Istanbul University-Cerrahpaşa

Obesity is a chronic metabolic disease characterised by an increase of body fat stores. It is a gateway to ill health, and it has become one of the leading causes of disability and death, affecting not only adults but also children and adolescents worldwide. In clinical practice, the body fatness is estimated by BMI, and the accumulation of intra-abdominal fat (marker for higher metabolic and cardiovascular disease risk) can be assessed by waist circumference. Complex interactions between biological, behavioural, social and environmental factors are involved in regulation of energy balance and fat stores. A comprehensive history, physical examination and laboratory assessment relevant to the patient's obesity should be obtained. Appropriate goals of weight management emphasise realistic weight loss to achieve a reduction in health risks and should include promotion of weight loss, maintenance and prevention of weight regain. Management of co-morbidities and improving quality of life of obese patients are also included in treatment aims. Balanced hypocaloric diets result in clinically meaningful weight loss regardless of which macronutrients they emphasise. Aerobic training is the optimal mode of exercise for reducing fat mass while a programme including resistance training is needed for increasing lean mass in middle-aged and overweight/obese individuals. Cognitive behavioural therapy directly addresses behaviours that require change for successful weight loss and weight loss maintenance. Pharmacotherapy can help patients to maintain compliance and ameliorate obesity-related health risks. Surgery is the most effective treatment for morbid obesity in terms of long-term weight loss. A comprehensive obesity management can only be accomplished by a multidisciplinary obesity management team. We conclude that physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment. Treatment should be based on good clinical care, and evidence-based interventions; should focus on realistic goals and lifelong multidisciplinary management.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

PURPOSE The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non–small-cell lung cancer and no disease progression after concurrent chemoradiotherapy. Consolidation durvalumab was associated with significant improvements in the primary end points of overall survival (OS; stratified hazard ratio [HR], 0.68; 95% CI, 0.53 to 0.87; P = .00251) and progression-free survival (PFS [blinded independent central review; RECIST v1.1]; stratified HR, 0.52; 95% CI, 0.42 to 0.65; P < .0001), with manageable safety. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned. METHODS Patients with WHO performance status 0 or 1 (any tumor programmed cell death-ligand 1 status) were randomly assigned (2:1) to durvalumab (10 mg/kg intravenously; administered once every 2 weeks for 12 months) or placebo, stratified by age, sex, and smoking history. Time-to-event end point analyses were performed using stratified log-rank tests. Medians and landmark survival rates were estimated using the Kaplan-Meier method. RESULTS Seven hundred and nine of 713 randomly assigned patients received durvalumab (473 of 476) or placebo (236 of 237). As of January 11, 2021 (median follow-up, 34.2 months [all patients]; 61.6 months [censored patients]), updated OS (stratified HR, 0.72; 95% CI, 0.59 to 0.89; median, 47.5 v 29.1 months) and PFS (stratified HR, 0.55; 95% CI, 0.45 to 0.68; median, 16.9 v 5.6 months) remained consistent with the primary analyses. Estimated 5-year rates (95% CI) for durvalumab and placebo were 42.9% (38.2 to 47.4) versus 33.4% (27.3 to 39.6) for OS and 33.1% (28.0 to 38.2) versus 19.0% (13.6 to 25.2) for PFS. CONCLUSION These updated analyses demonstrate robust and sustained OS and durable PFS benefit with durvalumab after chemoradiotherapy. An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and free of disease progression, establishing a new benchmark for standard of care in this setting.

Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug-resistant temporal lobe epilepsy (TLE). Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome. However, no international consensus about definitions and terminology has been achieved. A task force reviewed previous classification schemes and proposes a system based on semiquantitative hippocampal cell loss patterns that can be applied in any histopathology laboratory. Interobserver and intraobserver agreement studies reached consensus to classify three types in anatomically well-preserved hippocampal specimens: HS International League Against Epilepsy (ILAE) type 1 refers always to severe neuronal cell loss and gliosis predominantly in CA1 and CA4 regions, compared to CA1 predominant neuronal cell loss and gliosis (HS ILAE type 2), or CA4 predominant neuronal cell loss and gliosis (HS ILAE type 3). Surgical hippocampus specimens obtained from patients with TLE may also show normal content of neurons with reactive gliosis only (no-HS). HS ILAE type 1 is more often associated with a history of initial precipitating injuries before age 5 years, with early seizure onset, and favorable postsurgical seizure control. CA1 predominant HS ILAE type 2 and CA4 predominant HS ILAE type 3 have been studied less systematically so far, but some reports point to less favorable outcome, and to differences regarding epilepsy history, including age of seizure onset. The proposed international consensus classification will aid in the characterization of specific clinicopathologic syndromes, and explore variability in imaging and electrophysiology findings, and in postsurgical seizure control.

