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Due to several issues, standard treatments are not recommended for asymptomatic patients with moderate immune thrombocytopenia (ITP). Since platelet responses are reported in some patients with Helicobacter pylori (H. pylori)-positive ITP after eradication, we conducted a multicenter, phase 3 study to evaluate the safety and efficacy of recently established sequential eradication for these patients having moderate thrombocytopenia. Persistent or chronic ITP patients with platelet count (30 × 10

Venous thromboembolism (VTE), which includes pulmonary embolism and deep vein thrombosis, is a condition characterized by abnormal blood clot formation in the pulmonary arteries and the deep venous vasculature. It is often serious and sometimes even fatal if not promptly and appropriately treated. Moreover, the later consequences of VTE may result in reduced quality of life. The treatment of VTE depends on various factors, including the type, cause, and patient comorbidities. Furthermore, bleeding may occur as a side effect of VTE treatment. Thus, it is necessary to carefully weigh the benefits versus the risks of VTE treatment and to actively monitor patients undergoing treatment. Asian populations are known to have lower VTE incidences than Western populations, but recent studies have shown an increase in the incidence of VTE in Asia. A variety of treatment options are currently available owing to the introduction of direct oral anticoagulants. The current VTE treatment recommendation is based on evidence from previous studies, but it should be applied with careful consideration of the racial, genetic, and social characteristics in the Korean population.

Background Racial differences in genetic risk factors for venous thromboembolism (VTE) are elucidated, with factor V Leiden and prothrombin G20210A being prevalent among the Caucasian population but rare among non‐Caucasians. Objectives To assess the worldwide distribution of three gene polymorphisms previously identified as genetic risk factors among East Asian subpopulations: protein S (PS) Tokushima (p.Lys196Glu), protein C (PC) p.Arg189Trp, and PC p.Lys193del. Methods An international collaborative study group of seven centers in five countries—Japan, South Korea, Singapore, Hungary, and Brazil—was created, and genotype analyses were performed. A total of 2850 unrelated individuals (1061 patients with VTE and 1789 controls) were included. Results PS Tokushima was confined to Japanese patients with VTE (allele frequency, 2.35%) and controls (1.12%), with an odds ratio (OR) of 2.15 (95% confidence interval, 1.16‐3.99). PC p.Arg189Trp carriers were prevalent among Chinese and Malay patients with VTE in Singapore, with allele frequencies of 10.53% and 22.73%, respectively. Carriers of PC p.Lys193del were identified among Japanese and Korean patients with VTE (0.87% and 2.35%, respectively) and controls (0.36% and 1.07%, respectively), with the OR for VTE not being significant, and Chinese patients with VTE in Singapore (5.26%). In contrast, no carriers of PS Tokushima and two PC gene variants were found among patients with VTE or controls from Hungary, Brazil, or Indians in Singapore. Conclusion The three variants were prevalent among East and Southeast Asians, having some differences in geographic distribution, but were absent among Caucasian subpopulations and Brazilians.

Background Cancer-related fatigue (CRF) is a common symptom and has a negative impact on prognosis in cancer patients. CRF could be improved by Korean red ginseng (KRG). Patients and methods For this randomised and double-blinded trial, colorectal cancer patients who received mFOLFOX-6 were randomly assigned to either KRG 2000 mg/day (n = 219) or placebo (n = 219) for 16 weeks. CRF was evaluated using the mean area under the curve (AUC) change from baseline of brief fatigue inventory (BFI) as the primary endpoint. Fatigue-related quality of life, stress, and adverse events were evaluated as secondary endpoints. Results In the full analysis group, KRG up to 16 weeks improved CRF by the mean AUC change from baseline of BFI compared to placebo, particularly in “Mood” and “Walking ability” (P = 0.038, P = 0.023, respectively). In the per-protocol group, KRG led to improved CRF in the global BFI score compared with the placebo (P = 0.019). Specifically, there were improvements in “Fatigue right now,” “Mood,” “Relations with others,” “Walking ability,” and “Enjoyment of life” at 16 weeks (P = 0.045, P = 0.006, P = 0.028, P = 0.003, P = 0.036, respectively). In subgroups of female patients, ≥60 years old, with high compliance (≥80%) or more baseline fatigue, the beneficial effects of KRG were more enhanced than that of placebo. Although neutropenia was more frequent in KRG than placebo, the incidence of all adverse events was similar. Conclusions KRG could be safely combined with mFOLFOX-6 chemotherapy in colorectal cancer patients, and reduced CRF compared with placebo.

Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury, which results from uncontrolled complement activation. Delayed diagnosis and treatment of aHUS may result in end-stage renal disease (ESRD) and an associated dependence on dialysis. In extreme cases, it may cause death due to multi-organ failure. Eculizumab, a humanized monoclonal antibody against C5, inhibits the formation of the terminal membrane attack complex and is used to treat aHUS. Here, we report a 46-year-old male patient who suffered from aHUS relapse, despite prior treatment with repeated plasma exchange and hemodialysis. Eculizumab therapy improved his hematologic findings without use of hemodialysis. (Korean J Med 2020;95:124-128)

Thrombotic microangiopathy (TMA) is defined by specific clinical characteristics, including microangiopathic hemolytic anemia, thrombocytopenia, and pathologic evidence of endothelial cell damage, as well as the resulting ischemic end-organ injuries. A variety of clinical scenarios have features of TMA, including infection, pregnancy, malignancy, autoimmune disease, and medications. These overlapping manifestations hamper differential diagnosis of the underlying pathogenesis, despite recent advances in understanding the mechanisms of several types of TMA syndrome. Atypical hemolytic uremic syndrome (aHUS) is caused by a genetic or acquired defect in regulation of the alternative complement pathway. It is important to consider the possibility of aHUS in all patients who exhibit TMA with triggering conditions because of the incomplete genetic penetrance of aHUS. Therapeutic strategies for aHUS are based on functional restoration of the complement system. Eculizumab, a monoclonal antibody against the terminal complement component 5 inhibitor, yields good outcomes that include prevention of organ damage and premature death. However, there remain unresolved challenges in terms of treatment duration, cost, and infectious complications. A consensus regarding diagnosis and management of TMA syndrome would enhance understanding of the disease and enable treatment decision-making.

Venous thromboembolism (VTE) may lead to diminished quality of life and ultimately worse prognosis in cancer patients, but there is limited data on the incidence, risk factors and mortality impact of VTE in Asian primary central nervous system lymphoma (PCNSL) patients.To report the incidence, risk factors and mortality impact of VTE in Asian PCNSL patients.From 7 academic centers in Korea, 235 newly diagnosed PCNSL patients undergoing chemotherapy were retrospectively identified during period of January 2004 to September 2018.All patients but 12 (6 T-cell, 6 other B-cell) had diffuse large B-cell lymphoma. During the median follow-up of 21 months, 33 patient (14.0%) developed VTE. Of the VTE events, 11 (33.3%) were deep vein thrombosis (DVT), 15 (45.5%) were pulmonary thromboembolism (PTE), and 7 (21.2%) were DVT with PTE. The median time to VTE was 2 months and the one-year actuarial incidence was 11.7%. On multivariate analysis, ECOG performance ≥2, age60 years, female sex, and Hb10 g/dL were independently associated with VTE. The patients with VTE were associated with shorter disease specific survival (P = 0.046) and overall survival (P = 0.022).Overall, the incidence of VTE in Asian PCNSL seems to be lower compared to Western population. As VTE development is associated with overall survival and indicative of relapse, careful close monitoring is warranted.

Background/aims Seasonal variation is an environmental factor proposed to affect the incidence of venous thromboembolism (VTE). However, VTE seasonal variation is not well studied in Asian populations, which have different genetic determinants of VTE compared to Westerners. The present study aimed at investigating seasonal variation of VTE occurrence and the effect of various demographic factors (i.e., age, sex, and co-morbidities) on variation. Methods VTE seasonal variation was evaluated in 59,626 index cases (from January 2009 to December 2013) in the Korean Health Insurance Review and Assessment Service database. We quantified and compared VTE occurrence across four seasons, and additionally assessed monthly through a chronobiological analysis. Results VTE incidence varied both seasonally and monthly, with new cases peaking in the winter (January and February) and the lowest incidence in the summer (August and September). After adjusting for sex, age, type of VTE, and combined cancer diagnosis, winter remained a significant independent factor driving VTE incidence. Additionally, seasonal variation was prominent in patients aged 60 years or older and in patients with pulmonary embolism, but not so prominent in patients of aged less than 60 years and patients with deep vein thrombosis. Conclusion Seasonal variation was a weak but independent contributor to VTE incidence in a Korean population diagnosed from 2009 to 2013, especially in those individuals with old age or suffering from a pulmonary embolism.

Introduction Acquired haemophilia A (AHA) treatment involves the haemostatic treatment for acute haemorrhage and immunosuppressive therapy (IST) to eradicate FVIII inhibitory antibodies. Aim We assessed the clinical features of AHA and analysed treatment outcomes in Korea. We further identified prognostic factors affecting treatment outcomes. Methods Medical records of 55 patients with AHA from 18 institutions were reviewed retrospectively. Logistic and Cox regression analyses were performed to elucidate clinical factors affecting the achievement of complete remission (CR). The primary endpoint was time to CR after IST, and secondary endpoints were time to haemostasis, the achievement of CR, and overall survival (OS). Results Among the 55 patients, 50 (91%) had bleeding symptoms. Bleeding was severe in 74% of patients. Thirty-six (72%) patients received haemostatic therapy. Of the 42 patients who received IST, 23 (52%) received steroid alone, with a 52% response rate, and 10 (25%) received a combination of steroid and cyclophosphamide, with an 83% response rate. Five (16%) patients relapsed after a median duration of 220 days. There were eight deaths. In the Cox regression analysis, the FVIII inhibitor titre ≥ 20 BU/mL was the only significant prognostic factor affecting time to CR and haemostasis. No significant difference was observed in OS based on the inhibitor titre. Conclusion The present study demonstrated the demographic data of AHA in Korea and showed that FVIII inhibitory antibody titre was a predictor of time to achieve CR after IST.

