Showing papers by "Seoul National University Hospital published in 2023"

Novel Genetic Variants Associated with Chronic Kidney Disease Progression

Abstract: Background The incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated. Methods We conducted a genome-wide association study among 1738 patients with CKD, mainly from the KoreaN cohort study for Outcomes in patients With CKD. The outcome was eGFR slope. We performed a replication study for discovered single nucleotide polymorphisms (SNPs) with P <10 −6 in 2498 patients with CKD from the Chronic Renal Insufficiency Cohort study. Several expression quantitative trait loci (eQTL) studies, pathway enrichment analyses, exploration of epigenetic architecture, and predicting disruption of transcription factor (TF) binding sites explored potential biological implications of the loci. We developed and evaluated the effect of polygenic risk scores (PRS) on incident CKD outcomes. Results SNPs in two novel loci, TPPP and FAT1-LINC02374 , were replicated (rs59402340 in TPPP , P discovery =7.11×10 −7 , P CRIC =8.13×10 −4 , P meta =7.23×10 −8 ; rs28629773 in FAT1-LINC02374 , P discovery =6.08×10 −7 , P CRIC =4.33×10 −2 , P meta =1.87×10 −7 ). The eQTL studies revealed that the replicated SNPs regulated the expression level of nearby genes associated with kidney function. Furthermore, these SNPs were near gene enhancer regions and predicted to disrupt the binding of TFs. PRS based on the independently significant top 22 SNPs were significantly associated with CKD outcomes. Conclusions This study demonstrates that SNP markers in the TPPP and FAT1-LINC02374 loci could be predictive markers for the decline of eGFR in patients with CKD.

Positive Results from the Fecal Immunochemical Test Can Be Related to Dementia: A Nationwide Population-Based Study in South Korea

Abstract: Background: The fecal immunochemical test (FIT) is widely used in screening for colorectal cancer (CRC), but FIT results can be positive for diseases other than CRC. Objective: We investigated the association between positive results of FIT and the incidence of dementia using a nationwide database. Methods: FIT-positive participants were collected from a database provided by the Korean National Health Insurance Service. Results: The incidence of all kinds of dementia was higher in FIT-positive than FIT-negative subjects (p < 0.0001). FIT-positive participants had a higher risk of Alzheimer’s disease (AD) (p < 0.0001) and vascular dementia (p = 0.0002), compared to participants with FIT negativity. The risk of all kinds of dementia or AD in FIT-positive participants was higher in younger (age < 65 years) than older participants (p < 0.0001 for all kinds of dementia; p = 0.0002 for AD). Conclusion: FIT positivity was correlated with an increased risk of dementia, especially in participants under 65 years of age. The study suggests that clinicians can consider dementia when FIT-positive participants fail to show any malignancies.

Methane direct conversion to olefins, aromatics, and hydrogen over silica entrapped bimetallic MeFe-SiO2 (Me = Co, Ni, Pd, Pt) catalysts

Abstract: Here, MeFe-SiO2 (Me = Co, Ni, Pd, Pt) catalysts with bimetallic sites entrapped in a highly crystalline SiO2 structure were synthesized and used for the conversion of methane to olefins, aromatics, and hydrogen (MTOAH) at 1020°C. The MeFe-SiO2 catalysts showed polymorphic forms of cristobalite, quartz, and tridymite after reaction. Among the bimetallic catalysts, 0.5Pt1.0Fe-SiO2 exhibited the highest methane conversion (10.0%) with high hydrocarbon selectivity (79.9%) at 1020°C. In C2 (ethane, ethylene, acetylene) conversion with hydrogen co-feeding at 1020°C, acetylene was identified as a major coke precursor. MTOAH with different gas hourly space velocities (GHSV) showed that the 0.5Pt1.0Fe-SiO2 catalyst exhibited higher methane conversion and aromatics selectivity than the 1.0Fe-SiO2 catalyst. Density functional theory calculations showed that the Pt-Fe3C surface is energetically favorable for methane activation and inhibits graphitic coke deposition by C2 dehydrogenation. Consequently, a modification of the entrapped Fe sites by Pt addition improved the methane conversion and hydrocarbon selectivity of the catalyst.

