Health-related quality of life in KEYNOTE-010 : a phase II/III study of pembrolizumab versus docetaxel in patients with previously treated advanced, programmed death ligand 1-expressing NSCLC

Introduction: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score >= 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here. Methods: Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks or docetaxel 75 mg/m(2) every 3 weeks. HRQoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30 (C30), EORTC QLQ-Lung Cancer 13 (LC13), and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain. Results: Patient reported outcomes compliance was high across all three instruments. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or tumor proportion score status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had "deteriorated" status and more had "improved" status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true time to deterioration for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided p = 0.03), but not for the 2-mg/kg dose. Conclusions: These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

A comparison of immunohistochemical assays and FISH in detecting the ALK translocation in diagnostic histological and cytological lung tumor material.

Introduction:Detection of the ALK rearrangement in a solid tumor gives these patients the option of crizotinib as an oral form of anticancer treatment. The current test of choice is fluorescence in situ hybridization (FISH), but various cheaper and more convenient immunohistochemical (IHC) assays have been proposed as alternatives.Methods:Fifteen FISH-positive cases from patients, seven with data on crizotinib therapy and clinical response, were evaluated for the presence of ALK protein using three different commercially available antibodies: D5F3, using the proprietary automated system (Ventana), ALK1 (Dako), and 5A4 (Abcam). A further 14 FISH-negative and three uncertain (<15% rearrangement detected) cases were also retrieved. Of the total 32 specimens, 17 were excisions and 15 were computed tomography-guided biopsies or cytological specimens. All three antibodies were applied to all cases. Antibodies were semiquantitatively scored on intensity, and the proportion of malignant cells stained was documented. Cutoffs were set by receiver operating curve analysis for positivity to optimize correct classification.Results:All three IHC assays were 100% specific but sensitivity did vary: D5F3 86%, ALK 79%, 5A4 71%. Intensity was the most discriminating measure overall, with a combination of proportion and intensity not improving the test. No FISH-negative IHC-positive cases were seen. Two FISH-positive cases were negative with all three IHC assays. One of these had been treated with crizotinib and had failed to show clinical response. The other harbored a second driving mutation in the EGFR gene.Conclusions:IHC with all three antibodies is especially highly specific (100%) although variably sensitive (71%-86%), specifically in cases with scanty material. D5F3 assay was most sensitive in these latter cases. Occasional cases are IHC-positive but FISH-negative, suggesting either inaccuracy of one assay or occasional tumors with ALK rearrangement that do not express high levels of ALK protein

Immunoreactivity of proteins within 30-40 kDa range during the acute and the recovery phases in rats experimentally infected with Strongyloides venezuelensis

In experimental infection with Strongyloides venezuelensis, the acute and recovery phases can be distinguished, unlike human infections caused by Strongyloides stercoralis. The objective of this study was to evaluate the production of anti-Strongyloides IgG antibodies and the recognition of immunogenic protein bands during the acute and the recovery phases in rats experimentally infected with S. venezuelensis. Rats were infected subcutaneously with 400 or 4,000 S. venezuelensis infective larvae. The acute phase was characterized by elimination of a large number of eggs in the faeces on days 6-14 post infection; the recovery phase was characterized by the resolution of the infection between days 30 and 35 post infection. Differences in IgG levels were observed in the acute and the recovery phases. Different antigenic fractions were recognized in both phases of infection. It is concluded that proteins within the 30-40 kDa range are immunoreactive markers for both the acute and the recovery phases in rats experimentally infected with S. venezuelensis, particularly using membrane antigen

