북극 해빙 변화 및 북반구 대류권계면 변동성과 관련된 성층권-대류권 커플링의 계절내 진화 특성

학위논문(박사) -- 서울대학교대학원 : 자연과학대학 지구환경과학부, 2021.8. 김진주.Variations in stratospheric polar vortex and associated stratosphere-troposphere interaction during boreal winter play an important role in the subseasonal prediction of tropospheric weather. In order to better understand stratosphere-troposphere interaction, this study scrutinizes intraseasonal evolutionary characteristics of stratospheric polar vortex fluctuations in terms of two different physical variables: sea ice and tropopause. The leading two modes of winter Arctic sea ice cover variability and their linkage to stratospheric polar vortex variations are analyzed. The first mode represents an accelerating trend of Arctic sea ice decline associated with Arctic amplification, particularly in the Barents and Kara Seas. The second mode is associated with decadal-scale phase shifts of dipole sea ice anomalies in the North Atlantic caused by NAO circulation. The first two modes of sea ice variability represent respectively a forced climate change and internal variability. Sea ice reduction in the Barents and Kara Seas for the first mode is linked to a stratospheric vortex weakening during mid January–late February. The second mode with the dipole structure of positive sea ice anomalies in the Barents and Greenland Seas and negative anomalies in the Hudson Bay and Labrador Sea is related to a stratospheric vortex weakening during December–early February. The spatial evolutionary structure of anomalous polar vortex also exhibits differences between the two modes. When stratospheric anomalies are fully developed, stratospheric vortex is shifted to Eurasia in the first mode and to Europe in the second mode. These two sea ice modes with different low-frequency variations partly contribute to a long-term mean change in subseasonal evolution of stratospheric polar vortex. To identify general evolutionary characteristics in stratosphere-troposphere coupling, the leading modes of Northern Hemisphere tropopause variability for November–April and the associated stratosphere-troposphere variability were analyzed. The first two modes feature the intraseasonal evolution of tropopause pressure anomalies over the Arctic, which respond directly to stratospheric temperature fluctuations in association with stratospheric polar vortex variations. These two modes reflect the link between stratospheric polar vortex strength and high-latitude tropospheric circulation. The first mode represents a single-phase fluctuation of the stratospheric polar vortex from winter to early spring. The second mode describes a two-phase fluctuation of the stratospheric vortex with opposite signs in winter and in spring. Tropopause pressure anomalies near the mid-latitude tropospheric jet regions exhibit significant zonal variation. In the first mode, in particular, these mid-latitude tropopause anomalies are linked to asymmetric jet variations in the Atlantic and the Pacific regions. In regard to the Northern Annular mode, distinct vertical evolution structures of the two modes are practically related to the interannually varying structure of extreme vortex events with relatively long persistence. The results can help to improve the seasonal predictability of the Arctic climate by better understanding the evolutionary structure and potential timing of individual vortex events.