Surgical Outcomes in Patients With Low-Risk Papillary Thyroid Microcarcinoma from MAeSTro Study

Abstract: Objective: To investigate surgical, and clinical outcomes in patients with low-risk papillary thyroid microcarcinoma (PTMC) according to treatment options (immediate operation [IOP] vs. delayed operation following active surveillance (AS) [DOP]). Background: AS has been adopted as an alternative to immediate surgery in patients with low-risk PTMC. Although some patients undergo surgery during AS, there is little information on surgical, and clinical outcomes after delayed operation following AS. Methods: A multicenter prospective cohort study including 1177 patients was conducted at 3 tertiary hospitals in Korea from June 2016 to January 2020. Patients with low-risk PTMC were enrolled. The participants were self-assigned into AS or IOP, and during AS, the patients underwent surgery if there were signs of disease progression or if the patient’s choice changed. Results: A total of 516 patients underwent operation; 384 (74.4%) in the IOP group and 132 (25.6%) in the DOP group. Compared with the IOP group, the DOP group was significantly associated with a larger tumor size (P=0.002), higher rates of lymphatic invasion (P=0.002) and multifocality (P=0.008). However, the rates of total thyroidectomy, postoperative hypoparathyroidism and vocal cord palsy did not differ significantly between the groups (P= 0.283, P=0.184 and P=0.284, respectively). Of the 132 patients in the DOP group, disease progression was present in 39 (29.5%) patients. The DOP group with disease progression had a significantly higher rate of lymph node metastasis (P=0.021) and radioiodine therapy (P=0.025) than the DOP group without disease progression. Conclusions: These results suggest that AS might be considered an alternative treatment option for patients with low-risk PTMC regarding the extent of thyroidectomy and postoperative complications in the DOP group. To assess oncologic outcomes, long-term follow-up will be needed. Trial registration: ClinicalTrials.gov Identifier: NCT02938702.

The transcription factor Mef2d regulates B:T synapse–dependent GC-T _FH differentiation and IL-21–mediated humoral immunity

Abstract: Communication between CD4 T cells and cognate B cells is key for the former to fully mature into germinal center–T follicular helper (GC-T FH ) cells and for the latter to mount a CD4 T cell–dependent humoral immune response. Although this interaction occurs in a B:T synapse–dependent manner, how CD4 T cells transcriptionally regulate B:T synapse formation remains largely unknown. Here, we report that Mef2d, an isoform of the myocyte enhancer factor 2 (Mef2) transcription factor family, is a critical regulator of this process. In CD4 T cells, Mef2d negatively regulates expression of Sh2d1a , which encodes SLAM-associated protein (SAP), a critical regulator of B:T synapses. We found that Mef2d regulates Sh2d1a expression via DNA binding–dependent transcriptional repression, inhibiting SAP-dependent B:T synapse formation and preventing antigen-specific CD4 T cells from differentiating into GC-T FH cells. Mef2d also impeded IL-21 production by CD4 T cells, an important B cell help signaling molecule, via direct repression of the Il21 gene. In contrast, CD4 T cell–specific disruption of Mef2d led to a substantial increase in GC-T FH differentiation in response to protein immunization, concurrent with enhanced SAP expression. MEF2D mRNA expression inversely correlates with human systemic lupus erythematosus (SLE) patient autoimmune parameters, including circulating T FH –like cell frequencies, autoantibodies, and SLEDAI scores. These findings highlight Mef2d as a pivotal rheostat in CD4 T cells for controlling GC formation and antibody production by B cells.

