Gachon University Gil Medical Center

BACKGROUND: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). CONCLUSIONS: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

Endothelial dysfunction contributes to cardiovascular diseases, including hypertension, atherosclerosis, and coronary artery disease, which are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic disorders, including type 2 diabetes mellitus and obesity, which are also characterized by endothelial dysfunction. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct nonmetabolic branches of insulin-signaling pathways regulate secretion of the vasoconstrictor endothelin-1 in endothelium. Metabolic insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling, which in endothelium may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Therapeutic interventions in animal models and human studies have demonstrated that improving endothelial function ameliorates insulin resistance, whereas improving insulin sensitivity ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link cardiovascular and metabolic diseases. In the present review, we discuss pathophysiological mechanisms, including inflammatory processes, that couple endothelial dysfunction with insulin resistance and emphasize important therapeutic implications.

Abstract Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

Insulin resistance is the pivotal pathogenic component of many metabolic diseases, including type 2 diabetes mellitus, and is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin. Although the underlying mechanism of insulin resistance is not fully understood, several credible theories have been proposed. In this review, we summarize the functions of insulin in glucose metabolism in typical metabolic tissues and describe the mechanisms proposed to underlie insulin resistance, that is, ectopic lipid accumulation in liver and skeletal muscle, endoplasmic reticulum stress, and inflammation. In addition, we suggest potential therapeutic strategies for addressing insulin resistance.

Abstract A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

Insulin has important vascular actions to stimulate production of nitric oxide from endothelium. This leads to capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in classical insulin target tissues (e.g., skeletal muscle). Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways regulating endothelial production of nitric oxide share striking parallels with metabolic insulin-signaling pathways. Distinct MAPK-dependent insulin-signaling pathways (largely unrelated to metabolic actions of insulin) regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These and other cardiovascular actions of insulin contribute to coupling metabolic and hemodynamic homeostasis under healthy conditions. Cardiovascular diseases are the leading cause of morbidity and mortality in insulin-resistant individuals. Insulin resistance is typically defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin. This cardinal feature of diabetes, obesity, and dyslipidemia is also a prominent component of hypertension, coronary heart disease, and atherosclerosis that are all characterized by endothelial dysfunction. Conversely, endothelial dysfunction is often present in metabolic diseases. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling that in vascular endothelium contributes to a reciprocal relationship between insulin resistance and endothelial dysfunction. The clinical relevance of this coupling is highlighted by the findings that specific therapeutic interventions targeting insulin resistance often also ameliorate endothelial dysfunction (and vice versa). In this review, we discuss molecular mechanisms underlying cardiovascular actions of insulin, the reciprocal relationships between insulin resistance and endothelial dysfunction, and implications for developing beneficial therapeutic strategies that simultaneously target metabolic and cardiovascular diseases.

Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) may affect up to one third of stroke survivors. Various definitions of PSCI and PSD have been described. We propose PSD as a label for any dementia following stroke in temporal relation. Various tools are available to screen and assess cognition, with few PSD-specific instruments. Choice will depend on purpose of assessment, with differing instruments needed for brief screening (e.g., Montreal Cognitive Assessment) or diagnostic formulation (e.g., NINDS VCI battery). A comprehensive evaluation should include assessment of pre-stroke cognition (e.g., using Informant Questionnaire for Cognitive Decline in the Elderly), mood (e.g., using Hospital Anxiety and Depression Scale), and functional consequences of cognitive impairments (e.g., using modified Rankin Scale). A large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed. Currently, no specific biomarkers have been proven to robustly discriminate vulnerable patients ('at risk brains') from those with better prognosis or to discriminate Alzheimer's disease dementia from PSD. Further, neuroimaging is an important diagnostic tool in PSD. The role of computerized tomography is limited to demonstrating type and location of the underlying primary lesion and indicating atrophy and severe white matter changes. Magnetic resonance imaging is the key neuroimaging modality and has high sensitivity and specificity for detecting pathological changes, including small vessel disease. Advanced multi-modal imaging includes diffusion tensor imaging for fiber tracking, by which changes in networks can be detected. Quantitative imaging of cerebral blood flow and metabolism by positron emission tomography can differentiate between vascular dementia and degenerative dementia and show the interaction between vascular and metabolic changes. Additionally, inflammatory changes after ischemia in the brain can be detected, which may play a role together with amyloid deposition in the development of PSD. Prevention of PSD can be achieved by prevention of stroke. As treatment strategies to inhibit the development and mitigate the course of PSD, lowering of blood pressure, statins, neuroprotective drugs, and anti-inflammatory agents have all been studied without convincing evidence of efficacy. Lifestyle interventions, physical activity, and cognitive training have been recently tested, but large controlled trials are still missing.

