[Show abstract][Hide abstract] ABSTRACT: Little information is available on the long-term clinical outcome of patients with splanchnic vein thrombosis (SVT).
To assess the incidence rates of bleeding, thrombotic events, and mortality in a large international cohort of patients with SVT.
A prospective cohort study was conducted beginning May 2, 2008, and completed January 30, 2014, at hospital-based centers specialized in the management of thromboembolic disorders; a 2-year follow-up period was completed January 30, 2014, and data analysis was conducted from July 1, 2014, to February 28, 2015. Participants included 604 consecutive patients with objectively diagnosed SVT; there were no exclusion critieria. Information was gathered on baseline characteristics, risk factors, and antithrombotic treatment. Clinical outcomes during the follow-up period were documented and reviewed by a central adjudication committee.
Major bleeding, defined according to the International Society on Thrombosis and Hemostasis; bleeding requiring hospitalization; thrombotic events, including venous and arterial thrombosis; and all-cause mortality.
Of the 604 patients (median age, 54 years; 62.6% males), 21 (3.5%) did not complete follow-up. The most common risk factors for SVT were liver cirrhosis (167 of 600 patients [27.8%]) and solid cancer (136 of 600 [22.7%]); the most common sites of thrombosis were the portal vein (465 of 604 [77.0%]) and the mesenteric veins (266 of 604 [44.0%]). Anticoagulation was administered to 465 patients in the entire cohort (77.0%) with a mean duration of 13.9 months; 175 of the anticoagulant group (37.6%) received parenteral treatment only, and 290 patients (62.4%) were receiving vitamin K antagonists. The incidence rates (reported with 95% CIs) were 3.8 per 100 patient-years (2.7-5.2) for major bleeding, 7.3 per 100 patient-years (5.8-9.3) for thrombotic events, and 10.3 per 100 patient-years (8.5-12.5) for all-cause mortality. During anticoagulant treatment, these rates were 3.9 per 100 patient-years (2.6-6.0) for major bleeding and 5.6 per 100 patient-years (3.9-8.0) for thrombotic events. After treatment discontinuation, rates were 1.0 per 100 patient-years (0.3-4.2) and 10.5 per 100 patient-years (6.8-16.3), respectively. The highest rates of major bleeding and thrombotic events during the whole study period were observed in patients with cirrhosis (10.0 per 100 patient-years [6.6-15.1] and 11.3 per 100 patient-years [7.7-16.8], respectively); the lowest rates were in patients with SVT secondary to transient risk factors (0.5 per 100 patient-years [0.1-3.7] and 3.2 per 100 patient-years [1.4-7.0], respectively).
Most patients with SVT have a substantial long-term risk of thrombotic events. In patients with cirrhosis, this risk must be balanced against a similarly high risk of major bleeding. Anticoagulant treatment appears to be safe and effective in most patients with SVT.
JAMA Internal Medicine 07/2015; 175(9). DOI:10.1001/jamainternmed.2015.3184 · 13.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs play an important role in cancer initiation and development. The aim of this study was to investigate whether polymorphisms in miRNA machinery genes are associated with the development of colorectal cancer (CRC). RAN rs14035 CT heterozygotes and T allele carriers (CT + TT) genotypes had lower risk of CRC, while the DICER1 rs3742330, DROSHA rs10719, and XPO5 rs11077 polymorphisms were not associated with CRC in the full study sample. Specifically, male RAN rs14035 CT heterozygotes and XPO5 rs11077 AA genotype (CT/AA) carriers experienced reduced CRC susceptibility (both colon and rectal). Subgroup analysis demonstrated that the combined RAN rs14035 CT + TT genotype was associated with rectal cancer, but not colon cancer. In addition, the DICER1 rs3742330 AG genotype was associated with a significantly increased risk of colon cancer. Stratified analysis revealed the RAN rs14035 combined CT+TT genotype was associated with decreased CRC risk in male patients without diabetes mellitus (DM) and in patients with rectal cancer. In addition, we found the RAN rs14035 CC genotype was related to a decreased risk of CRC with respect to tumor size and metabolism of homocysteine and folate. Furthermore, patients diagnosed with hypertension or DM who carried the DROSHA rs10719 CC genotype showed increased CRC risk, while the XPO5 rs11077 AC+CC genotype led to increased CRC risk in patients with hypertension only. Our results indicate variations in RAN rs14035, DICER1 rs3742330, XPO5 rs11077, and DROSHA rs10719 of Korean patients are significantly associated with their risk of CRC.