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

We surveyed the 20-year outcome of a cohort of patients with Behçet syndrome with emphasis on both mortality and morbidity. During 1999 and 2000, we collected outcome information on 387/428 (90.4%) of a cohort of patients (262 male, 125 female) who had registered in a dedicated outpatient clinic between July 1977 and December 1983. In 245/345 (71.0%) patients, outcome information was based on a formal hospital reevaluation, and in the remaining patients, on detailed telephone interviews. Forty-two patients (9.8%) (39 male, 3 female) had died, mainly due to major vessel disease and neurologic involvement. Mortality, as measured by standardized mortality ratios (SMR), was specifically increased among young males, among whom morbidity was also the highest. However, the SMR tended to decrease significantly with the passage of time. The same was also true for all mucocutaneous and articular manifestations. Both the onset of eye disease and its greatest damage were also usually within the first few years of disease onset. These suggest that the "disease burden" of Behçet syndrome is usually confined to the early years of its course, and in many patients the syndrome "burns out." However, central nervous system involvement and major vessel disease are exceptions. They can have their onset late (5-10 yr) during the disease course. As reflected in the mortality figures, the disease was less severe among the females for almost each disease manifestation. There were no female patients with arterial aneurysms. Severely impaired vision did not always mean an eventual loss of useful vision, and those patients with a late onset of eye disease had a better visual prognosis.

BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

There has been an increased interest in speech pattern analysis applications of Parkinsonism for building predictive telediagnosis and telemonitoring models. For this purpose, we have collected a wide variety of voice samples, including sustained vowels, words, and sentences compiled from a set of speaking exercises for people with Parkinson's disease. There are two main issues in learning from such a dataset that consists of multiple speech recordings per subject: 1) How predictive these various types, e.g., sustained vowels versus words, of voice samples are in Parkinson's disease (PD) diagnosis? 2) How well the central tendency and dispersion metrics serve as representatives of all sample recordings of a subject? In this paper, investigating our Parkinson dataset using well-known machine learning tools, as reported in the literature, sustained vowels are found to carry more PD-discriminative information. We have also found that rather than using each voice recording of each subject as an independent data sample, representing the samples of a subject with central tendency and dispersion metrics improves generalization of the predictive model.

Cytotoxic agents have long been used in Behçet's syndrome, especially for eye involvement, but their effectiveness has been uncertain. We conducted a two-year randomized, placebo-controlled, double-blind trial of azathioprine (2.5 mg per kilogram of body weight per day) in Turkish men with Behçet's syndrome without eye disease (group 1; n = 25) or with eye disease (group 2; n = 48). Corticosteroid treatment remained available to all the patients. All six patients withdrawn from the study because of severe eye disease were receiving placebo (P less than 0.001). Azathioprine was superior to placebo in the prevention of new eye disease in group 1 (1 vs. 8 patients; P less than 0.01) and in group 2 among the 14 patients who at entry had disease in only one eye (P less than 0.001). There were fewer episodes of hypopyon uveitis (1 vs. 15; P less than 0.001) among the group 2 patients who took azathioprine. The patients taking azathioprine also had less frequent oral ulcers, genital ulcers, and arthritis. There were no serious side effects attributable to azathioprine. We conclude that azathioprine is effective in controlling the progression of Behçet's syndrome, especially its most serious manifestation, eye disease.

OBJECTIVE: Reliability and validity of the Mini Mental State Examination in differentiating mild dementia from normal controls in Turkish population. METHOD: The Standardized Mini Mental State Examination (SMMSE) and its instruction were translated into Turkish. A total of 212 subjects with mean age of 77 +/- 6, were recruited for the study. 71 were diagnosed to be demented and 141 were evaluated as normal controls. The scale total score was analysed for discriminant validity using Student's t-test. Sensitivity, specificity, positive and negative predictive values and kappa score were calculated for all of the scores between 18 and 29. Kappa value was calculated for the comparison of the dementia diagnosis between the two investigators using the best cut off score obtained in the analysis above. RESULTS: Statistical analysis revealed that the Turkish version of the SMMSE has high discriminant validity and interrater reliability in the diagnosis of mild dementia. The cut off score 23/24 was found to have the highest sensitivity (0.91), specificity (0.95), positive and negative predictive values (0.90 and 0.95) and kappa score (0.86). Interrater reliability analysis showed high correlation (r:0.99) and kappa value (0.92). CONCLUSION: The results of this study showed that the Turkish version of the SMMSE has high reliability and validity for the diagnosis of mild dementia in Turkish population.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

The present systematic review aimed to determine discrimination experiences of sexual and gender minority (SGM) individuals and attitudes toward SGM among health care staff in health care settings. Following PRISMA guidelines, the review was conducted in 3 databases (PubMed, Cochrane Library, Science Direct) using keywords of sexual and gender minority, including “gay,” “lesbian,” “bisexual,” “transgender,” “LGB,” “LGBT,” “health care discrimination,” “stigma,” “homophobia,” “transphobia,” and “attitudes of healthcare professionals” from May to September 2016. Predetermined inclusion criteria were selected. Thirty quantitative studies were eligible for inclusion in this review. Discriminative behaviors experienced by SGM individuals were stigma, denial or refusal of health care, and verbal or physical abuse. Knowledge and educational levels, beliefs, and religion of health care providers affected their attitudes toward SGM patients and their homophobia level. These findings revealed that health care providers needed more education about SGM issues, and SGM-friendly policies should be created for improving health care for SGM individuals.