Background/aims Limited data are available regarding the efficacy of rivaroxaban for the treatment of cancer-associated venous thromboembolism (VTE). The aim of this study was to evaluate the effectiveness and safety of rivaroxaban for the treatment of VTE in active cancer patients. Methods In this prospective, multicenter, open-label trial (NCT01989845), we enrolled patients with active cancer and objectively diagnosed lower-extremity deep vein thrombosis, pulmonary embolism (PE), or both from November 2013 to June 2016. Active cancer was defined as a histologically confirmed malignancy, which was diagnosed or treated within the previous 6 months, or as a recurrent/ metastatic cancer. Patients received oral rivaroxaban 15 mg twice daily for first 3 weeks, followed by 20 mg once daily for 6 months. The primary outcome was the symptomatic recurrent VTE and the secondary outcomes included any recurrent VTE, major or clinically relevant non-major (CRNM) bleeding events, and overall mortality. All study outcomes were validated by blinded central adjudication. Results Of 124 patients enrolled, 110 (88.7%) had solid cancer, 93 (75.0%) had metastatic disease, and 110 (88.7%) were receiving chemotherapy or radiotherapy. During the 6-month study period, seven patients experienced symptomatic recurrent VTE (cumulative incidence, 5.9%), and two patients experienced incidental recurrent PE (cumulative incidence of any recurrent VTE, 7.6%). Major bleeding events occurred in six patients (cumulative incidence, 5.3%) and CRNM bleeding events in 11 patients (cumulative incidence, 10.2%). Twenty-eight patients (overall mortality, 24.0%) died. Conclusion Rivaroxaban is effective and safe for the treatment of VTE in patients with active cancer.

Background Thrombotic microangiopathy (TMA), a rare but serious complication of systemic lupus erythematosus (SLE), is associated with poor outcomes to conventional immunosuppressive therapy. Recently, eculizumab, a humanised monoclonal antibody that blocks the complement factor 5, has been known to effectively treat atypical haemolytic uremic syndrome (aHUS). Here, we report a case of aHUS co-existing with lupus nephritis that was successfully treated with eculizumab. Case presentation A 23-year-old man presented with abdominal pain and diarrhoea. Initial laboratory tests have shown thrombocytopaenia, microangiopathic haemolytic anaemia, and acute kidney injury. Immunologic tests were consistent with SLE. Kidney biopsy have revealed lupus nephritis class IV-G with TMA. Genetic analysis have shown complement C3 gene mutations, which hints the co-existence of lupus nephritis with aHUS, a form of complement-mediated TMA. Although initial treatment with haemodialysis, plasma exchange, and conventional immunosuppressive therapy (steroid and cyclophosphamide) did not appreciably improve kidney function and thrombocytopaenia, the patient was able to respond to eculizumab therapy. Conclusions Due to the similar features of TMA and SLE, clinical suspicion of aHUS in patients with lupus nephritis is important for early diagnosis and prompt management. Timely administration of eculizumab should be considered as a treatment option for aHUS in lupus nephritis patients to yield optimal therapeutic outcomes.

Ultra-deep sequencing detects low-frequency genetic mutations with high sensitivity. We used this approach to prospectively examine mutations in the BCR/ABL1 tyrosine kinase from patients with newly diagnosed, chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor nilotinib. Between May 2013 and November 2014, 50 patients from 18 institutions were enrolled in the study. We screened 103 somatic mutations and found that mutations in the P-loop domain were the most frequent (173/454 mutations in the P-loop) and noted the presence of the V299 L mutation (dasatinib-resistant/nilotinib-sensitive) in 98 % of patients (49/50). No patients had Y253H, E255 V, or F359 V/C/I mutations, which would recommend dasatinib rather than nilotinib treatment. The S417Y mutation was associated with lower achievement of a major molecular response (MMR) at 6 months, and the V371A mutation was associated with reduced MMR and MR4.5 durations (MMR for 2 years: 100 % for no mutation vs. 75 % for mutation, P=0.039; MR4.5 for 15 months: 94.1 % vs. 25 %, P=0.002). Patients with known nilotinib-resistant mutations had lower rates of MR4.5 achievement. In conclusion, ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. Based on the results of these mutational analyses, nilotinib treatment is a promising option for Korean patients with CML.