PLoS ONE 07/2015; 10(7):e0131125. DOI:10.1371/journal.pone.0131125 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3′-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3′-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3′-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention.
[Show abstract][Hide abstract] ABSTRACT: Folate has essential roles in DNA synthesis, repair and methylation. Folate metabolism-related gene variants may modulate the levels of this vitamin and affect the cancer risk. Thus, whether these polymorphisms play an important role in carcinogenesis, particularly colorectal cancer (CRC) development, has been a subject interest. The present study investigated the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and the reduced folate carrier 1 (RFC1) genes and CRC risk. Polymorphisms in MTHFR (677C>T and 1298A>C), TS [1494del6 and the TS enhancer region (TSER)] and RFC1 (-43T>C, 80G>A and 696C>T) were characterized using polymerase chain reaction-restriction fragment length polymorphism in 477 CRC cases and 514 controls. Although no polymorphisms were significantly associated with the CRC risk in the overall sample, significant associations between folate metabolism-related polymorphisms and CRC risk were identified in the stratified analyses. The MTHFR 677CT/1298AC and MTHFR 1298AC+CC/TSER 2R3R genotypes in the presence of plasma folate levels ≤4.12 ng/ml were associated with significantly increased CRC risk. In addition, individuals with the MTHFR 677TT/TSER 3R3R or MTHFR 677/TSER 3R3R/TS 1494 0bp6bp+6bp6bp genotypes and diabetes mellitus (DM) were at an increased risk for CRC. Therefore, the data suggest that i) MTHFR polymorphisms combined with low plasma folate levels and ii) polymorphisms in folate metabolism-related genes combined with metabolic syndrome risk factors (hypertension and DM) increase the odds of developing CRC.
Molecular and Clinical Oncology 02/2015; 3(3). DOI:10.3892/mco.2015.520
[Show abstract][Hide abstract] ABSTRACT: Bortezomib (Velcade®) came into the spotlight as a target therapy for multiple myeloma. It acts through reversible inhibition of intracellular proteasomes, which triggers apoptosis, with relative selectivity for malignant cells. It has been hypothesized that the accumulation of damaged proteins in myocytes impairs cardiac function. Cardiotoxicity is a rare side effect of bortezomib treatment. We report a case of reversible systolic heart failure that probably occurred after bortezomib treatment in a patient with multiple myeloma. Patients being treated with bortezomib who have previously had cardiac comorbidities should undergo routine cardiac monitoring.
[Show abstract][Hide abstract] ABSTRACT: Polymorphisms in angiogenesis-related genes and metabolic syndrome (MetS) risk factors play important roles in cancer development. Moreover, recent studies have reported associations between a number of 3[prime]-UTR polymorphisms and a variety of cancers. The aim of this study was to investigate the associations of three VEGF 3[prime]-UTR polymorphisms (1451C > T [rs3025040], 1612G > A [rs10434], and 1725G > A [rs3025053]) and MS with colorectal cancer (CRC) susceptibility in Koreans.
A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of VEGF polymorphisms was performed by TaqMan allelic discrimination assays. Cancer risks of genetic variations and gene-environment interactions were assessed by adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of multivariate logistic regression analyses.
VEGF 1451C > T was significantly associated with rectal cancer risk (Dominant model; AOR =1.58; 95% CI =1.09 - 2.28; p =0.015) whereas VEGF 1725G > A correlated with MetS risk (Dominant model; AOR =1.61; 95% CI =1.06 - 2.46; p =0.026). Of the gene-environment combined effects, the interaction of VEGF 1451C > T and MetS contributed to increased RC risk (AOR =3.15; 95% CI =1.74 - 5.70; p < .001) whereas the combination of VEGF 1725G > A and MetS was involved with elevated CC risk (AOR =2.68; 95% CI =1.30 - 1.55; p =0.008).