북반구 겨울철의 성층권 극소용돌이 변동 및 관련 성층권-대류권 상호작용은 대류권 날씨의 계절내 예측에 있어서 중요한 요소들이다. 성층권-대류권 상호작용에 대해 좀 더 정확하게 이해하기 위하여, 본 연구에서는 해빙 및 대류권계면 변동과 관련해 성층권 극소용돌이 변동의 계절내 진화 특성을 면밀히 조사하였다. 먼저, 성층권 극소용돌이 변동에 영향을 미치는 요인 중 하나인 해빙 변동의 주요 모드가, 북극 온난화 증폭과 관련된 북극 해빙 감소 시그널과 북대서양 진동과 관련된 북대서양 쌍극 해빙 변동 시그널임을 확인하였다. 이는 바렌츠-카라해 해빙 감소의 가속화 시그널과 래브라도해 해빙의 십년규모 위상 감소 시그널을 반영하며, 두 해빙 변동 과정 모두 겨울철 성층권 소용돌이 약화를 동반한다. 하지만 해빙 변동 모드에 따라 성층권 극소용돌이 약화의 발생시기와 소용돌이의 위치 혹은 형태 변화는 다르게 나타났다. 첫번째 모드에서는 바렌츠-카라해의 해빙 감소와 함께 1월 중순에서 2월 말 동안에 소용돌이 약화가, 두 번째 모드에서는 바렌츠-그린란드해 해빙 증가 및 래브라도해-허드슨만의 해빙 감소와 함께 12월에서 2월초까지 소용돌이 약화가 동반된다. 지역적 변동 관점에서는, 소용돌이 약화 편차가 가장 발달 했을 때에 성층권 소용돌이가 첫번째 모드에서 유라시아쪽으로 이동하고, 두 번째 모드에서 유럽쪽으로 국한되어 이동하는 경향이 있음을 확인하였다. 또한 두 개 해빙 모드의 다른 장주기 변동이 겨울철 성층권 극소용돌이 진화의 장기 평균 변화에 기여함을 확인하였다. 한편, 이런 특정 대류권 요인에 관련된 성층권 소용돌이 변동뿐만 아니라 성층권 소용돌이의 보편적인 계절내 진화 특성 또한 명확하게 이해되지 못하고 있다. 본 연구에서는 성층권과 대류권 사이의 경계면에 해당하는 대류권계면 변동의 주요 모드와 관련해 11월~4월 기간 동안의 성층권-대류권 연직 변동 특성에 대해 분석하였다. 결과는 주요 대류권계면 변동이 성층권 극소용돌이의 겨울철-이른 봄철 동안 지속되는 단일 위상 변동과 겨울철-봄철에 반대되는 2개 위상 변동의 직접적 영향을 받음을 확인하였다. 동서평균장 관점에서는 두 모드 모두에서 성층권 소용돌이와 대류권 고위도 순환장의 일관된 진화 양상이 특징적으로 나타났다. 하지만, 지역적 관점에서는 성층권 소용돌이와 대류권 제트 변동 사이에 비대칭적 관계가 존재함을 확인하였다. 특히 첫번째 모드에서는 2-3월에 성층권 극소용돌이 약화와 함께 대서양 제트축은 적도쪽으로 이동하지만 태평양 제트축은 극쪽으로 이동하는 경향이 있음이 확인되었다. 또한 성층권 극소용돌이 개별 이벤트들의 발달 구조 및 발달 시기가 해마다 변동하는 것이 두 대류권계면 모드의 변동에 의존하고 있음을 확인하였다. 결과는 성층권-대류권 연직 변동의 주요 발달 특성 뿐만 아니라 개별 특성에 대한 심화된 이해를 가능하게 함으로써, 날씨의 계절내 예측성 향상에 도움을 줄 것으로 예상된다.Chapter 1. Introduction 1 1.1. Background and motivation 1 1.2. Objectives 6 Chapter 2. Data and Methodology 7 2.1. Data 7 2.2. Methodology 8 Chapter 3. Characteristics of stratospheric polar vortex fluctuations associated with sea ice variability in the Arctic winter 10 3.1. Leading modes of Arctic sea ice variability in winter 10 3.2. Variation of stratospheric polar vortex strength 16 3.3. Geometric characteristics of stratospheric anomalies during polar vortex weakening 23 3.4. Contribution to actual stratospheric vortex fluctuations 35 Chapter 4. Stratosphere-troposphere variability in connection with the leading modes of NH tropopause variability 39 4.1. Leading modes of NH tropopause pressure variation 39 4.2. Evolution in the Arctic stratosphere and troposphere and its linkage to the Arctic tropopause variability from a zonal mean perspective 49 4.3. Horizontal evolution patterns of the stratospheric and tropospheric circulation 60 4.4. Mid-latitude tropospheric jet fluctuation and its linkage to the tropopause undulation 68 4.5. Role of the two modes in actual stratospheric vortex fluctuations 73 Chapter 5. Concluding Remarks 81 References 85 국문초록 95박