Estudo clínico duplo cego comparando praziquantel com oxamniquine

Com objetivo de se compararem a tolerabilidade e eficácia do praziquantel e oxamniquine, procedeu-se a um estudo prospectivo duplo-cego envolvendo 120 pacientes com esquistossomose intestinal ou hepatintestinal. Os pacientes foram randomizados em dois grupos. Um foi tratado com praziquantel, na dose de 55 mg/kg de peso, o outro com oxamniquine, 15 mg/kg de peso, sempre administrados em dose única por via oral. O diagnóstico e seguimento parasitológicos basearam-se ho exame de fazes peio método de Kate Katz. Em 73 de 77 casos negativos após tratamento, executaram-se biópsias retais. Efeitos colaterais, principalmente tontura, sonolência, dores abdominais, cefaléia, náuseas e diarréia foram observados em 87% dos casos. Sua incidência, intensidade e duração foram semelhantes em ambos os grupos, mas a dor abdominal foi significativamente mais freqüente após praziquantel, havendo maior tendência para tontura intensa após oxamniquine. Observou-se aumento significante de alamina-aminotransferase e gama-glutamiltransferase após oxamniquine e de bilirrubina total após praziquantel. Um total de 48 pacientes tratados com praziquantel e 46 com oxamniquine completaram os exames de controle até o sexto mês. As percentages de cura foram de 79,2% e de 84,8% respectivamente, diferença não significativa. Os pacientes não curados mostraram redução média do número de ovos de 93,5% e de 84,1%, diferença não significativa. Cinco pacientes retratados com praziquantel curaram-se, mas somente um de três retratados com oxamniquine. Estes resultados mostram, que ambas as drogas-apesar de diferentes propriedades farmacológicas provocam reações colaterais semelhantes e apresentam eficácia terapêutica comparável.A double-blind clinical trial involving 120 patients with chronic schistosomiasis was carried out to compare the tolerability and efficacy of praziquantel and oxamniquine. The patients were randomly allocated into two groups. One was treated with praziquantel, 55 mg/kg of body weight CBWT), and the other one with oxamniquine, 15mg/kg bwt, administered in a single oral dose. The diagnosis and the parasitological follow-up was based on stool examinations by quantitative Kato-Katz method and on rectal biopsies. Side-effects mainly dizziness, sleepness, abdominal distress, headache, nausea and diarrhea were observed in 87% of the cases. Their incidence, intensity and duration were similar for both drugs but abdominal pain was significantly more frequent after praziquantel intake and severe dizziness was more commonly reported after oxamniquine. A significant increase of alanine-aminotransferase and y-glutamyltransferase was found with the latter drug and of total bilirubin with the former one. A total of 48 patients treated with praziquantel and 46 with oxamniquine completed with negative findings the required three post-treatment parasitological controls three slides of each stool sample on the first, third and sixth month. The achieved cure rates were 79.2% and 84.8%, respectively, a difference without statistical significance. The non-cured cases showed a mean reduction in the number of eggs per gram of feces of 93.5% after praziquantel and of 84.1% after oxamniquine. This diference also was not significant. Five patients retreated with praziquantel were cured but only one out of three treated a second time with oxamniquine. These findings show that both drugs despite their different chemical structures, pharmacological properties and mechanisms-of-action induce similar side-effects as well as a comparable therapeutical efficacy, in agreement with the results reported from analogous investigations

Perianal Pediatric Crohn Disease Is Associated With a Distinct Phenotype and Greater Inflammatory Burden

Objectives: Data on the outcomes of children with perianal Crohn disease (pCD) are limited, although its presence is often used for justifying early use of biologics. We aimed to assess whether pCD in children is associated with more severe outcomes as found in adults. Methods: Data were extracted from the ImageKids database, a prospective, multicenter, longitudinal cohort study. The study enrolled 246 children at disease onset or thereafter. All patients underwent comprehensive clinical, endoscopic, and radiologic evaluation at enrollment;98 children had repeat evaluation at 18 months. Results: Of the 234 included patients (mean age 14.2 +/- 2.4 years;131 [56%] boys), 57 (24%) had perianal findings, whereas only 21 (9%) had fistulizing perianal disease. Children with pCD had reduced weight and height z scores compared with non-pCD patients (-0.9 vs -0.35, P = 0.03 and -0.68 vs -0.23, respectively;P = 0.04), higher weighted pediatric CD activity index (32 [interquartile range 16-50] vs 20 [8-37];P = 0.004), lower serum albumin (3.6 +/- 0.7 vs 4.5 +/- 0.8, P = 0.016), and higher magnetic resonance enterography global inflammatory score (P = 0.04). Children with pCD had more rectal (57% vs 38%, P = 0.04), and jejunal involvement (31% vs 11% P = 0.003) and a higher prevalence of granulomas (64% vs 23%, P = 0.0001). Magnetic resonance enterography-based damage scores did not differ between groups. Patients with skin tags/fissures only, had similar clinical, endoscopic, and radiologic characteristics as patients with no perianal findings. Conclusions: Pediatric patients with pCD with fistulizing disease have distinct phenotypic features and a predisposition to a greater inflammatory burden

Patterns and predictors of co-morbidities in Tuberculosis: A cross-sectional study in the Philippines.

Diabetes and undernutrition are common risk factors for TB, associated with poor treatment outcomes and exacerbated by TB. We aimed to assess non-communicable multimorbidity (co-occurrence of two or more medical conditions) in Filipino TB outpatients, focusing on malnutrition and diabetes. In a cross-sectional study, 637 adults (70% male) from clinics in urban Metro Manila (N = 338) and rural Negros Occidental (N = 299) were enrolled. Diabetes was defined as HbA1c of ≥6.5% and/or current diabetes medication. Study-specific HIV screening was conducted. The prevalence of diabetes was 9.2% (54/589, 95%CI: 7.0-11.8%) with 52% newly diagnosed. Moderate/severe undernutrition (body mass index (BMI) <17 kg/2) was 20.5% (130/634, 95%CI: 17.4-23.9%). Forty percent of participants had at least one co-morbidity (diabetes, moderate/severe undernutrition or moderate/severe anaemia (haemoglobin <11 g/dL)). HIV infection (24.4%, 74/303) was not associated with other co-morbidities (but high refusal in rural clinics). Central obesity assessed by waist-to-hip ratio was more strongly associated with diabetes (Adjusted Odds Ratio (AOR) = 6.16, 95%CI: 3.15-12.0) than BMI. Undernutrition was less common in men (AOR = 0.44, 95%CI: 0.28-0.70), and associated with previous history of TB (AOR = 1.97, 95%CI: 1.28-3.04) and recent reduced food intake. The prevalence of multimorbidity was high demonstrating a significant unmet need. HIV was not a risk factor for increased non-communicable multimorbidity

