Objective: Familial intracranial aneurysms (FIAs) are found in approximately 6%–20% of patients with intracranial aneurysms (IAs), suggesting that genetic predisposition likely plays a role in its pathogenesis. The aim of this study was to identify possible IA-associated variants using whole exome sequencing (WES) in selected Korean families with FIA. Materials and Methods: Among the 26 families in our institutional database with two or more IA-affected first-degree relatives, three families that were genetically enriched (multiple, early onset, or common site involvement within the families) for IA were selected for WES. Filtering strategies, including a family-based approach and knowledge-based prioritization, were applied to derive possible IA-associated variants from the families. A chromosomal microarray was performed to detect relatively large chromosomal abnormalities. Results: Thirteen individuals from the three families were sequenced, of whom seven had IAs. We noted three rare, potentially deleterious variants (PLOD3 c.1315G>A, NTM c.968C>T, and CHST14 c.58C>T), which are the most promising candidates among the 11 potential IA-associated variants considering gene-phenotype relationships, gene function, co-segregation, and variant pathogenicity. Microarray analysis did not reveal any significant copy number variants in the families. Conclusion Using WES, we found that rare, potentially deleterious variants in PLOD3, NTM, and CHST14 genes are likely responsible for the subsets of FIAs in a cohort of Korean families.

Background: Plasma cell myeloma (PCM) is caused by immune dysregulation. We evaluated the expression of immune checkpoint programmed cell death protein-1 (PD-1) on T cell subsets in PCM patients according to disease course and cytogenetic abnormalities.This study aimed to find a target group suitable for therapeutic use of PD-1 blockade in PCM. Methods: A total of 188 bone marrow (BM) samples from 166 PCM patients and 32 controls were prospectively collected between May 2016 and May 2017. PD-1 expression on BM T cell subsets was measured using flow cytometry. Results: At diagnosis, the median PD-1 expression on CD4+ T cells was 24.6%, which did not significantly differ from that in controls. After stem cell transplantation, PD-1 expression on CD4+ T cells was higher than that at diagnosis (P < 0.001), regardless of residual disease. PD-1 expression on CD4+ T cells in patients with residual disease after chemotherapy was significantly higher than that at diagnosis (P = 0.001) and after complete remission following chemotherapy (P = 0.044). PD-1 expression on CD8+ T cells was higher in PCM patients with cytogenetic abnormalities, including monosomy 13, 1q gain, complex karyotype, and hypodiploidy. Conclusions PD-1 blockade might have therapeutic potential in refractory PCM patients after chemotherapy, especially in those with high- or intermediate-risk cytogenetic abnormalities.

Rare neurovascular diseases (RNVDs) have not been well-recognized in Korea. They involve the central nervous system and greatly affect the patients’ lives. However, these diseases are difficult to diagnose and treat due to their rarity and incurability. We established a list of RNVDs by referring to the previous literature and databases worldwide to better understand the diseases and their current management status. We categorized 68 RNVDs based on their pathophysiology and clinical manifestations and estimated the prevalence of each disease in Korea. Recent advances in genetic, molecular, and developmental research have enabled further understanding of these RNVDs. Herein, we review each disease, while considering its classification based on updated pathologic mechanisms, and discuss the management status of RNVD in Korea.

Rare neurovascular diseases (RNVDs) have not been well-recognized in Korea. They involve the central nervous system and greatly affect the patients’ lives. However, these diseases are difficult to diagnose and treat due to their rarity and incurability. We established a list of RNVDs by referring to the previous literature and databases worldwide to better understand the diseases and their current management status. We categorized 68 RNVDs based on their pathophysiology and clinical manifestations and estimated the prevalence of each disease in Korea. Recent advances in genetic, molecular, and developmental research have enabled further understanding of these RNVDs. Herein, we review each disease, while considering its classification based on updated pathologic mechanisms, and discuss the management status of RNVD in Korea.