Atmospheric Circulation and Precipitation Fields over the tropical Indo-Pacific Region Associated with the Biennial Oscillation of Sea Surface Temperature

학위논문 (석사)-- 서울대학교 대학원 : 지구환경과학부, 2015. 8. Kim, Kwang-Yul.Temporal and spatial patterns of atmospheric circulation and precipitation over Indo-Pacific region are analyzed in conjunction with the biennial mode of sea surface temperature anomalies (SSTA). It is investigated how the biennial mode modifies the Asian-Australian monsoon precipitation, which features the seasonal migration of precipitation band. In an attempt to document the impact of the biennial mode on the Asia-Australian monsoon precipitation, two-year cycle variability of SSTA and key atmospheric variables is separated from the seasonal cycle via Cyclostationary EOF (CSEOF) analysis. The monthly Extended Reconstruction SST version 3 (ERSST v.3) and the twentieth century reanalysis version 2 (20CR) are used. The biennial evolution of atmospheric variables is clearly seen over the central Indo-Pacific region (90°-150°E, 20°S-20°N). In boreal summer, local meridional circulation is a distinguishing characteristic over the central Indo-Pacific region, whereas a north-south expanded branch of an intensified zonal circulation develops in austral summer. In boreal summer, low-level anticylonic/cyclonic circulation over the western North Pacific is linked with the northern branch of the local meridional circulation. Essential factors responsible for the distinctive atmospheric responses in the two seasons are the intensity and size of SSTA over the central-eastern Pacific and the different timings of the phase transition in the tropical Pacific and the Indian Ocean. The impact of the biennial mode is clearly different between the two seasons with substantially different impact on the Asian monsoon and the Australian monsoon.Abstract i Contents iii List of Figures iv 1. Introduction 1 2. Data and Method 2.1. Data 5 2.2. CSEOF analysis 5 2.3. Regression Analysis in CSEOF Space 6 3. Results and Discussion 3.1. The seasonal cycle of precipitation 8 3.2. The bidnnial mode of sea surface temperature 11 3.3. Temporal evolution of atmospheric circulation in the biennial mode 14 3.4. Change in moisture flux and precipitation in the biennial mode 20 3.5. Difference in the biennial reponse between the two hemispheres 28 4. Concluding remarks 35 References 41 국문초록 46Maste

Synthesis and Characterization of Allyl Polysulfone Derivatives for Membrane Application and Polystyrene Sulfonate Derivatives for Draw Solute Application

학위논문 (박사)-- 서울대학교 대학원 : 화학생물공학부, 2017. 2. 이종찬.This study presents synthesis and characterization of novel polymeric materials and their application to water treatment. Firstly, A series of ultrafiltration (UF) membranes based on polysulfone and mussel-inspired poly(dopamine methacrylamide) (PDMA) were prepared by a versatile in situ process composed of grafting-through polymerization and consecutive non-solvent induced phase separation. Nisin, a low molecular weight antimicrobial peptide, was subsequently immobilized on the surface of the UF membrane through the reaction between its N-terminal NH2 group and the catechol group in PDMA for microbial mitigation. The resulting nisin containing UF membranes showed outstanding fouling resistance and flux recovery ability due to the hydrophilic characteristics of PDMA moiety in the membrane. Furthermore, it is worth noting that the resulting membranes exhibit the antimicrobial activity against the Staphylococcus aureus (ATCC 6538) due to the nisin moiety. Second, thin film composite (TFC) polyamide membrane with tailored support structure was prepared for forward osmosis (FO) application. The porous polysulfone-based substrate was fabricated using the grafting-through polymerization of allyl polysulfone and dimethylaminoethyl methacrylate (DMAEMA), followed by non-solvent induced phase separation. 1,3,5-tricarbonyl trichloride and m-phenylene diamine were employed as the monomers for the interfacial polymerization to form a thin polyamide selective layer. poly(dimethylaminoethyl methacrylate) (PDMAEMA) moieties in the substrate was then convert into zwitterionic sulfobetaine moieties to impart fouling resistance. When the TFC membrane prepared in this study was tested in the FO system, a remarkably large water permeation flux value (~63.2 LMH) was observed with a small ratio of reverse solute flux to water permeation flux (Js/Jv) of < 0.02 g/L in the active layer against draw solution (AL-DS) mode using 2 M NaCl solution as a draw solution and DI water as a feed solution. Especially, the zwitterionic substrate in the TFC membrane exhibited fouling resistance against synthetic wastewater feed stream. Third, a series of oligomeric poly(tetrabutylphosphonium styrenesulfonate)s (PSSP#, where # is the number of monomer units in the oligomer) were prepared from tetrabutylphosphonium styrenesulfonate (SSP) as a monomer for application as a draw solute in a FO system. Although the water permeation flux values in the FO system using the oligomeric PSSP as a draw solute were slightly smaller than those using the monomeric SSP, the reverse solute flux values using the PSSPs were found to be much smaller than those using the SSP, indicating that the oligomers are more efficient draw solute materials in the FO system than the low molecular weight monomer. For example, when 20 wt% of the PSSP5 aqueous solution is used as the draw solution, the water permeation flux and reverse solute flux values are 14.50 LMH and 0.14 gMH, respectively, and when 20 wt% of the SSP aqueous solution is used, they are 16.28 LMH and 0.53 gMH, respectively. Since PSSPs have a lower critical solution temperature (LCST), the PSSP in water could be simply separated by heating to above the LCST without any other separation process. Moreover, it was found that the PSSPs have excellent bactericidal property above 99.9 % against Escherichia coli (ATCC 8739).1. Introduction 1 1.1. Polymers for membrane filtration 2 1.2. Draw solutes in forward osmosis 4 1.3. Motivation 7 1.4. References 9 2. Antifouling and Antimicrobial Membranes for Ultrafiltration (UF) Application 13 2.1. Introduction 14 2.2. Experimental 16 2.3. Results and Discussion 26 2.4. Conclusion 38 2.5. References 39 3. Thin Film Composite (TFC) Membranes for Forward Osmosis (FO) Application 67 3.1. Introduction 67 3.2. Experimental 69 3.3. Results and Discussion 77 3.4. Conclusion 83 3.5. References 84 4. Oligomeric Draw Solutes for FO Application 106 4.1. Introduction 107 4.2. Experimental 110 4.3. Results and Discussion 118 4.4. Conclusion 130 4.5. References 131 5. Abstract in Korean 160Docto