Effect of Tulobuterol Patch Versus Placebo on the Occurrence of Respiratory Adverse Events in Children Undergoing Tonsillectomies: A Randomized Controlled Trial

Abstract: BACKGROUND: Perioperative respiratory adverse events are common in children. We aimed to evaluate the effect of the transdermal β-2 agonist, tulobuterol, compared with that of placebo on the incidence of perioperative respiratory adverse events in pediatric patients undergoing tonsillectomy. METHODS: In this triple-blinded (patient, anesthesia provider, and outcome assessor) randomized controlled trial, 188 patients were randomly allocated to receive tulobuterol or a placebo. The tulobuterol groups received a tulobuterol patch (1 mg) masked with a bandage, whereas the placebo only received the bandage. The assigned bandage was applied to the patients 8 to 10 hours before the surgery. The primary outcome was the occurrence of any perioperative respiratory adverse events: oxygen desaturation <95%, airway obstruction, laryngospasm, bronchospasm, severe coughing, or stridor. The outcomes were evaluated using the average relative effect test, which estimates the effect of individual components of a composite outcome and then averages effects across components. RESULTS: A total of 88 and 94 patients who received tulobuterol and placebo, respectively, were analyzed. The incidence of any perioperative respiratory adverse event was lower with tulobuterol (n = 13/88; 14.7%) than that with the placebo (n = 40/94; 42.5%), with an estimated average relative risk (95% confidence interval) across components of 0.35 (0.20–0.60; P < .001). The symptoms of airway obstruction were lower with tulobuterol (n = 8/88; 9.0%) than that with the placebo (n = 32/94; 34.0%), with relative risk (95% CI) of 0.31 (0.17–0.56; P < .001). The occurrence of severe coughing was lower with tulobuterol (n = 1/88; 1.1%) than that with the placebo (n = 8/94; 8.5%), with relative risk (95% CI) of 0.15 (0.03–0.68; P = .014). CONCLUSIONS: In preschool children undergoing tonsillectomy, the preoperative application of a tulobuterol patch could decrease the occurrence of perioperative respiratory adverse events. Further studies are needed to elucidate the effect of the tulobuterol patch in a broad spectrum of pediatric anesthesia. Export

Energy-efficient self-locking micropump system using single bi-stable electromagnetic actuator

Abstract: While electromagnetic micropumps have potential for the low operating voltage within a compact configuration, the significant power consumption level due to the continuous current input during pumping operations could hinder the application to battery-driven systems such as wearable drug delivery devices. This paper presents an energy-efficient and self-locking micropump system using a single bi-stable electromagnetic actuator with a double-sided tubing. The proposed bi-stable electromagnetic actuator consists of a single-body iron mover and a PM-attached stator, the combination of which can minimize the reluctance of the magnetic flux path induced by a current excitation, thereby achieving the high energy-efficiency. The actuator is integrated into the micropump system with a double-sided tubing configuration, which provides (i) the assistant force during switching motions in order to reduce the energy consumption, (ii) the self-primed pumping operation with a sequence of the pumping phase and the loading phase, and (iii) the self-locking characteristic to prevent unwanted flows during non-operating states. The low-voltage and low-energy characteristics of the proposed micropump system are experimentally validated. The switching voltage and the switching energy are measured to be a minimum of 0.43 V and 1.88 mJ, respectively. The pumping volume is measured to be 1.52 μL per pumping cycle, and the micropump can maintain the self-locking characteristic up to a pressure of 24 kPa by the latching force of 3.7 N from the actuator. The proposed energy-efficient and self-locking micropump system can be readily applicable in various applications where the reliable pumping with the low-power and low-voltage characteristics are required such as wearable drug delivery systems.