PURPOSE The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover. METHODS Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed. RESULTS With a median follow-up of 44.0 months, 405 OS events had occurred and 208 placebo-treated patients (39.5%) had crossed over to apalutamide. The median treatment duration was 39.3 (apalutamide), 20.2 (placebo), and 15.4 months (crossover). Compared with placebo, apalutamide plus ADT significantly reduced the risk of death by 35% (median OS not reached v 52.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P < .0001) and by 48% after adjustment for crossover (hazard ratio, 0.52; 95% CI, 0.42 to 0.64; P < .0001). Apalutamide plus ADT delayed second progression-free survival and castration resistance ( P < .0001 for both). Health-related quality of life, per total Functional Assessment of Cancer Therapy-Prostate, in both groups was maintained through the study. Safety was consistent with previous reports. CONCLUSION The final analysis of TITAN confirmed that, despite crossover, apalutamide plus ADT improved OS, delayed castration resistance, maintained health-related quality of life, and had a consistent safety profile in a broad population of patients with mCSPC.

The first contact for patients with obesity for any medical treatment or other issues is generally with General Practitioners (GPs). Therefore, given the complexity of the disease, continuing GPs' education on obesity management is essential. This article aims to provide obesity management guidelines specifically tailored to GPs, favouring a practical patient-centred approach. The focus is on GP communication and motivational interviewing as well as on therapeutic patient education. The new guidelines highlight the importance of avoiding stigmatization, something frequently seen in different health care settings. In addition, managing the psychological aspects of the disease, such as improving self-esteem, body image and quality of life must not be neglected. Finally, the report considers that achieving maximum weight loss in the shortest possible time is not the key to successful treatment. It suggests that 5-10% weight loss is sufficient to obtain substantial health benefits from decreasing comorbidities. Reducing waist circumference should be considered even more important than weight loss per se, as it is linked to a decrease in visceral fat and associated cardiometabolic risks. Finally, preventing weight regain is the cornerstone of lifelong treatment, for any weight loss techniques used (behavioural or pharmaceutical treatments or bariatric surgery).

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

OBJECTIVES: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. METHODS: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. CONCLUSIONS: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

INTRODUCTION: In the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53-0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42-65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized. METHODS: Patients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan-Meier method. RESULTS: Overall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2-64.9), updated OS (HR = 0.71; 95% CI: 0.57-0.88) and PFS (HR = 0.55; 95% CI: 0.44-0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively. CONCLUSION: These updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).

IMPORTANCE: Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors. OBJECTIVE: To evaluate the antitumor activity of pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively. INTERVENTIONS: Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062. MAIN OUTCOMES AND MEASURES: Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing. RESULTS: At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months [95% CI, 2.0-9.8 months] for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy. CONCLUSIONS AND RELEVANCE: Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.

Obesity is a chronic metabolic disease affecting adults and children worldwide. It has become one of the leading causes of death, as obesity is known to be the main risk factor for a number of non-communicable diseases, in particular type 2 diabetes. This close relationship led to the connotation 'diabesity', highlighting the fact that the majority of individuals with diabetes are overweight or obese. Until today the BMI is still used to classify overweight and obesity. Since reduced muscle mass is highly prevalent throughout the BMI range, the measurement of body composition is strongly recommended. Moreover, it is essential for monitoring the course of weight reduction, which is part of every effective anti-obesity treatment. Weight reduction can be achieved via different weight loss strategies, including lifestyle intervention (diet and exercise), pharmacotherapy, or bariatric surgery. However, not all of these strategies are suitable for all patients, and any further needs should be considered. Besides, attention should also be drawn to concomitant therapies. These therapies may promote additional weight gain and further trigger the deterioration of blood glucose control. Thus, therapeutic strategies are warranted, which can be easily used for the management of obese patients with type 2 diabetes to achieve their glycemic and weight loss goals.

INTRODUCTION: In the phase 3 PACIFIC study of patients with unresectable stage III NSCLC without progression after chemoradiotherapy, durvalumab demonstrated significant improvements versus placebo in the primary end points of progression-free survival (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.42-65, p < 0.0001) and overall survival (OS) (HR = 0.68, 95% CI: 0.53-0.87, p = 0.00251), with manageable safety and no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study. METHODS: Patients, stratified by age, sex, and smoking history, were randomized (2:1) to receive durvalumab, 10 mg/kg intravenously every 2 weeks, or placebo for up to 12 months. OS was analyzed by using a stratified log-rank test in the intention-to-treat population. Medians and rates at 12, 24, and 36 months were estimated by the Kaplan-Meier method. RESULTS: As of January 31, 2019, 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months. The updated OS remained consistent with that previously reported (stratified HR = 0.69 [95% CI: 0.55-0.86]); the median OS was not reached with durvalumab but was 29.1 months with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. All secondary outcomes examined showed improvements consistent with previous analyses. CONCLUSIONS: Updated OS data from PACIFIC, including 3-year survival rates, demonstrate the long-term clinical benefit with durvalumab after chemoradiotherapy and further establish the PACIFIC regimen as the standard of care in this population.