Kwang Hyuk Lee

White matter microstructural changes in pure Alzheimer's disease and subcortical vascular dementia.

Recent studies have demonstrated that Alzheimers disease (AD) and subcortical vascular dementia (SVaD) have white matter (WM) microstructural changes. However, previous studies on AD and SVaD rarely eliminated the confounding effects of patients with mixed Alzheimers and cerebrovascular disease pathologies. Therefore, our aim was to evaluate the divergent topography of WM microstructural changes in patients with pure AD and SVaD.

Quantitative analysis of NPTX2 hypermethylation is a promising molecular diagnostic marker for pancreatic cancer.

Objectives: Percutaneous fine-needle aspiration cytology or biopsy has been used for pathological confirmation in pancreatic cancer. Sometimes, it is difficult to approach the mass because of surrounding major vessels, and there is a risk of seeding. Although endoscopic retrograde cholangiopancreatography (ERCP)-guided pancreatic duct brush cytology is less invasive, its reliability is very low. Recently, aberrantly methylated genes were reported in pancreatic cancer tissue. This study was to develop a novel molecular diagnostic approach based on epigenetic characteristics. Methods: We enrolled pathologically proven 33 pancreatic cancer patients and 22 benign pancreaticobiliary disease patients. The ERCP-guided pancreatic duct brush cytology samples were obtained. Genomic DNA was extracted, and NPTX2 CpG island hypermethylation was examined quantitatively by real-time polymerase chain reaction amplification after chemical modification. Results: Pancreatic cancer cytology samples had statistically significant higher levels of NPTX2 methylation compared with benign diseases, and the optimal cutoff value of NPTX2 methylation was 1.2%. The sensitivity was 87%, and specificity was 80%, whereas pathological examination by ERCP-guided pancreatic duct brush cytology had a sensitivity of 38%. Conclusions: The quantitative analysis of NPTX2 hypermethylation may play a role in making highly sensitive and less invasive diagnosis of pancreatic cancer. Therefore, NPTX2 hypermethylation could be a promising molecular diagnostic marker.

A comparison of bilateral stenting methods for malignant hilar biliary obstruction.

BACKGROUND/AIMS Despite common use of stent-instent methods for endoscopic bilateral metal stenting in malignant hilar obstruction, the longevity of these stents and clinical outcomes of patients who receive them are less well known than for the side-by-side method. We aimed to compare treatment outcomes according to bilateral stenting method. METHODOLOGY A total of 41 patients were divided into two groups: a bilateral side-by-side metal stenting group (side-by-side group, n=19) and a bilateral stent-in-stent metal stenting group (stent-in-stent group, n=22). RESULTS During the study period, successful drainage was achieved in 15 of 19 patients (78.9%) with the side-by-side placement, which did not differ significantly from the proportion with the stent-in-stent placement (18 of 22 patients, 81.8%). The two groups did not differ significantly in rates of early complications (31.6% vs. 22.7%, p=0.725), late complications (36.8% vs. 50.0%, p=0.531) or death (47.4% vs. 54.5%, p=0.647). Comparing stent patency and survival curves according to bilateral stenting type, patients with stent-in-stent placement and those with side-by-side placement did not differ significantly (p=0.771 and p=0.769). CONCLUSIONS Our results show no significant difference in clinical outcomes, including stent patency and overall survival, between side-by-side and stent-in-stent bilateral metal stenting in patients with malignant hilar obstruction.

Routine cardiac evaluation in patients with ischaemic stroke and absence of known atrial fibrillation or coronary heart disease: transthoracic echocardiography vs. multidetector cardiac computed tomography

Background and purpose:  Cardiac evaluation is routinely conducted in patients with ischaemic stroke because embolisms originating from the heart are an important cause of stroke. We compared the prevalence of cardioaortic sources of cerebral embolism (CSCE) in patients with ischaemic stroke detected by transthoracic echocardiography (TTE) and/or multidetector cardiac computed tomography (MDCT). Additionaly, we investigated the frequency and severity of asymptomatic coronary artery disease (CAD) in patients who underwent MDCT.