Our results implicate that VEGF 1451C > T and 1725G > A may predispose to CRC susceptibility and the genetic contributions may be varied with the presence of MetS.
BMC Cancer 11/2014; 14(1):881. DOI:10.1186/1471-2407-14-881 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To gain insight into the natural history of cytomegalovirus (CMV) infection following unrelated cord blood transplantation (UCBT) in seropositive patients, we analyzed the data of 349 seropositive patients who received UCBT in Korea between 2000 and 2011. CMV reactivation occurred in 49 % (171/349) of the CMV-seropositive transplant recipients at a median of 31 days post UCBT. One hundred sixty-four out of 171 patients (96 %) received preemptive therapy. The median duration of CMV reactivation was 29 days. In multivariate analysis, weight >22 kg, use of total body irradiation, use of pre-transplant antithymocyte globulin, graft-versus-host disease (GVHD) prophylaxis with mycophenolate mofetil, and presence of grade II-IV acute GVHD were independent predictors of CMV reactivation. CMV reactivation did not impact transplantation-related mortality (TRM), leukemia relapse, or survival. CMV disease was diagnosed in 62 patients (17.8 %) at a median 55 days after UCBT. Longer duration of CMV reactivation was the only risk factor for progression to CMV disease (p = 0.01). CMV disease resulted in higher TRM (56.0 vs. 31.4 %, p < 0.01) and lower survival (36.1 vs. 55.1 %, p = 0.02).
Annals of Hematology 11/2014; 94(3). DOI:10.1007/s00277-014-2222-x · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
The metabolic syndrome (MetS) may contribute to the pathogenesis of venous thromboembolism (VTE), but this association requires additional investigation.
Approach and results:
We performed a patient-level meta-analysis of case-control and cohort studies that evaluated the role of MetS and risk of unprovoked VTE. For case-control studies, odds ratios and 95% confidence intervals were calculated using logistic regression analysis to estimate the influence of individual variables on the risk of VTE; χ(2) tests for trend were used to investigate the effect of increasing number of components of MetS on the risk of VTE and to explore the influence of abdominal obesity on this relationship. For cohort studies, hazard ratios and 95% confidence interval were calculated using multivariable Cox regression analysis. Six case-control studies were included (908 cases with unprovoked VTE and 1794 controls): in multivariate analysis, MetS was independently associated with VTE (odds ratio, 1.91; 95% confidence interval, 1.57-2.33), and both MetS and abdominal obesity were better predictors of unprovoked VTE than obesity defined by the body mass index. Two prospective cohort studies were included (26,531 subjects and 289 unprovoked VTE events): age, obesity, and abdominal obesity, but not MetS were associated with VTE.
Case-control but not prospective cohort studies support an association between MetS and VTE. Abdominal adiposity is a strong risk factor for VTE.
[Show abstract][Hide abstract] ABSTRACT: Hereditary protein S deficiency from a mutation in the PROS1 gene causes a genetic predisposition to develop venous thromboembolic disorders in humans. Recently, the acknowledgment of the clinical significance of large copy number mutations in protein S deficiency has increased. In this study, the authors investigated the genomic architecture of PROS1 in order to understand the microscopic sequence environment leading to large intragenic copy number mutations in the gene. The study subjects were 3 unrelated male patients with hereditary protein S deficiency from a tandem duplication mutation involving exons 5-10 of PROS1. Breakpoint analyses revealed 10-bp microhomology sequences in the intervening sequence (IVS)-4 and IVS-10 at the duplication junction without additional sequence changes, suggesting a single replication-based event as the potential molecular mechanism of rearrangement and founder effect in the mutant alleles. Further analyses on nucleotide sequences flanking the microhomology sequence revealed the presence of a repeat element (LTR-ERV1) and quadruplex-forming G-rich sequences in IVS-4. The results from genotyping multi-allelic short tandem repeats supported founder effect in the identical mutations in the 3 unrelated patients. In conclusion, we identified unique genomic architectures in the intervening sequences of PROS1 that underlie a large intragenic tandem duplication mutation leading to inherited thrombophilia.