Swallowing problems: Major components of nutritional deficits in adults with cerebral palsy

Abstract: Individuals with cerebral palsy have many health problems associated with their neurological disorders. In adults with cerebral palsy, dysphagia symptoms are common and can have a tremendous effect on nutrition and swallowing-related quality of life. The Eating and Drinking Ability Classification System is an ordinal scale that can be used in adults with cerebral palsy to assess how they eat and drink in everyday life. It is a reliable and valid tool to evaluate the ability of adults with cerebral palsy to chew and swallow, the food or fluid textures manageable by them, changes in breathing associated with swallowing, choking symptoms, and the level of assistance required to bring food or liquids to the mouth. This chapter describes the swallowing problems in adults with cerebral palsy and discusses the usability and clinical importance of the Eating and Drinking Ability Classification System in cerebral palsy based on prior research and our clinical experience. In addition, this chapter discusses the evaluation of dysphagia in adults with cerebral palsy and nutritional problems associated with dysphagia. Lastly, this chapter describes relevant nutritional supplements according to the results of the dysphagia evaluation.

C-Arm Computed Tomographic Image Fusion for Repetitive Transarterial Chemoembolization of Hepatocellular Carcinoma

Abstract: The aim of this study was to evaluate the potential implications of fusion imaging with C-arm computed tomography (CACT) scans for repetitive conventional transarterial chemoembolization (cTACE) for hepatocellular carcinoma.Fifty-six cTACE sessions were performed using fusion CACT images from September 2020 to June 2021 in a tertiary referral center, and the data were retrospectively analyzed. Fusion of unenhanced and enhanced CACT images was considered when previously accumulated iodized oil hampered the identification of local tumor progression or intrahepatic distant metastasis (indication A), when a tumor was supplied by multiple arteries with different origins from the aorta and missing tumor enhancement was suspected (indication B), or when iodized oil distribution on immediate post-cTACE CACT images needed to be precisely compared with the pre-cTACE images (indication C). Fusion image quality, initial tumor response, time to local progression (TTLP) of index tumors, and time to progression (TTP) were evaluated.The fusion quality was satisfactory with a mean misregistration distance of 1.4 mm. For the 40 patients with indication A, the initial tumor responses at 3 months were nonviable, equivocal, and viable in 27 (67.5%), 4 (10.0%), and 9 (22.5%) index tumors, respectively. The median TTLP and TTP were 14.8 months and 4.5 months, respectively. For 10 patients with indication B, the median TTLP and TTP were 8.3 months and 2.6 months, respectively. Among the 6 patients with indication C, 2 patients were additionally treated at the same cTACE session after confirming incomplete iodized oil uptake on fusion imaging.Fusion CACT images are useful in patients with hepatocellular carcinoma undergoing repetitive cTACE.

Navigation Guided Spine Surgery

Abstract: Since the introduction of the basic principle of stereotactic surgery, navigation-guided spine surgery has evolved from using fluoroscopy to computed tomography-guided navigation systems. Among them, the O-arm scanner-based system has been most commonly used due to its advantages. Many studies have shown the safety and accuracy of instrumentation with image-guided spinal navigation systems. Efficacy in the surgical resection of tumors, accuracy in spinal instrumentation, and safety with less radiation exposure for the surgical team and patients have also been reported. With image-guided spinal navigation, simultaneous insertion of the cage from the front and the pedicle screw and rod systems from the back is possible. This surgical technique is named one stop oblique lumbar interbody fusion-ONE (OLIF-ONE). By comparing total operation time, clinical outcomes, and radiological outcomes, OLIF-ONE might reduce surgical time with no significant difference between conventional OLIF procedures in outcomes. OLIF-ONE enabled surgeons to correct spondylolisthesis before insertion of cage and it facilitated to insert the interbody cage at the “sweet spot” which was not easy with a conventional OLIF procedure.