Repetitive leg movements mimicking periodic leg movement during sleep in a brain‐dead patient

Sir, Spontaneous movements are noted in up to 75% of brain-dead patients [1]. We present a brain-dead patient who showed periodic leg movement (PLM) mimicking periodic limb movement during sleep. Informed consent was obtained from the patient’s family. A 50-year-old untreated hypertensive man became abruptly comatose. He scored 3 on the Glasgow Coma Scale at initial examination in another hospital. Brain computed tomography showed a massive intracranial hemorrhage in the left hemisphere (Fig. 1). He was transferred to our hospital for verification of brain death and donation of organs for transplantation after 24 h in coma. Apart from hypertension, his medical history was unremarkable. His family denied any history of sleep disorders. The first examination to determine brain death was performed immediately according to the national guidelines and the American Academy of Neurology Practice Parameters [2] as follows: (i) thorough clinical neurological examination, including documentation of coma, the absence of brainstem reflexes, and apnea; (ii) these clinical features were verified to be present for at least 6 h for determination of irreversibility; (iii) hypothermia, drug intoxication, and other metabolic causes of coma were excluded; (iv) Electroencephalogram was recorded as a confirmatory test after the second examination and to demonstrate electrocerebral inactivity. The patient was in a state of coma, and strong painful stimulation did not evoke any motor response. His pupils were largely dilated and unresponsive to light. No oculocephalic movements were elicited by rapid turning of the head. The caloric test showed no reflex eyeball movement. Corneal and cough reflexes were absent. The apnea test revealed no spontaneous respiratory drive at a 60 mmHg partial pressure of arterial carbon dioxide (baseline arterial blood gas: pH 7.398, PaCO2 40.2 mmHg, PaO2 372.8 mmHg; 8 min after apnea: pH 7.226, PaCO2 71.6 mmHg, PaO2 533.3 mmHg). At this time, the patient did not show any spontaneous or reflex movement. After a 12-h observation period, the second evaluation for brain death revealed no change in his neurological status. EEG demonstrated electrocerebral inactivity, confirming brain death. Subsequently, his right leg moved periodically. The periodic movement occurred approximately 10 to 20 times per hour without apparent provocation. It consisted of dorsiflexion of the foot and slight flexion of the knee and hip lasting for 2–3 s and recurring at a frequency of approximately once every 20–30 s (Fig. 2). It was approximately 30 h before these periodic movements ceased. Spontaneous or reflex movements such as plantar responses, muscle stretch reflexes, abdominal reflexes, plantar withdrawal, and finger jerks have been reported in patients with brain death. They are considered spinal reflexes and therefore do not preclude the diagnosis of brain death [1]. PLM during sleep involves repetitive, stereotypic extension of the great toe and dorsiflexion of the ankle with occasional flexion of the knee and hip, each movement lasting approximately 0.5–5.0 s with

Prevalence and detection of low-allele-fraction variants in clinical cancer samples

Accurate detection of genomic alterations using high-throughput sequencing is an essential component of precision cancer medicine. We characterize the variant allele fractions (VAFs) of somatic single nucleotide variants and indels across 5095 clinical samples profiled using a custom panel, CancerSCAN. Our results demonstrate that a significant fraction of clinically actionable variants have low VAFs, often due to low tumor purity and treatment-induced mutations. The percentages of mutations under 5% VAF across hotspots in EGFR, KRAS, PIK3CA, and BRAF are 16%, 11%, 12%, and 10%, respectively, with 24% for EGFR T790M and 17% for PIK3CA E545. For clinical relevance, we describe two patients for whom targeted therapy achieved remission despite low VAF mutations. We also characterize the read depths necessary to achieve sensitivity and specificity comparable to current laboratory assays. These results show that capturing low VAF mutations at hotspots by sufficient sequencing coverage and carefully tuned algorithms is imperative for a clinical assay.High-throughput sequencing is used to identify somatic variants in cancer patients. Here, the authors perform panel-based profiling of 5095 clinical samples and demonstrate that many clinically-actionable variants have low variant allele fractions, requiring assays with high detection sensitivity.

Prediction of carcinoma after resection in subjects with ampullary adenomas on endoscopic biopsy.