We report a case of atypical hemolytic uremic syndrome (HUS) that occurred after childbirth. A 33-year-old female was admitted to the emergency room, complaining of abdominal pain six days after giving birth to twins. The patient was diagnosed with hemoperitoneum due to hepatic hemangioma rupture and a left lateral hepatectomy was performed. Angioembolization was performed for the accompanying uterine artery bleeding. After that, her kidney function worsened after the 12th day postpartum. Microangiopathic anemia, thrombocytopenia and renal dysfunction were observed. Shiga toxin-producing Escherichia coli was negative in the stool. Plasma ADMATS 13 activity was normal. After transfer to the nephrology department with suspected atypical HUS, the patient underwent fresh frozen plasma (FFP) transfusion with three hemodialysis sessions. The patient improved without additional dialysis, but a renal biopsy was performed because of persistent proteinuria. Renal pathologic findings were compatible with thrombotic microangiopathy. A genetic test for atypical HUS revealed variants of uncertain significance in the complement factor H related (CFHR) 4 gene and the presence of CFHR3-CFHR1 copy number gain. The CFHR3-CFHR1 copy number gain found in this case is a rare causative mutation of atypical HUS. This case suggests that genetic testing of atypical HUS should include analysis of CFH-CFHR rearrangements as well as general screening for complement-associated genes.

Cord blood transplantation (CBT) is a valuable alternative to bone marrow transplantation in adults without readily available donors. We conducted this study to investigate the feasibility of CBT for adult patients with acute leukemia with regards to impact of different conditioning and graft-versus-host disease (GVHD) prophylaxis regimens on clinical outcomes. From 16 centers in Korea, 41 acute myeloid leukemia (AML) and 29 ALL (acute lymphoblastic leukemia) patients undergoing CBT were enrolled. For AML patients, the neutrophil engraftment was observed in 87.5% of reduced intensity conditioning (RIC) and 72.0% of myeloablative conditioning (MAC) (p = 0.242). The median RFS was 5 months and OS 7 months. Conditioning regimen did not affect relapse free survival (RFS) or overall survival (OS). GVHD prophylaxis using calcineurin inhibitors (CNI) plus methotrexate was associated with better RFS compared to CNI plus ATG (p = 0.032). For ALL patients, neutrophil engraftment was observed in 55.6% of RIC and 90.0% of MAC (p = 0.034). The median RFS was 5 months and OS 19 months. MAC regimens, especially total body irradiation (TBI)-based regimen, were associated with both longer RFS and OS compared to other conditioning regimens. In conclusion, individualized conditioning regimens will add value in terms of enhancing safety and efficacy of CBT.

Patient: Female, 49-year-old Final Diagnosis: Atypical hemolytic uremic syndrome Symptoms: Edema Medication:— Clinical Procedure: Plasmapheresis • immune moderating Specialty: Nephrology Objective: Rare disease Background: Hemolytic uremic syndrome (HUS) can be categorized as primary (typical or atypical) or secondary (with a coexisting diseases). Typical HUS usually means shiga-toxin-medicated and thrombotic thrombocytopenic purpura. Secondary HUS is often initiated by coexisting diseases or conditions such as infections, transplantation, cancer, and autoimmune disease. Atypical HUS (aHUS) is usually induced by genetic mutations of one or several complement-regulating genes and associated with dysregulated complement activation. In the era of compliment-inhibiting therapy, early recognition of aHUS is important for patient prognosis. However, compliment-inhibiting therapy is not always beneficial in patients with secondary HUS. Case Report: We present a case of a 49-year-old woman with aHUS, which was caused by a novel genetic point mutation of complement factor H gene (p.Gly1110Ala) mimicking secondary HUS with scleroderma. Instead of administering eculizumab treatment for C5 polymorphism, the patient was successfully treated with mycophenolate mofetil. Conclusions: HUS has complex and mixed etiologies and requires genetic testing. Attention should be paid to new point mutations in aHUS.

Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA), characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and renal failure. In more than half of cases, genetic defects leading to overactivation of the alternative complement system have been identified. In this study, we investigated genetic defects in Korean adult patients with aHUS. Materials and methods Sixty-six Korean adult patients with aHUS were ascertained from the Korean TMA Registry. Genetic variants of 15 aHUS-related genes (eight core genes [CFH, CFB, CFI, CD46, C3, THBD, PLG, and DGKE] and seven candidate genes [CFP, C4BPA, and CHFR1-5]) were analyzed from exome sequencing data. Multiplex ligation-dependent probe amplification of CFH and related genes was performed to detect hybrid genes or large deletions. Results Thirty patients (45%) had at least one aHUS-related variant (s) in eight core genes (total 40 variant alleles). The most frequently affected gene was CFH (13/40, 32%), followed by THBD (8/40, 20%) and CD46 (7/40, 18%). The two most common variants were Asp486Tyr of THBD (N = 7) and Tyr1058His-Val1060Leu of CFH (N = 5, linked on the same allele), accounting for 30% (12/40). In seven candidate genes, 19 variants were detected. When combined, 40 patients (61%) had at least one variant in 15 core or candidate genes. No patients had anti-CFH Ab or hybrid gene/CFHR1 homozygous deletions. Conclusions The genetic profile of Korean adult aHUS was unique with recurrent missense variants, demonstrating ethnicity- and age-dependent differences in the genetic background of aHUS.