A Comparative Study on the Competitiveness Improvement Strategies in Global and Korean Freight Forwarders

우리나라 국제물류주선업(Freight Forwarder) 기업들은 30년 이상 지속되어온업계 규모 확장에도 불구하고 영세하고 소규모인 업체가 대다수인 상황이며 선진국의 동일 업계와 비교하여 보았을 때 그 기능과 역할 및 규모와 서비스 측면에서 다양한 차이점을 보이고 있다. 이 사업을 영위하고 있는 국제물류주선업자(이하 포워더)를 자본형태 및 국적, 사업구조 기준으로 크게 외국계 글로벌 포워더와 국내 로컬 포워더로 구분할 수 있다. 상반된 두 포워더는 구체적으로 어느 부문에서 차이점을 가지고 있는지, 동시에 서로 상반된 강점과 약점요인이 있다고 실무종사자들에게 알려진 바를 실증분석 해보고자 하였다. 본 연구는 상반된 두 포워더의 경쟁력 요인을 비교분석하고 그에 따른 전략을 제시하기 위하여 전문가 델파이(Delphi) 인터뷰 방식으로 기초조사를 실시하고, 수집된 비정형 자료를 토대로 SWOT 전략을 도출하는 방법으로 수행하였다. 상반된 두 포워더 형태의 SWOT 분석을 통해 구분 된 요인 중 위협요인에 지목된 요인으로 인해 업계 전반적인 침체와 수익률 저하의 연관성을 찾고, 시장 상황에서 문제를 직면한 해당 업체들의 구체적인 전략과 정부의 지원정책이 필요한 점을 시사하였다. 관련협회 및 관계부처에 요구되는 포워딩 업계의 구조적 문제와 구체적인 진단 및 컨설팅의 필요성을 제시하고, 정책적인 지원과 전략적 제휴 및 인수합병 추진, 그리고 새로운 수익모델 창출을 위한 지원시스템의 확충 등의 실질인 지원방향을 피력한다.제 1 장 서론 1 제 1 절 연구 배경 및 목적 1 제 2 절 연구의 방법과 구성 내용 3 1. 연구의 방법 3 2. 연구 구성 내용 4 제 2 장 국제물류주선업체의 이론적 고찰 및 현황 5 제 1 절 국제물류주선업체의 구분 5 1. 국제물류주선업의 정의 5 2. 국제물류주선업의 형태구분 및 특징 6 제 2 절 국제물류주선업의 현황 7 1. 글로벌 국제물류주선업의 현황 7 2. 국내 국제물류주선업의 현황 및 문제점 9 제 3 절 국제물류주선업체의 인수합병 현황 18 1. 인수합병의 정의 및 종류 18 2. 국제물류주선업체의 인수합병 현황 21 제 4 절 국제물류주선업체에 관한 선행연구 26 1. 선행연구 26 2. 이론적 고찰 및 연구 한계점 31 제 3 장 연구방법 및 실증분석 33 제 1 절 연구 모형의 설계 33 제 2 절 전문가 델파이 조사 33 1. 델파이 방법의 개요 33 2. 델파이의 일반적 절차 34 3. 델파이 방법 적용 시 중요한 문제 35 4. 델파이 실증분석 35 제 3 절 SWOT 분석 36 제 4 절 전략 분석 39 제 4 장 국제물류주선업체의 경쟁력 제고를 위한 전략 사례 분석 42 제 1 절 사례분석 정의 및 방법 42 제 2 절 인수합병을 통한 국내 진출 사례 42 제 3 절 Joint Venture 국내 진출 사례 45 제 4 절 국내 일반 물류기업의 전략 사례 46 제 5 절 시사점 및 한계점 48 제 5 장 결론 50 참고문헌 56Maste