Data from Association Between Metabolic Syndrome and Risk of Esophageal Cancer: a Nationwide Population-Based Study

Abstract: <div>AbstractBackground:<p>Metabolic syndrome (MetS) is believed to increase the risk of esophageal cancer. However, most studies have been conducted in Western countries, focusing on esophageal adenocarcinoma (EAC). We aimed to investigate the association between MetS and risk of esophageal cancer in nationally representative large dataset in Korea, where esophageal squamous cell carcinoma (ESCC) is predominant.</p>Methods:<p>We analyzed the health examinations and claims data from the Korean National Health Insurance Service (NHIS). A total of 6,795,738 subjects who received an NHIS provided health examination in 2009 (index year) were included. Cox proportional hazards models were used to estimate multivariable adjusted HRs (aHR) and 95% confidence intervals (CI) for the association of MetS and its components (elevated waist circumference, blood pressure, triglycerides, fasting blood glucose, reduced high-density lipoprotein cholesterol) with the risk of esophageal cancer.</p>Results:<p>During a mean (± SD) follow-up of 8.2 (± 1.1) years, 6,414 cases of esophageal cancer occurred. MetS was associated with an increased risk of esophageal cancer (aHR, 1.11; 95% CI, 1.05–1.18). Among the components of MetS, elevated waist circumference (aHR, 1.24; 95% CI, 1.16–1.33), high blood pressure (aHR, 1.29; 95% CI, 1.22–1.37), and fasting blood glucose (aHR, 1.16; 95% CI, 1.11–1.22) were associated with increased risk of esophageal cancer.</p>Conclusions:<p>MetS was associated with an increased risk of esophageal cancer.</p>Impact:<p>Our findings suggest that individuals with MetS may be at increased risk for esophageal cancer, specifically ESCC. Further studies are needed to establish the relationship between MetS and esophageal cancer.</p></div>

Data from Association Between Metabolic Syndrome and Risk of Esophageal Cancer: a Nationwide Population-Based Study

Abstract: <div>AbstractBackground:<p>Metabolic syndrome (MetS) is believed to increase the risk of esophageal cancer. However, most studies have been conducted in Western countries, focusing on esophageal adenocarcinoma (EAC). We aimed to investigate the association between MetS and risk of esophageal cancer in nationally representative large dataset in Korea, where esophageal squamous cell carcinoma (ESCC) is predominant.</p>Methods:<p>We analyzed the health examinations and claims data from the Korean National Health Insurance Service (NHIS). A total of 6,795,738 subjects who received an NHIS provided health examination in 2009 (index year) were included. Cox proportional hazards models were used to estimate multivariable adjusted HRs (aHR) and 95% confidence intervals (CI) for the association of MetS and its components (elevated waist circumference, blood pressure, triglycerides, fasting blood glucose, reduced high-density lipoprotein cholesterol) with the risk of esophageal cancer.</p>Results:<p>During a mean (± SD) follow-up of 8.2 (± 1.1) years, 6,414 cases of esophageal cancer occurred. MetS was associated with an increased risk of esophageal cancer (aHR, 1.11; 95% CI, 1.05–1.18). Among the components of MetS, elevated waist circumference (aHR, 1.24; 95% CI, 1.16–1.33), high blood pressure (aHR, 1.29; 95% CI, 1.22–1.37), and fasting blood glucose (aHR, 1.16; 95% CI, 1.11–1.22) were associated with increased risk of esophageal cancer.</p>Conclusions:<p>MetS was associated with an increased risk of esophageal cancer.</p>Impact:<p>Our findings suggest that individuals with MetS may be at increased risk for esophageal cancer, specifically ESCC. Further studies are needed to establish the relationship between MetS and esophageal cancer.</p></div>

L-type Ca²⁺channels mediate regulation of glutamate release by subthreshold potential changes