Considering difficulties in on-site ADAMTS13 testing and the performance instability of PLASMIC score according to ethnicity, we developed a prediction tool, MED-TMA (machine learning (ML) method for differential diagnosis (DDx) of thrombotic microangiopathy (TMA)) to support clinical decision. Data from 319 patients visiting 31 hospitals in Korea clinically diagnosed with primary TMA was randomly separated by 2:1 into two groups - the development dataset (D-set, n = 212), the validation dataset (V-set, n = 107). Feature elimination was conducted to select optimal clinical predictors. We developed the model with the selected features using ML methods, verifying using V-set. After the feature elimination using 19 clinical variables, five variables were selected with high importance value. Among nine ML methods, four ML methods were chosen considering the Area Under the Curves (AUC) and the correlation between the methods using D-set. We developed MED-TMA based on an optimized ensemble model with the selected four ML methods resulting in AUC values of 0.945 and 0.924 in D-set and V-set, respectively. In addition to the binary outcome, MED-TMA was capable of providing a probability for DDx of TMA. The ensemble approach driven MED-TMA showed comparable accurate and intuitive decision support for DDx of TMA to that of the existing models based on a single ML method. We provide a web-based nomogram for the appropriate use of effective but costly therapeutics to treat TMA patients (http://hematology.snu.ac.kr/medtma/).

In colorectal carcinogenesis, the unique molecular and genetic changes that occur within cells result in specific CRC phenotypes. The involvement of the long non-coding RNA, HOTAIR, in cancer development, progression, and metastasis is well-established. Various studies have reported on the contribution of HOTAIR to cancer pathogenesis. Therefore, we selected four HOTAIR polymorphisms (rs7958904G>C, rs1899663G>T, rs4759314A>G, and rs920778T>C) to evaluate the association of each variant with CRC prevalence and prognosis. We conducted a case–control study of 850 individuals to identify the genotype frequencies of each polymorphism. The study population included 450 CRC patients and 400 control individuals that were randomly selected following a health screening. Notably, rs7958904 and rs1899663, their hetero genotype, and the dominant model were significantly different when compared to the healthy control group (rs7958904; AOR = 1.392, 95% CI = 1.052–1.843, P = 0.021). To evaluate the effect of HOTAIR polymorphisms on the survival rate, we analyzed patient mortality and relapse occurrence within 3 and 5 years with Cox-regression analysis. The rs7958904 CC polymorphism mortality rate was significantly higher than the GG polymorphism mortality rate (adjusted HR = 2.995, 95% CI = 1.189–7.542, P = 0.021). In addition, the rs920778 CC genotype was significantly different than the TT genotype (adjusted HR = 3.639, 95% CI = 1.435–9.230, P = 0.007). In addition, this study confirmed that genetic variants of HOTAIR alter the mRNA expression level (P < 0.01). We suggest that HOTAIR rs7958904G>C which is associated with CRC prevalence and mortality is a potential biomarker for CRC. The association between HOTAIR gene polymorphisms and CRC prevalence were reported for the first time.

Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. In this global, phase 3, single arm study in complement inhibitor-naive adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. The primary endpoint was complete thrombotic microangiopathy response defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine. Secondary endpoints included changes in hematologic variables and renal function. Safety was also evaluated. Ravulizumab treatment resulted in an immediate, complete, and sustained C5 inhibition in all patients. Complete thrombotic microangiopathy response was achieved in 53.6% of patients. Normalization of platelet count, lactate dehydrogenase and 25% or more improvement in serum creatinine was achieved in 83.9%, 76.8% and 58.9% of patients, respectively. Improvement in estimated glomerular filtration rate by one or more stage was achieved in 68.1% of patients by day 183. No unexpected adverse events were reported across a safety analysis set of 58 patients. Four deaths occurred (three within one month of study initiation, including one in a patient excluded based on eligibility criteria after the first dose) with none considered treatment-related by the study investigator. Thus, treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events in adults with atypical hemolytic uremic syndrome.