Obesity is a prevalent and complex disease. The prevalence of obesity in Korea increased from 29.7% in 2010 to 35.7% in 2018, with the prevalence of abdominal obesity being 23.8% in 2018. Obesity contributes to medical costs and socioeconomic burden due to associated comorbidities. The treatment and management of obesity is changing based on new clinical evidence. The 2020 Korean Society for the Study of Obesity Guideline for the Management of Obesity in Korea summarizes evidence-based recommendations and treatment guidelines.

Abstract The discovery of drivers of cancer has traditionally focused on protein-coding genes 1–4 . Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers 6,7 , raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53 , in the 3′ untranslated regions of NFKBIZ and TOB1 , focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

OBJECTIVE: The number of people with metabolic syndrome is increasing worldwide, and changes in socioenvironmental factors contribute to this increase. Therefore, investigation of changes in metabolic syndrome and its components in South Korea, where rapid socioenvironmental changes have occurred in recent years, would be foundational in setting up an effective strategy for reducing this increasing trend. RESEARCH DESIGN AND METHODS: We compared the prevalence and pattern of metabolic syndrome among participants in the Korean National Health and Nutrition Examination Surveys for 1998, 2001, 2005, and 2007. In each survey, stratified, multistage, probability-sampling designs and weighting adjustments were conducted to represent the entire Korean population. The revised National Cholesterol Education Program criteria were used as the definition of metabolic syndrome. All biochemical parameters were measured in a central laboratory. RESULTS: A total of 6,907 (mean ± SE age 45.0 ± 0.2 years), 4,536 (45.5 ± 0.2), 5,373 (47.1 ± 0.2), and 2,890 (49.9 ± 0.3) Koreans over 20 years of age have participated in the studies in 1998, 2001, 2005, and 2007, respectively. The age-adjusted prevalence of metabolic syndrome increased significantly from 24.9% in 1998, 29.2% in 2001, and 30.4% in 2005 to 31.3% in 2007. Among the five components, the level of low HDL cholesterol increased the most, by 13.8% over the 10 years. Abdominal obesity and hypertriglyceridemia followed, with 8.7 and 4.9% increases, respectively. CONCLUSIONS: Because dyslipidemia and abdominal obesity were major factors in increasing the prevalence of metabolic syndrome in Koreans for the past 10 years, lifestyle interventions should be conducted at the national level to reduce the burden and consequences of metabolic syndrome.