Abstract: ABSTRACT Subthreshold depolarization enhances neurotransmitter release evoked by action potentials and plays a key role in modulating synaptic transmission by combining analog and digital signals. This process is known to be Ca 2+ -dependent. However, the underlying mechanism of how small changes in basal Ca 2+ caused by subthreshold depolarization can regulate transmitter release triggered by a large increase in local Ca 2+ is not well understood. This study aimed to investigate the source and signaling mechanisms of Ca 2+ that couple subthreshold depolarization with the enhancement of glutamate release in hippocampal cultures and CA3 pyramidal neurons. Subthreshold depolarization increased presynaptic Ca 2+ levels, the frequency of spontaneous release, and the amplitude of evoked release, all of which were abolished by blocking L-type Ca 2+ channels. A high concentration of intracellular Ca 2+ buffer or blockade of calmodulin and phospholipase C abolished depolarization induced increases in transmitter release. Estimation of the readily releasable pool size using hypertonic sucrose showed depolarization induced increases in readily releasable pool size, and this increase was abolished by blockade of calmodulin or phospholipase C. Our results provide mechanistic insights into the modulation of transmitter release by subthreshold potential change and highlight the role of L-type Ca 2+ channels in coupling subthreshold depolarization to the activation of Ca 2+ -dependent signaling molecules that regulate transmitter release. SIGNIFICANCE Neuronal activities are encoded by action potentials, but subthreshold changes in resting membrane potentials also play important roles in regulating neuronal functions including synaptic transmission. It is, however, poorly understood how small changes in basal Ca 2+ induced by subthreshold depolarization regulate transmitter release triggered by a large increase in local Ca 2+ in presynaptic terminals. We demonstrate that L-type Ca 2+ channels are the major source of presynaptic Ca 2+ influx at basal state and during subthreshold depolarization, resulting in the activation of signaling molecules such as calmodulin and phospholipase C, which facilitate transmitter release by increasing both release probability and the readily releasable pool size. Our results provide mechanistic insight into how subthreshold potential changes contribute to regulating transmitter release.

Genotype–phenotype correlation of X-linked Alport syndrome observed in both genders: a multicenter study in South Korea

Abstract: Abstract The genotype–phenotype correlation of the X-linked Alport syndrome (XLAS) has been well elucidated in males, whereas it remains unclear in females. In this multicenter retrospective study, we analyzed the genotype–phenotype correlation in 216 Korean patients (male:female = 130:86) with XLAS between 2000 and 2021. The patients were divided into three groups according to their genotypes: the non-truncating group, the abnormal splicing group, and the truncating group. In male patients, approximately 60% developed kidney failure at the median age of 25.0 years, and kidney survival showed significant differences between the non-truncating and truncating groups ( P < 0.001, hazard ratio (HR) 2.8) and splicing and truncating groups ( P = 0.002, HR 3.1). Sensorineural hearing loss was detected in 65.1% of male patients, while hearing survival periods showed a highly significant difference between the non-truncating and truncating groups ( P < 0.001, HR 5.1). In female patients, approximately 20% developed kidney failure at the median age of 50.2 years. The kidney survival was significantly different between the non-truncating and truncating groups ( P = 0.006, HR 5.7). Our findings support the presence of genotype–phenotype correlation not only in male patients but also in female patients with XLAS.

The characteristics of atmospheric SF6 in the Korean Peninsula during 2017-202

Abstract: Sulfur hexafluoride (SF6) is a most potent anthropogenic greenhouse gas with a global warming potential of 23,900 over a 100-year time horizon. There are no natural sink sources in the troposphere and they are destructed by photolysis and electron attachment in the mesosphere. &#160;SF6 is mainly used for electrical insulation, circuit breaker, and plasma etching processes in the semiconductor industry. For monitoring changes in atmospheric SF6 in Korean Peninsula, 3 surface in-situ greenhouse gas monitoring stations, Anmyeondo (AMY), Jeju Gosan (JGS), and Ulleungdo (ULD), have been operating. AMY started its operation in 2007 and JGS and ULD followed in 2017. Due to the advantage of their locations surrounding the Korean Peninsula at the Western, Southern, and Eastern ends, they can provide information on the inflow and outflow of the SF6 in the Korean Peninsula. According to the data from 2017 to 2020, the increasing trend of background mole fraction of SF6 from the stations was in good agreement with that of the global monitoring stations, Mauna Loa and Cape Grim. Each station shows the characteristic enhancement tendency by wind direction and speed, which implies the possible influence of the regional emission source and long-range transport. In addition, based on the analysis with HYSPLIT model the central area of the Korean Peninsula is identified as an emission source region, as well as central part of China and Japan.