In colorectal carcinogenesis, the unique molecular and genetic changes that occur within cells result in specific CRC phenotypes. The involvement of the long non-coding RNA, HOTAIR, in cancer development, progression, and metastasis is well-established. Various studies have reported on the contribution of HOTAIR to cancer pathogenesis. Therefore, we selected four HOTAIR polymorphisms (rs7958904G>C, rs1899663G>T, rs4759314A>G, and rs920778T>C) to evaluate the association of each variant with CRC prevalence and prognosis. We conducted a case–control study of 850 individuals to identify the genotype frequencies of each polymorphism. The study population included 450 CRC patients and 400 control individuals that were randomly selected following a health screening. Notably, rs7958904 and rs1899663, their hetero genotype, and the dominant model were significantly different when compared to the healthy control group (rs7958904; AOR = 1.392, 95% CI = 1.052–1.843, P = 0.021). To evaluate the effect of HOTAIR polymorphisms on the survival rate, we analyzed patient mortality and relapse occurrence within 3 and 5 years with Cox-regression analysis. The rs7958904 CC polymorphism mortality rate was significantly higher than the GG polymorphism mortality rate (adjusted HR = 2.995, 95% CI = 1.189–7.542, P = 0.021). In addition, the rs920778 CC genotype was significantly different than the TT genotype (adjusted HR = 3.639, 95% CI = 1.435–9.230, P = 0.007). In addition, this study confirmed that genetic variants of HOTAIR alter the mRNA expression level (P < 0.01). We suggest that HOTAIR rs7958904G>C which is associated with CRC prevalence and mortality is a potential biomarker for CRC. The association between HOTAIR gene polymorphisms and CRC prevalence were reported for the first time.

Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML‐CP). We investigated the 2‐year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open‐label, multi‐institutional phase 4 study, 110 Philadelphia chromosome‐positive CML‐CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24‐month cumulative MR 4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per‐patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow‐up of 22.2 months, the 24‐month cumulative MR 4.5 rate was 56.2% (95% confidence interval, 44.0%–8.3%), and the median time to MR 4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR 4, and MR 4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML‐CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.

The authors regret that 2 investigators were not included in the 311 Study Group. Members of the 311 Study Group are listed in the Appendix. The authors would like to apologize for any inconvenience caused.

Differential treatment strategies are applied in thrombotic microangiopathy (TMA) according to the sub-classifications. Hence, it is worthwhile to overview clinical manifestations and outcomes of overall TMA patients according to sub-classifications. We analyzed TMA patients whose serum lactate dehydrogenase levels >250 IU/L, with the presence of schistocytes in their peripheral blood smear, or with typical vascular pathologic abnormalities in their renal biopsy. We compared clinical manifestations including overall survival (OS) and renal survival according to TMA causes. A total of 117 TMA patients (57 primary and 60 secondary TMA) were analyzed. Renal symptom was the most common manifestation in whole patients, while renal function at diagnosis was worst in pregnancy-related TMA group. Primary TMA patients had more frequent CNS symptom and hematologic manifestation compared to secondary TMAs. Among secondary TMAs, pregnancy- and HSCT-related TMA patients showed prevalent hemolytic features. During 150.2 months of follow-up, 5-year OS rate was 64.8%. Poor prognostic factors included older age, combined hematologic and solid organ malignancies, lower hemoglobin levels, and lower serum albumin levels. There was no significant difference in OS between primary and secondary TMAs. Seventy-eight percent of patients experienced AKI during TMA. Five-year death-censored renal survival rate was poor with only 69.2%. However, excellent renal outcome was observed in pregnancy-associated TMA. TMA showed various clinical manifestations according to their etiology. Notably, both OS and renal survival were poor regardless of their etiologies except pregnancy-associated TMA. Physicians should differentiate a variety of TMA categories and properly manage this complex disease entity.

Essentials Data on venous thromboembolism (VTE) after L-asparaginase (L-asp) in Asian lymphoma are scarce. This is a population-based study in Asian patients with lymphoid disease and L-asp-related VTE. The overall incidence of L-asp-associated VTE was similar to reports on Caucasians. This first and largest study in Asians shows that mainly adult patients are at risk of thrombosis. SummaryBackground L-asparaginase (L-asp)-associated venous thromboembolism (VTE) is a serious adverse complication associated with acute lymphoblastic leukemia (ALL) and lymphoma treatment. The incidence rate of L-asp-related VTE in Asian cancer patients is not well known. Methods We performed a population-based study between 2009 and 2013 using claim databases, including both diagnostic and medication codes, such as anti-cancer treatment with L-asp and VTE diagnoses from the starting date until 3 months after cessation of L-asp. Results A total of 3286 patients were prescribed L-asp treatment for any type of lymphoid malignancy including ALL and lymphoma; 116 patients (3.5%) experienced VTE. The most common site of thrombosis was the upper extremities (34.5%). Cerebral vein thrombosis (1.7%) occurred in two pediatric patients; 2.4% (43/1795) of pediatric patients and 4.9% (72/1486) of adult patients suffered from VTE, respectively; 2.7% (56/2064) of ALL and 4.9% (59/1217) of lymphoma patients were diagnosed with VTE after L-asp exposure. After univariate analysis, both the diagnosis of lymphoma (vs. ALL) and being an adult patient (vs. pediatric patient) were risk factors for VTE occurrence. However, after multivariate analysis, only age > 18 remained a risk factor for VTE (odds ratio, 1.79; 95% confidence interval, 1.14–2.81). Conclusions This is the first and largest population-based study in Asian patients with lymphoid malignancies treated with L-asp demonstrating that adult patients are at elevated risk of thrombosis after L-asp exposure. The overall incidence of L-asp-related VTE amongst these patients was similar to that in Caucasian populations.