BACKGROUND: JL1, a CD43 epitope and mucin family cell surface glycoprotein, is expressed on leukemic cells. An anti-JL1 antibody combined with a toxic substance can have targeted therapeutic effects against JL1-positive leukemia; however, JL1 expression on bone marrow (BM) lymphoma cells has not been assessed using flow cytometry. We investigated JL1 expression on BM lymphoma cells from patients with non-Hodgkin lymphoma (NHL) to assess the potential of JL1 as a therapeutic target. METHODS: Patients with BM involvement of mature B-cell (N=44) or T- and natural killer (NK)-cell (N=4) lymphomas were enrolled from May 2015 to September 2016. JL1 expression on BM lymphoma cells was investigated using flow cytometry. Clinical, pathological, and cytogenetic characteristics, and treatment responses were compared according to JL1 expression status. RESULTS: Of the patients with NHL and BM involvement, 37.5% (18/48) were JL1-positive. Among mature B-cell lymphomas, 100%, 38.9%, 33.3%, 100%, and 25.0% of Burkitt lymphomas, diffuse large B-cell leukemias, mantle cell leukemias, Waldenstrom macroglobulinemia, and other B-cell lymphomas, respectively, were JL1-positive. Three mature T- and NK-cell NHLs were JL1-positive. JL1 expression was associated with age (P=0.045), complete response (P=0.004), and BM involvement at follow-up (P=0.017), but not with sex, performance status, the B symptoms, packed marrow pattern, cytogenetic abnormalities, or survival. CONCLUSIONS JL1 positivity was associated with superior complete response and less BM involvement in NHL following chemotherapy.

BACKGROUND: Waldenström macroglobulinemia (WM) is a subset of lymphoplasmacytic lymphoma (LPL) with bone marrow (BM) involvement and an IgM monoclonal gammopathy of any level. We aimed to identify the clinical, laboratory, and BM findings of patients with WM and to evaluate the usefulness of CD154 for the diagnosis and prognosis of WM. METHODS: We reviewed the medical records and BM studies and/or flow cytometric immunotyping of 31 patients with untreated WM. Semiquantitative immunohistochemistry (CD20, CD138, tryptase, and CD154) of BM was performed. RESULTS: Only six patients presented with symptoms of hyperviscosity syndrome. Eleven patients had solid cancer and/or another hematologic malignancy. Mast cells (MC) increased in all samples, with some in close contact with tumor cells. Tryptase-positive MC (17.1/ high-power fields [HPF], 1.2–72.0/HPF) and CD154-positive MC (8.6/HPF, 0.1–31.1/HPF) were observed. The high CD154-positive MC (≥8.6/HPF) group showed a lower overall five-year survival rate than the low CD154-positive MC (<8.6/HPF) group (71.9% vs. 100.0%; P=0.012). Flow cytometric immunophenotyping of BM aspirates showed increased B lymphocytes and plasma cells with a normal phenotype (CD138⁺/CD38⁺/CD19⁺/CD45⁺/CD56⁻). CONCLUSIONS Approximately one third of WM patients showed other malignancies and all patients had increased MC. Immunohistochemistry and flow cytometric immunophenotyping are useful for diagnosing WM, and increased CD154-positive MC can indicate poor prognosis.