Status of Next-Generation Sequencing-Based Genetic Diagnosis in Hematologic Malignancies in Korea (2017-2018)

Background: The aim of this study was to investigate the status of next generation sequencing (NGS)-based genetic diagnosis in hematologic malignancies in Korea in 2017 and 2018. Methods: A structured questionnaire was provided to specialists in charge of the genetic testing of hematologic malignancies via e-mail. The questionnaire consisted of 37 questions reflecting the situation of the institutions for each year and were based on an assessment of the status of the hematologic malignancy NGS test (19 questions) and the institution’s opinion on the NGS test (18 questions). Results: A total of 12 and 14 laboratories, in 2017 and 2018, respectively, replied to our survey and their answers were further analyzed. Most laboratories were performing NGS panel testing for acute leukemia and myeloid malignancies, and a small proportion of laboratories were testing NGS for lymphoid malignancies. The majority of participants agreed that NGS testing should be essential for the initial diagnostic workup. Conclusions: Variation in NGS panel tests, including choice of gene and platform by different laboratories, were observed. Standardized panels and interpretation, centered around the Korean Society for Genetic Diagnostics, is needed to reduce inter-laboratory variation in NGS test results.ope

Performances of CYFRA 21-1, Carcinoembryonic Antigen and Their Combination for Lung Cancer Diagnosis

"Background: The aim of this study was to compare the efficiency of cytokeratin 19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA) for the diagnosis of lung cancer and to establish the optimal cut-off values. Methods: We retrospectively reviewed the medical records of 1,176 subjects with CYFRA 21-2 and CEA data; they were classified into 93 lung cancer cases and 1,083 total controls, including 146 age-matched controls. Multivariate analysis was used to determine the relationship between the concentration of each tumor marker and lung cancer diagnosis. The diagnostic efficiencies of tumor markers were evaluated using receiver operating characteristic curve analysis and areas under the curve (AUCs) were calculated. The optimal cut-offs for CYFRA 21-1 and CEA were also estimated. Results: Age, CYFRA 21-1, and CEA concentrations were independently associated with lung cancer diagnosis. Diagnostic efficiency of each tumor marker and its’ combination was different according to the histological types of lung cancer. For non-small cell lung cancer, the AUCs for the two-marker combination were the highest: 0.8661 and 0.7559 for total and age-matched controls, respectively. For squamous cell carcinoma, the AUCs for CYFRA 21-1 were the highest: 0.9245 and 0.8428 for total and age-matched controls, respectively. The sensitivity and specificity of CYFRA 21-1 and CEA for lung cancer diagnosis were improved when the cutoffs determined based on this study were applied. Conclusions: CYFRA 21-1 and CEA could be useful markers for diagnosing lung cancer and single or combination of markers may be useful according to different histological types of lung cancer."22Nkc

혈액종양 정량 분자유전 검사법의 검정 권고안

Quantitative molecular genetic tests are increasingly used for the detection and quantification of target molecules or genetic alterations. When introducing a new assay into clinical laboratories, it is necessary to verify the manufacturers’ claimed performance characteristics within individual laboratories. Appropriate assay verification procedures are essential to ensure the quality of test results in clinical laboratories. This study aimed to provide recommendations for the verification of quantitative molecular genetic testing focused on the hemato-oncology field in clinical genetic laboratories. Based on a literature review, we provide recommendations for the performance verification of quantitative molecular hemato-oncology tests. The performance characteristic elements that comprise the verification procedures are presented and exemplified. These recommendations can assist individual clinical laboratories in verifying quantitative molecular diagnostic assays.ope