Identification of Active Pulmonary Tuberculosis Among Patients With Positive Interferon-Gamma Release Assay Results

Abstract: To evaluate the accuracy of a deep learning-based computer-aided detection (CAD) system in identifying active pulmonary tuberculosis on chest radiographs (CRs) of patients with positive interferon-gamma release assay (IGRA) results in different scenarios of clinical implementation.We collected the CRs of consecutive patients with positive IGRA results. Findings of active pulmonary tuberculosis on CRs were independently evaluated by the CAD and a thoracic radiologist, followed by interpretation using the CAD. Sensitivity and specificity were evaluated in different scenarios: (a) radiologists' interpretation, (b) radiologists' CAD-assisted interpretation, and (c) CAD-based prescreening (radiologists' interpretation for positive CAD results only). We conducted a reader test to compare the accuracy of the CAD with those of 5 radiologists.Among 1780 patients (men, 53.8%; median age, 56 y), 44 (2.5%) were diagnosed with active pulmonary tuberculosis. The CAD-assisted interpretation exhibited a higher sensitivity (81.8% vs. 72.7%; P =0.046) but lower specificity than the radiologists' interpretation (84.1% vs. 85.7%; P <0.001). The CAD-based prescreening exhibited a higher specificity than the radiologists' interpretation (88.8% vs. 85.7%; P <0.001) at the same sensitivity, with a workload reduction of 85.2% (1780 to 263). In the reader test, the CAD exhibited a higher sensitivity than radiologists (72.7% vs. 59.5%; P =0.005) at the same specificity (88.0%), and CAD-assisted interpretation significantly improved the sensitivity of radiologists' interpretation (72.3%; P <0.001).For identifying active pulmonary tuberculosis among patients with positive IGRA results, deep learning-based CAD can enhance the sensitivity of interpretation. CAD-based prescreening may reduce the radiologists' workload at an improved specificity.

Data from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with &lt;i&gt;ALK&lt;/i&gt;-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

Abstract: <div>AbstractPurpose:<p>Central nervous system metastases are a prominent cause of morbidity and mortality in patients with <i>ALK</i>-positive (<i>ALK</i>⁺) non–small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with <i>ALK</i>⁺ NSCLC metastatic to the brain and/or leptomeninges.</p>Patients and Methods:<p>Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses.</p>Results:<p>Per investigator assessment, in arms 1 (<i>n</i> = 42), 2 (<i>n</i> = 40), 3 (<i>n</i> = 12), and 4 (<i>n</i> = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6–52.0), 30.0% (16.6–46.5), 50.0% (21.1–78.9), and 59.1% (43.2–73.7); whole-body DCR (95% CI): 66.7% (50.5–80.4), 82.5% (67.2–92.7), 66.7% (34.9–90.1), and 70.5% (54.8–83.2); intracranial ORRs (95% CI): 39.3% (21.5–59.4), 27.6% (12.7–47.2), 28.6% (3.7–71.0), and 51.5% (33.5–69.2). In arm 5 (<i>n</i> = 18), whole-body ORR was 16.7% (95% CI, 3.6–41.4) and DCR was 66.7% (95% CI, 41.0–86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood–brain barrier.</p>Conclusions:<p>Ceritinib showed antitumor activity in patients with <i>ALK</i>⁺ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease.</p><p><i>See related commentary by Murciano-Goroff et al., p. 2477</i></p></div>

Data from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with &lt;i&gt;ALK&lt;/i&gt;-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