Silent brain infarction (SBI) is a cerebral infarction identified through brain imaging. In particular, studies have shown that the presence of SBI in elderly patients increases their risk of cognitive dysfunction, impairment and dementia. However, little research has been published on the relevance of SBI to these risks for the Korean population. The association between potassium voltage‑gated channel subfamily Q member 2 (KCNQ2), transcription factor 4 (TCF4) and regulator of G‑protein signaling 18 (RGS18) genotypes and SBI were investigated using whole‑exome sequencing and PCR restriction fragment length polymorphism (RFLP) analysis. The study population included 407 patients with SBI (171 males) and 401 control subjects (172 males). Genotyping was performed using PCR RFLP. Interestingly, TCF4 rs9957668T>C polymorphisms were associated with SBI prevalence [TT vs. CC: adjusted odds ratio (AOR), 1.815, 95% confidence intervals (CI), 1.202‑2.740; TT vs. TC+CC: AOR, 1.492, 95% CI, 1.066‑2.088; TT+TC vs. CC: AOR, 1.454, 95% CI, 1.045‑2.203]. The combination of KCNQ2 rs73146513A>G and TCF4 rs9957668T>C genotypes was associated with increasing SBI prevalence (AG/CC: AOR, 3.719, 95% CI, 1.766‑7.833; AA/CC: AOR, 3.201, 95% CI, 1.387‑7.387). The present study showed that TCF4 rs9957668T>C polymorphisms may be risk factors for SBI. Therefore, the TCF4 rs9957668T>C polymorphism may serve as a biomarker for increased risk of SBI in the Korean population.

Venous thromboembolism (VTE) involves the formation of a blood clot, typically in the deep veins of the leg or arm (deep vein thrombosis), which then travels via the circulatory system and ultimately lodges in the lungs, resulting in pulmonary embolism. A number of microRNAs (miRNAs) are well-known regulators of thrombosis and thrombolysis, and mutations in miRNA biogenesis genes, such as DICER1, DROSHA have been implicated in miRNA synthesis and function. We investigated the genetic association between polymorphisms in four miRNA biogenesis genes, DICER1 rs3742330A &gt, G, DROSHA rs10719T &gt, C, RAN rs14035C &gt, T and XPO5 rs11077A &gt, C, and VTE in 503 Koreans: 300 controls and 203 patients. Genotyping was assessed with polymerase chain reaction-restriction fragment length polymorphism assays. We detected associations between polymorphisms in RAN and XPO5 and VTE prevalence (RAN rs14035CC + CT versus TT: p = 0.018, XPO5 rs11077AA + AC versus CC: p &lt, 0.001). Analysis of allele combinations of all four polymorphisms (DICER1, DROSHA, RAN, XPO5) revealed that A-T-T-A was associated with decreased VTE prevalence (p = 0.0002), and A-T-C-C was associated with increased VTE prevalence (p = 0.027). Moreover, in subjects with provoked VTE, the DROSHA rs10719T &gt, C, polymorphism was associated with increased disease prevalence (TT versus TC + CC: p &lt, 0.039). Our study demonstrates that RAN and XPO5 polymorphisms are associated with risk for VTE in Korean subjects.

Background Atypical hemolytic uremic syndrome (aHUS) involves dysregulation of the complement system, but whether this also occurs in thrombotic thrombocytopenic purpura (TTP) remains unclear. Although these conditions are difficult to differentiate clinically, TTP can be distinguished by low (

Despite much progress in microRNA (miRNA) research, information regarding the association between miRNAs and venous thromboembolism (VTE), especially in Asian patients, remains limited. This case-control study sought to determine the correlation between the presence of polymorphisms in the genes encoding the miRNAs miR-146a, miR-149, miR-196a2, miR-499, and VTE in Korean patients. We observed no statistically significant differences in the genotype frequency of miRNA polymorphisms between 300 control individuals and 203 VTE patients. However, we observed a significant association between three allelic combinations of miRNA polymorphisms and VTE risk. Overall, our findings suggest that specific miRNA polymorphisms are associated with the risk of VTE in a Korean population.

The publisher regrets that the members of the 311 Study Group were not included as collaborative authors. Members of the 311 Study Group are listed in the Appendix. The publisher would like to apologize for any inconvenience caused.

Venous thromboembolism occurs commonly in patients with cancer. Direct oral anticoagulants are non-inferior to conventional anticoagulants for the treatment of venous thromboembolism. We hypothesised that edoxaban, a direct oral inhibitor of activated clotting factor Xa, might be more suitable than conventional anticoagulants in the management of cancer-associated venous thromboembolism. The aim of this study was to assess the efficacy and safety of edoxaban compared with warfarin in a subgroup of patients with cancer enrolled in the Hokusai-VTE trial. We did a prespecified subgroup analysis in August, 2013, and a post-hoc analysis of non-inferiority and safety in March, 2016, of the patients with cancer enrolled in the randomised, double-blind, double-dummy, multicentre, Hokusai-VTE trial done between Jan 28, 2010, and Oct 31, 2012. In this study, patients aged at least 18 years with acute symptomatic deep-vein thrombosis or acute symptomatic pulmonary embolism (with or without deep-vein thrombosis) were assigned to receive edoxaban 60 mg once per day (or 30 mg once per day for patients with a creatinine clearance of 30-50 mL/min, bodyweight

The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and modulates cancer growth, invasion, and angiogenesis. The present study investigated the association between five PAI-1 gene polymorphisms and colorectal cancer (CRC) risk. Five PAI-1 polymorphisms (&minus, 844G&gt, A [rs2227631], &minus, 675 4G&gt, 5G [rs1799889], +43G&gt, A [rs6092], +9785G&gt, A [rs2227694], and +11053T&gt, G [rs7242]) were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay in 459 CRC cases and 416 controls. Increased CRC risk was more frequently associated with PAI-1 &minus, 675 5G5G polymorphism than with 4G4G (adjusted odds ratio (AOR) = 1.556, 95% confidence interval (CI): 1.012&ndash, 2.391, p = 0.04). In contrast, for the PAI-1 +11053 polymorphism, we found a lower risk of CRC with the GG genotype (AOR = 0.620, 95% CI: 0.413&ndash, 0.932, p = 0.02) than with the TT genotype, as well as for recessive carriers (TT + TG vs. GG, AOR = 0.662, 95% CI: 0.469&ndash, 0.933, p = 0.02). The +43AA genotype was associated with lower overall survival (OS) than the +43GG genotype. Our results suggest that the PAI-1 genotype plays a role in CRC risk. This is the first study to identify an association between five PAI-1 polymorphisms and CRC incidence worldwide.

The incidence of venous thromboembolism (VTE) is lower in Asian populations than in Western populations. The objective of the present study was to evaluate the annual age- and sex-adjusted incidence (ASR) of VTE from 2009 to 2013 in South Korea. In addition, annual change in the pattern of VTE treatment during the study period was estimated because a new direct oral anticoagulant (DOAC) had become available and was covered by health insurance in Korea beginning in January 2013. VTE cases from 2009 to 2013 were retrospectively identified based on both diagnostic and medication codes of anticoagulants used for initial treatment using the Korean Health Insurance Review and Assessment Service (HIRA) databases. The incidence of VTE increased yearly. It was significantly higher in the older population than in the younger population, and it was higher in females than in males. In 2009, ASRs of VTE, deep vein thrombosis, and pulmonary embolism were 21.3, 8.1, and 13.2 cases per 100,000 individuals, respectively in 2009. These increased to 29.2, 12.7, and 16.6 cases per 100,000, respectively, in 2013. Prescription rates of warfarin and low-molecular-weight heparin decreased with the introduction of a new anticoagulant in 2013. The proportion of subjects who underwent mechanical procedures decreased annually. The ASR of VTE in Korea continuously increased from 2009 to 2013, reflecting an increased awareness and detection of VTE as well as improved survival of patients with cancer and other morbidities. Following its introduction, DOAC rapidly replaced other anticoagulants for the treatment of VTE.

BACKGROUND AND PURPOSE MicroRNA (miRNA) expression has been examined in multiple conditions, including various cancers, neurological diseases, and cerebrovascular diseases, particularly stroke. Existing evidence indicates that miRNA biosynthesis and function play crucial roles in ischemic stroke physiology and pathology. In this study, we selected six known polymorphisms in miRNA-biogenesis genes; DICER rs13078A>T, rs3742330A>G; DROSHA rs10719T>C, rs6877842G>C; Ran GTPase (RAN) rs14035C>T; exportin 5 (XPO5) rs11077A>C. METHODS We analyzed the associations between these polymorphisms and disease status and clinical factors in 585 ischemic stroke patients and 403 controls. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS The DICER rs3742330A>G (AA vs. AG+GG: adjusted odds ratio [AOR], 1.360; 95% confidence interval [CI], 1.024 to 1.807; P=0.034) and DROSHA rs10719T>C polymorphisms (TT vs. CC: AOR, 2.038; 95% CI, 1.113 to 3.730; P=0.021) were associated with ischemic stroke prevalence. During a mean follow-up of 4.80±2.11 years, 99 (5.91%) of the stroke patients died. In multivariate Cox proportional hazard regression models, a significant association was found between RAN rs14035 and survival of large artery disease patients with ischemic stroke (CC vs. TT: adjusted hazard ratio, 5.978; P=0.015). CONCLUSIONS An association was identified between the DICER and DROSHA polymorphisms and ischemic stroke. Specifically, polymorphisms (rs3742330 and rs10719) were more common in stroke patients, suggesting that they may be associated with an increased risk of ischemic stroke.