In-depth circulating tumor DNA sequencing for prognostication and monitoring in natural killer/T-cell lymphomas

Background: Epstein-Barr virus (EBV) quantitation and current imaging modalities are used for diagnosis and disease monitoring in Extranodal NK/T cell lymphoma (ENKTL) but have limitations. Thus, we explored the utility of circulating tumor DNA (ctDNA) as a diagnostic biomarker. Methods: Through in-depth sequencing of 118 blood samples collected longitudinally at different time points from 45 patients, we examined the mutational profile of each sample, estimated its impact on the clinical outcome, and assessed its role as a biomarker in comparison with EBV DNA quantitation. Results: The ctDNA concentration was correlated with treatment response, stage, and EBV DNA quantitation. The detection rate of ctDNA mutation was 54.5%, with BCOR (21%) being the most commonly mutated gene in newly diagnosed patients; TP53 mutation (33%) was the most prevalent in patients that experienced a relapse. Additionally, patients in complete remission exhibited a rapid clearance of ENKTL-related somatic mutations, while relapsed patients frequently presented with persisting or emerging mutations. We detected ctDNA mutations in EBV-negative patients (50%) and mutation clearance in EBV-positive patients in remission, suggesting ctDNA genotyping as an efficient complementary monitoring method for ENKTL. Additionally, mutated DDX3X (PFS HR, 8.26) in initial samples predicted poor outcome. Conclusion: Our results suggest that ctDNA analysis can be used to genotype at diagnosis and estimate the tumor burden in patients with ENKTL. Furthermore, ctDNA dynamics indicate the potential use of testing it to monitor therapeutic responses and develop new biomarkers for precision ENKTL therapy.ope

Aggressive NK Cell Leukemia with RAB29-NUCKS1 Gene Rearrangement: A Case Report

Aggressive natural killer (NK) cell leukemia (ANKL) is a rare form of leukemia that may be accompanied by various chromosomal abnormalities such as del(6)(q21q25) or del(11q). Here, we describe a case of a patient with ANKL and an RAB29-NUCKS1 rearrangement that has never been described before. An RNA fusion panel test found a gene fusion between exon 5 of RAB29 and exon 2 of NUCKS1 at chromosome 1q32.1. Additionally, reverse-transcription polymerase chain reaction and Sanger sequencing confirmed cryptic RAB29-NUCKS1 fusion. RAB29 encodes a protein that regulates exocytic and endocytic pathways. NUCKS1 encodes a chromatin-associated protein involved in DNA damage responses. Further studies will be necessary to understand the molecular pathogenesis of ANKL related to an RAB29-NUCKS1 rearrangement.ope

Therapy-related Acute Lymphoblastic Leukaemia has a Unique Genetic Profile Compared to De Novo Acute Lymphoblastic Leukaemia

Background: Unlike therapy-related myeloid neoplasms, therapy-related acute lymphoblastic leukaemia (tr-ALL) is poorly defined due to its rarity. However, increasing reports have demonstrated that tr-ALL is a distinct entity with adverse genetic features and clinical outcomes. Methods: We compared the clinicopathological characteristics and outcomes of patients diagnosed with tr-ALL (n = 9) or de novo ALL (dn-ALL; n = 162) at a single institution from January 2012 to March 2021. The mutational landscapes of eight tr-ALL and 63 dn-ALL patients were compared from a comprehensive next-generation sequencing panel. Results: All tr-ALL patients had the B-cell phenotype. The most frequently mutated genes were IKZF1 (37%), CDKN2A (14%), SETD2 (13%), and CDKN2B (11%) in dn-ALL, whereas TP53 (38%) and RB1 (25%) mutations were most common in tr-ALL. tr-ALL patients did not show a statistically significant difference in overall survival (p = 0.70) or progression-free survival (p = 0.94) compared to dn-ALL patients. Conclusions: In this study, we determined the clinical and genetic profiles of Korean patients with tr-ALL. We found alterations in genes constituting the TP53/RB1 pathway are more frequent in tr-ALL. Due to the rarity of the disease, multi-institutional studies involving a larger number of patients are required in future study.ope