BACKGROUND: Several studies have compared the treatment effects of coronary stenting and coronary-artery bypass grafting (CABG). However, there are limited data regarding the long-term outcomes of these two interventions for patients with unprotected left main coronary artery disease. METHODS: We evaluated 1102 patients with unprotected left main coronary artery disease who underwent stent implantation and 1138 patients who underwent CABG in Korea between January 2000 and June 2006. We compared adverse outcomes (death; a composite outcome of death, Q-wave myocardial infarction, or stroke; and target-vessel revascularization) with the use of propensity-score matching in the overall cohort and in separate subgroups according to type of stent. RESULTS: In the overall matched cohort, there was no significant difference between the stenting and CABG groups in the risk of death (hazard ratio for the stenting group, 1.18; 95% confidence interval [CI], 0.77 to 1.80) or the risk of the composite outcome (hazard ratio for the stenting group, 1.10; 95% CI, 0.75 to 1.62). The rates of target-vessel revascularization were significantly higher in the group that received stents than in the group that underwent CABG (hazard ratio, 4.76; 95% CI, 2.80 to 8.11). Comparisons of the group that received bare-metal stents with the group that underwent CABG and of the group that received drug-eluting stents with the group that underwent CABG produced similar results, although there was a trend toward higher rates of death and the composite end point in the group that received drug-eluting stents. CONCLUSIONS: In a cohort of patients with unprotected left main coronary artery disease, we found no significant difference in rates of death or of the composite end point of death, Q-wave myocardial infarction, or stroke between patients receiving stents and those undergoing CABG. However, stenting, even with drug-eluting stents, was associated with higher rates of target-vessel revascularization than was CABG.

Typical radiologic findings of a pulmonary metastasis include multiple round variable-sized nodules and diffuse thickening of interstitium. In daily practice, however, atypical radiologic features of metastases are often encountered that make distinction of metastases from other nonmalignant pulmonary diseases difficult. A detailed knowledge of the atypical radiologic features of a pulmonary metastasis with a good understanding of the histopathologic background is essential for correct diagnosis. Squamous cell carcinoma is regarded as the most common cell type of a cavitating metastasis, but metastatic nodules from adenocarcinomas and sarcomas also cavitate occasionally. Calcification can occur in a metastatic sarcoma or adenocarcinoma, which makes differentiation from a benign granuloma or hamartoma difficult. Peritumoral hemorrhage results in areas of nodular attenuation surrounded by a halo of ground-glass opacity. Pneumothorax commonly occurs in metastases from an osteosarcoma. Air-space consolidation is often seen in cases of metastases from gastrointestinal tract malignancies. Even though tumor emboli in pulmonary arteries can be seen at computed tomography, diagnosis is difficult because they are located in small or medium arteries. A common radiologic appearance of an endobronchial metastasis is an atelectasis. In cases of an endobronchial or a solitary pulmonary metastasis, differentiation between bronchogenic carcinoma and metastasis is difficult. Dilated vascular structures within the mass can be seen in metastatic sarcomas. A sterilized metastasis after chemotherapy is radiologically indistinguishable from a residual viable tumor. Benign tumors such as uterine leiomyomas and giant cell tumors of the bone rarely metastasize to the lung.

Cystic lesions of the retroperitoneum can be classified as either neoplastic or nonneoplastic. Neoplastic lesions include cystic lymphangioma, mucinous cystadenoma, cystic teratoma, cystic mesothelioma, müllerian cyst, epidermoid cyst, tailgut cyst, bronchogenic cyst, cystic change in solid neoplasms, pseudomyxoma retroperitonei, and perianal mucinous carcinoma. Nonneoplastic lesions include pancreatic pseudocyst, nonpancreatic pseudocyst, lymphocele, urinoma, and hematoma. Because the clinical implications of and therapeutic strategies for retroperitoneal cystic masses vary depending on the cause, the ability to noninvasively differentiate between masses is important. Although there is substantial overlap of computed tomographic (CT) findings in various retroperitoneal cysts, some CT features, along with clinical characteristics, may suggest a specific diagnosis. CT may provide important information regarding lesion location, size, and shape; the presence and thickness of a wall; the presence of septa, calcifications, or fat; and involvement of adjacent structures. The most important clinical parameters include patient gender, age, symptoms, and clinical history. Familiarity with the CT and clinical features of various retroperitoneal cystic masses facilitates accurate diagnosis and treatment.

Loss of skeletal muscle mass and strength has recently become a hot research topic with the extension of life span and an increasingly sedentary lifestyle in modern society. Maintenance of skeletal muscle mass is considered an essential determinant of muscle strength and function. Myokines are cytokines synthesized and released by myocytes during muscular contractions. They are implicated in autocrine regulation of metabolism in the muscle as well as in the paracrine/endocrine regulation of other tissues and organs including adipose tissue, the liver, and the brain through their receptors. Till date, secretome analysis of human myocyte culture medium has revealed over 600 myokines. In this review article, we summarize our current knowledge of major identified and characterized myokines focusing on their biological activity and function, particularly in muscle mass and function.