Background/Goals: The endoscopic treatment of ampullary adenomas is established; however, the false-negative rate of endoscopic biopsy for carcinoma is 20% to 30%, and it remains uncertain whether identifiable features predict malignancy. Our aim in this study was to evaluate the predictable factors of malignancy in ampullary adenomas on endoscopic biopsy. Study: Ninety-one subjects diagnosed with ampullary adenoma on endoscopic biopsy were confirmed after endoscopic or surgical resection of ampullary lesions between 1995 and 2011 respectively. Clinical, laboratory, radiologic, and endoscopic findings were compared between patients with adenoma and carcinoma after resection. We examined the predictors of malignancy in ampullary adenoma on endoscopic biopsy. Results: The malignancy rate in ampullary adenomas on endoscopic biopsy was 26.4%. Univariate analysis revealed that presence of symptoms, villous components, high-grade dysplasia (HGD), papilla enlargement on computed tomography, duct dilatation on radiologic imaging, bilirubin>2 mg/dL, aspartate aminotransferase>40 IU/L, alanine aminotransferase>40 IU/L, and alkaline phosphatase>90 U/L were associated with malignancy in patients over 65 years of age. HGD [odds ratio, 6.86 (95% confidence interval, 1.58-29.79)] and ductal dilatation [odds ratio, 11.12 (95% confidence interval, 2.27-54.37)] were independently associated with malignancy in multivariate analysis. The sensitivity and negative predictive value for ≥1 risk factors were 95.83% and 96.77%, respectively. The presence of 2 risk factors resulted in a high specificity (96%) and positive predictive value (84%) for malignancy. Conclusions: HGD and ductal dilatation are significant predictors of malignancy in ampullary adenomas. When these risk factors are present, precautions should be taken in the consideration of malignancy in patients with ampullary adenoma.

Is Health Screening Beneficial for Early Detection and Prognostic Improvement in Pancreatic Cancer

Background/Aims The aim of this study was to evaluate the usefulness of health screening for early detection and improved prognosis in pancreatic cancer. Methods Between 1995 and 2008, 176,361 examinees visited the Health Promotion Center (HPC). Twenty patients diagnosed with pancreatic cancer were enrolled. During the same period, 40 patients were randomly selected from 2,202 patients diagnosed with pancreatic cancer at the Out Patient Clinic (OPC) for comparison. Results Within the HPC group, 10 patients were initially suspected of having pancreatic cancer following abnormal ultrasonographic findings, and 9 patients had suspected cases following the detection of elevated serum CA 19-9. The curative resection rate was higher in the HPC group than in the OPC group (p=0.011). The median survival was longer in the HPC group than in the OPC group (p=0.000). However, there was no significant difference in the 3-year survival rate between the two groups. Asymptomatic patients (n=6/20) in the HPC group showed better curative resection and survival rates than symptomatic patients. However, the difference was not statistically significant. Conclusions Health screening is somewhat helpful for improving the curative resection rate and median survival of patients with pancreatic cancer detected by screening tests. However, the benefit of this method in improving long-term survival is limited by how early the cancer is detected.

Abstract 96: Targeted sequencing from endoscopic ultrasound-guided fine needle aspirates of pancreatic ductal adenocarcinoma

Next-generation sequencing (NGS) that enables the analyses of massively parallel sequences of DNA can advance the understanding of the underlying molecular pathophysiologies of cancer. Such recent genomic analyses have revealed a complex mutational landscape in surgical specimens of PDAC. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is used in the diagnosis of pancreatic cancer. Several genomic analyses using EUS-FNA in PDAC have been undertaken in a small number of patients. This study evaluated the feasibility of targeted NGS of specimens obtained using EUS-FNA to clarify genetic markers associated with the prognosis of pancreatic cancer. One hundred sixty six patients who underwent EUS-FNA with pathologically confirmed PDAC were included. Genomic DNA was extracted and quality control metrics of DNA analytes were measured. The specimens that passed a quality control test (N = 101, 61%) underwent NGS using a customized cancer panel (CancerSCAN) enriched in the exons of 83 genes. Clinical prognostic factors associated with survival in PDAC were age, performance status, CA 19-9 level, curative resection, chemotherapy, tumor mass size, tumor location, stage and metastasis site in univariate analysis (P = 0.020, Citation Format: Joo Kyung Park, Kwang Hyuk Lee, Jong Kyun Lee, Kyu Taek Lee, Woong-Yang Park, Dae-Soon Son. Targeted sequencing from endoscopic ultrasound-guided fine needle aspirates of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 96.