PURPOSE: Hereditary hemorrhagic telangiectasia (HHT), a rare genetic vascular disorder, has been rarely reported in South Korea. We investigated the current prevalence and presenting patterns of genetically confirmed HHT in South Korea. MATERIALS AND METHODS: We defined HHT patients as those with proven mutations on known HHT-related genes (ENG, ACVRL1, SMAD4, and GDF2) or those fulfilling 3 or 4 of the Curaçao criteria. A computerized systematic search was performed in PubMed and KoreaMed using the following search term: (“hereditary hemorrhagic telangiectasia” AND “Korea”) OR (“Osler-Weber-Rendu” AND “Korea”). We also collected government health insurance data. HHT genetic testing results were collected from three tertiary hospitals in which the genetic tests were performed. We integrated patient data by analyzing each case to obtain the prevalence and presenting pattern of HHT in South Korea. RESULTS: We extracted 90 cases from 52 relevant articles from PubMed and KoreaMed. An additional 22 cases were identified from the three Korean tertiary hospitals after excluding seven cases that overlapped with those in the published articles. Finally, 112 HHT patients were identified (41 males and 71 females, aged 4–82 years [mean±standard deviation, 45.3±20.6 years]). The prevalence of HHT in South Korea is about 1 in 500,000, with an almost equal prevalence among men and women. Forty-nine patients underwent genetic testing, of whom 28 had HHT1 (ENG mutation) and 19 had HHT2 (ACVRL1 mutation); the other two patients were negative for ENG, ACVRL1, and SMAD4 mutations. CONCLUSION: The prevalence of HHT is underestimated in Korea. The rate of phenotypic presentation seems to be similar to that found worldwide. Korean health insurance coverage is limited to representative genetic analysis to detect ENG and ACVRL1 mutations. Further genetic analyses to detect HHT3, HHT4, and other forms of HHT should be implemented.
Arteriovenous Fistula ; Arteriovenous Malformations ; Diagnosis ; Epistaxis ; Female ; Genetic Testing ; Hemorrhage ; Humans ; Insurance, Health ; Korea ; Male ; Prevalence ; Telangiectasia, Hereditary Hemorrhagic ; Tertiary Care Centers

POEMS syndrome is a rare paraneoplastic syndrome, which includes polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes due to plasma cell (PC) neoplasm. Diagnosis of this disease is challenging because of its rarity and complex clinical manifestations. We attempted to identify the key clinical features and characteristic bone marrow (BM) findings of POEMS syndrome, by reviewing the medical records and BM analyses of 24 Korean patients. Frequent clinical manifestations included polyneuropathy (100%), monoclonal gammopathy (100%), organomegaly (92%), extravascular volume overload (79%), and endocrinopathy (63%). The BM analyses revealed mild PC hyperplasia (median PCs: 5.5%) and frequent megakaryocytic hyperplasia (88%), megakaryocyte clusters (88%), and hyperlobation (100%). Flow cytometry of BM aspirates using CD138/CD38/CD45/CD19/CD56 showed normal (67%, 4/6) or neoplastic PC immunophenotypes (33%, 2/6). A diagnosis of POEMS syndrome must be considered when a patient suspected of having PC dyscrasia shows the above clinical presentation and BM findings.
Bone Marrow ; Diagnosis ; Flow Cytometry ; Humans ; Hyperplasia ; Medical Records ; Megakaryocytes ; Paraneoplastic Syndromes ; Paraproteinemias ; Plasma Cells ; POEMS Syndrome ; Polyneuropathies ; Skin

Recent advances in chemotherapy have led to increased survival rates for patients with hematologic malignancies. However, standard chemotherapies, including alkylating agents for non-Hodgkin lymphoma, could induce therapy-related myeloid neoplasms (t-MNs), a group of disorders categorized by the World Health Organization in 2008. Here, we report a case of coexistence of bone marrow (BM)-involved refractory marginal zone B-cell lymphoma (MZL) and therapy-related myelodysplastic syndrome (t-MDS). Simultaneous presence of refractory lymphoma and t-MN in the BM is rare, and this is the first report in Korea. The patient received allogeneic hematopoietic stem cell transplantation (HSCT) to cure both the MZL and t-MDS. Since the HSCT, he has been stable for 21 months without any evidence of recurrence.
Alkylating Agents ; Bone Marrow ; Drug Therapy ; Hematologic Neoplasms ; Hematopoietic Stem Cell Transplantation ; Humans ; Korea ; Lymphoma ; Lymphoma, B-Cell, Marginal Zone* ; Lymphoma, Non-Hodgkin ; Myelodysplastic Syndromes* ; Recurrence ; Survival Rate ; World Health Organization