Abstract Transcript alterations often result from somatic changes in cancer genomes 1 . Various forms of RNA alterations have been described in cancer, including overexpression 2 , altered splicing 3 and gene fusions 4 ; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 5 . Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis , of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed ‘bridged’ fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.

Premature ovarian insufficiency (POI) is the loss of normal ovarian function before the age of 40 years, a condition that affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old. It is biochemically characterized by amenorrhea with hypoestrogenic and hypergonadotropic conditions, in some cases, causing loss of fertility. Heterogeneity of POI is registered by genetic and non-genetic causes, such as autoimmunity, environmental toxins, and chemicals. The identification of possible causative genes and selection of candidate genes for POI confirmation remain to be elucidated in cases of idiopathic POI. This review discusses the current understanding and future prospects of heterogeneous POI. We focus on the genetic basis of POI and the recent studies on non-coding RNA in POI pathogenesis as well as on animal models of POI pathogenesis, which help unravel POI mechanisms and potential targets. Despite the latest discoveries, the crosstalk among gene regulatory networks and the possible therapies targeting the same needs to explore in near future.

PURPOSE Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). METHODS Eligible patients, aged ≥ 18 years with R/R CLL, were randomly assigned 1:1 centrally and stratified by del(17p) status, Eastern Cooperative Oncology Group performance status score, and number of prior lines of therapy. Patients received acalabrutinib monotherapy or investigator’s choice (idelalisib plus rituximab [I-R] or bendamustine plus rituximab [B-R]). The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC) in the intent-to-treat population. Key secondary end points included IRC-assessed overall response rate, overall survival, and safety. RESULTS From February 21, 2017, to January 17, 2018, a total of 398 patients were assessed for eligibility; 310 patients were randomly assigned to acalabrutinib monotherapy (n = 155) or investigator’s choice (n = 155; I-R, n = 119; B-R, n = 36). Patients had received a median of two prior therapies (range, 1-10). After a median follow-up of 16.1 months (range, 0.03-22.4 months), median PFS was significantly longer with acalabrutinib monotherapy (PFS not reached) compared with investigator’s choice (16.5 months [95% CI, 14.0 to 17.1 months]; hazard ratio, 0.31 [95% CI, 0.20 to 0.49]; P &lt; .0001). Estimated 12-month PFS was 88% (95% CI, 81% to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator’s choice. Serious adverse events occurred in 29% of patients (n = 44 of 154) treated with acalabrutinib monotherapy, 56% (n = 66 of 118) with I-R, and 26% (n = 9 of 35) with B-R. Deaths occurred in 10% (n = 15 of 154), 11% (n = 13 of 118), and 14% (n = 5 of 35) of patients receiving acalabrutinib monotherapy, I-R, and B-R, respectively. CONCLUSION Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with R/R CLL.

Type 2 diabetes is caused by chronic insulin resistance and progressive decline in beta-cell function. Optimal beta-cell function and mass is essential for glucose homeostasis and beta-cell impairment leads to the development of diabetes. Elevated levels of circulating fatty acids (FAs) and disturbances in lipid metabolism regulation are associated with obesity, and they are major factors influencing the increase in the incidence of type 2 diabetes. Chronic free FA (FFA) treatment induces insulin resistance and beta-cell dysfunction; therefore, reduction of elevated plasma FFA levels might be an important therapeutic target in obesity and type 2 diabetes. Lipid signals via receptors, and intracellular mechanisms are involved in FFA-induced apoptosis. In this paper, we discuss lipid actions in beta cells, including effects on metabolic pathways and stress responses, to help further understand the molecular mechanisms of lipotoxicity-induced type 2 diabetes.