Abstract: <div>AbstractPurpose:<p>Central nervous system metastases are a prominent cause of morbidity and mortality in patients with <i>ALK</i>-positive (<i>ALK</i>⁺) non–small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with <i>ALK</i>⁺ NSCLC metastatic to the brain and/or leptomeninges.</p>Patients and Methods:<p>Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses.</p>Results:<p>Per investigator assessment, in arms 1 (<i>n</i> = 42), 2 (<i>n</i> = 40), 3 (<i>n</i> = 12), and 4 (<i>n</i> = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6–52.0), 30.0% (16.6–46.5), 50.0% (21.1–78.9), and 59.1% (43.2–73.7); whole-body DCR (95% CI): 66.7% (50.5–80.4), 82.5% (67.2–92.7), 66.7% (34.9–90.1), and 70.5% (54.8–83.2); intracranial ORRs (95% CI): 39.3% (21.5–59.4), 27.6% (12.7–47.2), 28.6% (3.7–71.0), and 51.5% (33.5–69.2). In arm 5 (<i>n</i> = 18), whole-body ORR was 16.7% (95% CI, 3.6–41.4) and DCR was 66.7% (95% CI, 41.0–86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood–brain barrier.</p>Conclusions:<p>Ceritinib showed antitumor activity in patients with <i>ALK</i>⁺ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease.</p><p><i>See related commentary by Murciano-Goroff et al., p. 2477</i></p></div>

Lower risk of depression after smoking cessation and alcohol abstinence in patients with gastric cancer who underwent gastrectomy: A population‐based, nationwide cohort study

Abstract: Although depression is associated with poor treatment outcomes in patients with cancer, little is known about whether lifestyle modifications could help prevent depression. The authors aimed to identify the effect of lifestyle modifications, including smoking cessation, alcohol abstinence, and starting regular physical activity, on new-onset depression in patients with gastric cancer who underwent surgery.By using the Korean National Health Insurance Service database, patients with gastric cancer who underwent surgery between 2010 and 2017 were identified. Self-reported lifestyle behaviors within 2 years before and after surgery were analyzed using the health examination database. Patients were classified according to changes in lifestyle behaviors, and their risk of new-onset depression was compared.Among 18,902 patients, 2302 (12.19%) developed depression (26.00 per 1000 person-years). Smoking cessation (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.66-0.91) and alcohol abstinence (HR, 0.79; 95% CI, 0.69-0.90) were associated with reduced risk of depression development compared with persistent smoking and persistent drinking, respectively. Starting regular physical activity was not associated with risk of depression. When lifestyle behaviors after gastrectomy were scored from 0 to 3 points (1 point each for not smoking, not drinking, and being physically active), the risk of depression tended to decrease as lifestyle scores increased from 0 points (reference) to 1 point (HR, 0.69; 95% CI, 0.55-0.83), 2 points (HR, 0.60; 95% CI, 0.50-0.76), and 3 points (HR, 0.55; 95% CI, 0.45-0.68).Smoking cessation and alcohol abstinence are associated with reduced risk of developing depression in patients with gastric cancer who undergo surgery.

Gate Ringing in Superjunction MOSFETs with a Parasitic Capacitance in the Load Inductor

Abstract: In this paper, the origin of the gate oscillations with a stray capacitance in the load inductor is analyzed with a device/circuit mix-mode simulation. It is found that the gate ringing occurs when the superjunction device reaches its pinch-off potential (the n-pillar and the p-pillar are fully depleted by the lateral depletion process). The progress of the depletion profiles of the superjunction leads to a rapid change of the drain-to-source capacitance and the dV/dt. Finally, the dV/dt causes a sudden change of the current flow rate across the stray capacitance of the load inductor and the device while triggering the parasitic inductances. Based on these results, a comparative study was carried out with an ideal inductive load switching and, finally, the dampers for relieving the gate ringing were investigated.