[Show abstract][Hide abstract] ABSTRACT: Background
Data on the incidence of venous thromboembolism (VTE) following major surgery in Asian populations are limited.Methods
Using the Korean Health Insurance Review and Assessment Service database, we performed a nationwide population-based epidemiologic study to estimate the incidence of VTE after major orthopaedic, cancer, and benign surgeries. VTE cases were identified from all patients undergoing major surgery between 2007 and 2011 using both diagnostic and drug codes as treatment evidence of VTE within 5 weeks of surgery. We also calculated the relative risk of VTE in major orthopaedic and cancer surgery compared to benign surgery.ResultsThe overall rates of postoperative VTE were 1.24%, 0.67%, and 0.05% for major orthopaedic, cancer, and benign surgeries, respectively. Hip fracture (1.60%) and colorectal cancer surgeries (1.67%) were associated with the highest rates of VTE, and the rates steadily increased during the study period. Advanced age, female sex, and general anaesthesia were independent risk factors for VTE. Patients undergoing surgery for colorectal, pancreatic, ovarian, and oesophageal cancer, and major orthopaedic surgery had more than a 20-fold higher risk of VTE than those undergoing benign surgery.Conclusions
This is the largest epidemiologic study to investigate the incidence of VTE after major surgery in Asia, demonstrating that the rates of postoperative VTE are lower than in Caucasian populations. This study contributes to a better understanding of the differences in postoperative VTE development between Korean and Caucasian populations; the data also suggest that perioperative prophylactic strategies in Asians should be based on studies of such populations.This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 05/2014; 12(7). DOI:10.1111/jth.12611 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Silent brain infarction (SBI) is an asymptomatic cerebrovascular disorder. The aim of the present study was to investigate the association between adrenoceptor‑α2 (ADRA2) gene polymorphisms and SBI. A total of 361 patients with SBI and 467 healthy control subjects were examined. The polymerase chain reaction was performed to genotype the ADRA2A 1780G>A, ADRA2B 301‑303 insertion/deletion (I/D) and ADRA2C 322‑325I/D polymorphisms. The frequency of the ADRA2C 322‑325I/D polymorphism was significantly different between patients with SBI and control subjects. When interaction analyses were performed for vascular risk factors, the ADRA2C 322‑325ID genotype increased the risk for SBI in the presence of hypertension and elevated plasma homocysteine levels. The ADRA2C 322‑325ID genotype and plasma homocysteine levels showed a significant synergistic effect for SBI. In addition, the ADRA2A 1780AA genotype was associated with elevated plasma homocysteine levels. Although further analysis of the association between ADRA2 polymorphisms and clinical risk factors of SBI is required, the present study of a limited set of SBI risk factors with ADRA2 polymorphisms provides the first evidence of the involvement of ADRA2 gene family members in the development of SBI. Further studies using larger and more heterogeneous populations are required to validate the association of ADRA2 polymorphisms with SBI.
Molecular Medicine Reports 03/2014; 9(6). DOI:10.3892/mmr.2014.2072 · 1.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxaliplatin is a platinum compound used in patients with gastrointestinal malignancies. It is known to evoke a drug-induced immune-mediated thrombocytopenia, which has not been reported in Korea. We describe a 53-year-old man who developed oxaliplatin-induced immune-mediated thrombocytopenia during chemotherapy for colon cancer. Oxaliplatin-dependent IgG platelet antibodies were detected in his serum on flow cytometry. He was treated with immunoglobulin and corticosteroids without any complications. Physicians should consider oxaliplatin-induced immune-mediated thrombocytopenia, when a sudden, isolated thrombocytopenia develops during chemotherapy with oxaliplatin.