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Pengaruh lama penyimpanan bubuk beluntas (Pluchea indica Less.) dalam tea bag terhadap perubahan sifat fisikokimia air seduhan

Daun beluntas merupakan tanaman perdu yang sering digunakan sebagai obat tradisional. Pemanfaatan daun beluntas sebagai minuman seduhan teh beluntas menjadi salah satu inovasi. Pengolahan beluntas yang dikemas dalam tea bag akan lebih efisien dan juga lebih praktis. Produk bubuk sangat sensitif dan mudah mengalami perubahan selama penyimpanan. Berdasarkan hal tersebut maka lama penyimpanan bubuk beluntas dalam tea bag diduga berpengaruh pada sifat fisikokimia seperti kekeruhan, total asam dan pH dari minuman seduhan teh beluntas. Tujuan penelitian yang dilakukan adalah untuk mengetahui pengaruh lama penyimpanan bubuk daun beluntas dalam tea bag terhadap perubahan sifat fisikokimia meliputi kekeruhan, pH, dan total asam pada air seduhan teh beluntas. Rancangan penelitian yang digunakan yaitu rancangan acak kelompok (RAK) dengan satu faktor yaitu lama penyimpanan bubuk beluntas dalam tea bag yang terdiri dari 9 taraf perlakuan yaitu P1 (0 minggu), P2 (2 minggu), P3 (4 minggu), P4 (6 minggu), P5 (10 minggu), P6 (14 minggu), P7 (18 minggu), P8 (22 minggu) dan P9 (26 minggu) dengan ulangan sebanyak tiga kali. Parameter utama yang diuji yaitu sifat fisikokimia meliputi kadar air, pH, kekeruhan dan total asam. Data yang diperoleh dilakukan analisa varian (ANOVA) pada α=5% dan dilanjutkan analisa regresi linear untuk menentukan model trendline dan melihat kecenderungan kurva. Hasil penelitian menunjukkan bahwa lama penyimpanan bubuk daun beluntas berpengaruh terhadap sifat fisikokimia air seduhan. Kadar air, kekeruhan, derajat keasaman (pH) dan total asam masing-masing sebesar 8,88%-8,37% (db), 5,68-15,90 NTU; 6,85-8,10 dan 0,43-0,95 mg asam klorogenat/100g bahan. Kinetika degradasi kadar air mengikuti orde 0 dengan perkiraan umur simpan 148 hari

Patterns of non-communicable comorbidities at start of tuberculosis treatment in three regions of the Philippines: The St-ATT cohort.

Diabetes and undernutrition are common risk factors for tuberculosis (TB), associated with poor treatment outcomes and exacerbated by TB. Limited data exist describing patterns and risk factors of multiple comorbidities in persons with TB. Nine-hundred participants (69.6% male) were enrolled in the Starting Anti-TB Treatment (St-ATT) cohort, including 133 (14.8%) initiating treatment for multi-drug resistant TB (MDR-TB). Comorbidities were defined as: diabetes, HbA1c ≥6.5% and/or on medication; hypertension, systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg and/or on medication; anaemia (moderate/severe), haemoglobin <11g/dL; and, undernutrition (moderate/severe) body-mass-index <17 kg/m2. The most common comorbidities were undernutrition 23.4% (210/899), diabetes 22.5% (199/881), hypertension 19.0% (164/864) and anaemia 13.5% (121/899). Fifty-eight percent had ≥1 comorbid condition (496/847), with 17.1% having ≥2; most frequently diabetes and hypertension (N = 57, 6.7%). Just over half of diabetes (54.8%) and hypertension (54.9%) was previously undiagnosed. Poor glycemic control in those on medication (HbA1c≥8.0%) was common (N = 50/73, 68.5%). MDR-TB treatment was associated with increased odds of diabetes (Adjusted odds ratio (AOR) = 2.48, 95% CI: 1.55–3.95); but decreased odds of hypertension (AOR = 0.55, 95% CI: 0.39–0.78). HIV infection was only associated with anaemia (AOR = 4.51, 95% CI: 1.01–20.1). Previous TB treatment was associated with moderate/severe undernutrition (AOR = 1.98, 95% CI: 1.40–2.80), as was duration of TB-symptoms before starting treatment and household food insecurity. No associations for sex, alcohol or tobacco use were observed. MDR-TB treatment was marginally associated with having ≥2 comorbidities (OR = 1.52, 95% CI: 0.97–2.39). TB treatment programmes should plan for large proportions of persons requiring diagnosis and management of comorbidities with the potential to adversely affect TB treatment outcomes and quality of life. Dietary advice and nutritional management are components of comprehensive care for the above conditions as well as TB and should be included in planning of patient-centred services

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN