment could achieve the prespecified benchmark of MetS remission in ≥50% at 2.5 years. Exploratory outcomes focused on MetS components, weight, and patient-centered benefits on energy/vitality and psychosocial status. RESULTS MetS remission was achieved in 53.8% after a median of 2.5 years. At 2.5 years, an increase of +15.4% reported eating ≥3 servings of vegetables/day, +7.7% engaged in ≥150 minutes of moderate-to-vigorous physical activity/week; and +11.5% reported experiencing no depression in the past 2 weeks. Weight loss ≥5% was achieved by 38.5%, and energy/vitality, negative affect, and social support improved. Median group attendance over 2.5 years was 73.8%. CONCLUSIONS It is plausible that this lifestyle program can produce a remission in the MetS, sustained through 2.5 years. After refinements to enhance precision and strength, progression to feasibility pilot testing and a randomized clinical trial will determine its efficacy as a cost-effective lifestyle option for managing the MetS in the current health care system. (PsycINFO Database Record