Blood Research 03/2014; 49(1):61-4. DOI:10.5045/br.2014.49.1.61
[Show abstract][Hide abstract] ABSTRACT: In 2010, we proposed the first Korean Guidelines for the Prevention of Venous Thromboembolism (VTE). It was applicable to Korean patients, by modifying the contents of the second edition of the Japanese guidelines for the prevention of VTE and the 8th edition of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines. From 2007 to 2011, we conducted a nationwide study regarding the incidence of VTE after major surgery using the Health Insurance Review and Assessment Service (HIRA) database. In addition, we have considered the 9th edition of the ACCP Evidenced-Based Clinical Practice Guidelines, published in 2012. It emphasized the importance of clinically relevant events as opposed to asymptomatic outcomes with preferences for both thrombotic and bleeding outcomes. Thus, in the development of the new Korean guidelines, three major points were addressed: 1) the new guidelines stratify patients into 4 risk groups (very low, low, moderate, and high) according to the actual incidence of symptomatic VTE from the HIRA databases; 2) the recommended optimal VTE prophylaxis for each group was modified according to condition-specific thrombotic and bleeding risks; 3) guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and/or physician advice.
Journal of Korean medical science 02/2014; 29(2):164-171. DOI:10.3346/jkms.2014.29.2.164 · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary autoimmune myelofibrosis, the development of which is not preceded by a well-defined autoimmune disease, has recently been defined as a distinct clinicopathologic syndrome. We report herein a case of a 68-year-old woman who was diagnosed with primary autoimmune myelofibrosis and present a review of the literature. The patient manifested peripheral pancytopenia, was positive for autoantibodies, and developed myelofibrosis with no preceding autoimmune or hematologic disorders. Her condition was dramatically improved after administration of prednisolone.
[Show abstract][Hide abstract] ABSTRACT: To investigate the association between potentially functional plasminogen activator inhibitor-1 (PAI-1) genetic polymorphisms and primary ovarian insufficiency (POI).
Urban university-based hospital.
A cohort of 137 POI patients and 227 controls.
Genotyping of five PAI-1 polymorphisms (-844G>A [rs2227631], -675 4G/5G [rs1799889], 43G>A (Ala>Thr) [rs6092], 9785G>A [rs2227694], and 11053T>G [rs7242]) was assessed by polymerase chain reaction-restriction fragment length polymorphism assay.
PAI-1 polymorphisms 9785GA+AA, -844A/9785A, 4G/9785A, and 9785A/11053G were associated with POI occurrence. Moreover, -844GA+AA and 11053TG+GG were associated with lower serum E2 levels in controls.
We have identified an association between five PAI-1 polymorphisms and POI occurrence. However, the mechanism underlying the function of these polymorphisms in POI remains to be determined. Further studies are needed to improve understanding of the roles of PAI-1 polymorphisms and genes in related pathways, using a larger and more heterogeneous cohort.
Fertility and sterility 12/2013; 101(3). DOI:10.1016/j.fertnstert.2013.11.015 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The microRNA (miR)-34 family is a direct transcriptional target of tumor-suppressor TP53 and loss of miR-34 function may impair TP53-mediated cell cycle arrest and apoptosis. In the present study, we investigated whether the single nucleotide polymorphisms (SNPs) rs4938723 (T>C) in the promoter region of miR-34b/c and Arg72Pro (G>C) in codon 72 of TP53 are independently or complementarily associated with the risks and clinical outcomes of colorectal cancer (CRC) and whether the combined effect of these SNPs and metabolic risk factors are related to CRC. We evaluated the SNPs in 545 CRC patients and 428 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequence analysis. We found that the GC and GC/CC genotypes of TP53 Arg72Pro were associated with decreased risk of CRC (adjusted OR = 0.727 for GC; OR = 0.735 for GC/CC). The combined genotypes of TT-GC and CC-GG were significantly associated with reduced CRC risk (adjusted OR = 0.628 for TT-GC; OR = 0.381 for CC-GG, respectively). The SNP rs4938723 and diabetes mellitus (DM) together were associated with an increased CRC risk, but the SNP TP53 Arg72Pro CC with DM showed a protective effect against CRC. These findings indicate that rs4938723 in the promoter region of pri-miR-34b/c and the SNP in TP53 codon 72 were related to decreased risk of CRC in the population studied and those metabolic diseases and genetic variants influence each other with regard to CRC susceptibility.