Venous Thromboembolism in Japanese Patients with Gynecologic Cancer.

OBJECTIVE: Gynecologic cancer, including cervical, endometrial, and ovarian cancer, comprises the fifth leading type of cancer and is an important malignant disease in women. Previous studies in Western countries have reported respective prevalence rates for venous thromboembolism (VTE) of 3.3%-18.7%, 0.8%-8.1%, and 7.2%-20.9%. In this study, we aimed to identify the characteristics associated with VTE in Japanese patients. METHODS: We carried out a retrospective cohort study to compare the clinicopathological characteristics of patients with each gynecologic cancer with and without concomitant VTE. Patients: Patients with cervical, endometrial, or ovarian cancer treated at Fukui Prefectural Hospital, Japan, from April 2010 to March 2020. RESULTS: Among 699 patients with gynecologic cancer, 50 developed VTE within 5 years after their cancer diagnosis, including 16/357 patients with cervical cancer (5.6%), 12/185 with endometrial cancer (6.8%), and 22/157 with ovarian cancer (14.6%). The 1-year mortality rate after symptomatic VTE onset was 47.8%. The VTE group included significantly more older patients and more patients with advanced cancer or poor performance status compared with the non-VTE group. There was no significant difference in the rate of surgical treatment. Symptomatic, but not asymptomatic VTE, was associated with shorter survival. CONCLUSION: Several baseline characteristics differed between patients with and without VTE. The incidences of VTE and some risk factors were similar in Japanese patients with gynecologic cancers compared with patients in other countries. Patients with VTE had some factors that worsened their prognosis, with patients with gynecologic cancer and symptomatic VTE having an especially poor prognosis.

Venous Thromboembolism in Japanese Patients With Pancreatic Cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in Japan. Previous studies from other countries have reported venous thromboembolism prevalence rates of 12 to 36% in patients with pancreatic cancer. In this study, we aimed to determine the incidence of VTE in patients with PDAC in Japan and compare the characteristics of patients with and without VTE. METHODS: In this retrospective cohort study, clinicopathological characteristics of patients with and without concomitant VTE were compared. PATIENTS: Patients with PDAC treated at Fukui Prefectural Hospital, Japan from 2010 to 2019. RESULTS: The 1-year survival rate of all patients with pancreatic cancer was 40.7%. Among 432 patients with PDAC, 31 developed VTE. Seventeen (55%) patients received anticoagulant therapy. Compared with the non-VTE group, the VTE group had significantly more patients whose body mass index was >25 kg/m² (p = .035) and had a significantly higher rate of chemotherapy (p = .024). There was no significant difference in median survival time from PDAC diagnosis between the VTE and non-VTE groups. The 6-month mortality rate after VTE diagnosis was 54.8%. PDAC-related death was the most frequent cause of death, and thrombus-related death was not observed. CONCLUSION: Several baseline characteristics differed between patients with and without VTE. The incidence of VTE in patients with PDAC is high. However, because the prognosis of PDAC itself remains quite poor, VTE may not have a significant effect on prognosis.

Venous Thromboembolism in Patents With Lung Cancer.

Lung cancer is the leading cause of death from cancer in Japan. Studies in other countries have reported a venous thromboembolism (VTE) rate of 4%-20% in cancer patients. In this study, we aimed to determine the incidence of VTE in lung cancer patients in Japan and compared the characteristics of patients with and without VTE. In this retrospective cohort study, the clinicopathological characteristics of study patients with and without concomitant VTE were compared. Patients with lung cancer treated at Fukui Prefectural Hospital, Japan from 2008 to 2017. Of the 1471 patients with lung cancer studied, 28 developed VTE. Five patients developed pulmonary thromboembolism (PTE) alone, 9 PTE with concomitant deep vein thrombosis, and 14 deep vein thrombosis alone. Compared with patients in the non-VTE group, the VTE group was significantly younger (mean value ± SD 66.3 ± 10.1 vs. 73.0 ± 10.6 years, p = 0.001), contained significantly more patients with stage IIIb-IV disease (p = 0.002), and had a significantly higher rate of chemotherapy (p < 0.001) and radiation therapy (p = 0.007). There was no significant difference in median survival time from lung cancer diagnosis between the VTE and non-VTE groups. The 1-year mortality rate after VTE diagnosis was 60.7%. Lung cancer was the most frequent cause of death, followed by infection and VTE. Several baseline characteristics differed between patients with and without VTE. The prognosis may worsen after development of VTE, suggesting that lung cancer patients should be carefully monitored for it.

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

Primary Percutaneous Coronary Intervention by a Stentless Technique for Acute Myocardial Infarction with Idiopathic Thrombocytopenic Purpura: A Case Report and Review of the Literature.

A 78-year-old man who had been diagnosed with idiopathic thrombocytopenic purpura (ITP) was admitted to our hospital with chest pain, cold sweating and nausea. An electrocardiogram and echocardiogram revealed an ST elevated acute lateral myocardial infarction. He underwent an immediate cardiac catheterization. An occluded left circumflex artery was detected by coronary angiography. Reperfusion was performed successfully by non-slip element balloon angioplasty alone, without stenting, to avoid prolonged dual anti-platelet therapy. In this report we discussed the management strategies of acute myocardial infarction in a patient with concomitant ITP.

Very late stent thrombosis after sirolimus-eluting stent implantation: evaluation by intravascular ultrasound and optical coherence tomography.

A 58-year-old man was admitted to our hospital with acute anterior myocardial infarction that occurred 4 years after single sirolimus-eluting stent (SES) implantation in the left anterior descending artery. He had been undergoing continuous dual antiplatelet therapy. Emergency coronary angiography showed total thrombotic occlusion and peri-stent contrast staining at the SES site. The lesion was evaluated using intravascular ultrasound (IVUS) and optical coherence tomography (OCT) after thrombectomy. Vessel remodeling was detected on IVUS, and multiple interstrut hollows and thrombi were observed on OCT. These findings were associated with very late stent thrombosis after SES implantation.

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects.

BACKGROUND: The half of hyperalphalipoproteinemia (HALP) in Japan is caused by CETP gene mutations. Other than two prevalent mutations (D442G and Intron 14 splicing donor site +1G>A), some rare CETP mutations are found in Japanese HALP subjects. METHODS: CETP gene analysis of genomic DNA from subjects was performed by restriction fragment length polymorphism (RFLP) and sequencing analysis. Mutations which were suspected to cause a splicing defect or a protein secretion defect were investigated in COS-1 cells transfected with a CETP minigene construct or a cDNA expression vector. RESULTS: Each of three subjects was identified as a carrier of CETP gene mutation of a compound heterozygote of c.653_654delGGinsAAAC and Intron 14 splicing donor site +1G>A, a heterozygote of c.658G>A or a homozygote of L261R. The c.658G>A mutation was located at the last nucleotide of exon 7, and it was confirmed to cause splicing abnormality revealed by the CETP minigene analysis. The L261R CETP was not secreted to conditioned media of the cells. CONCLUSIONS: Three novel CETP gene mutations are responsible for HALP by CETP deficiency. It is predicted that there are more rare CETP gene mutations in Japanese, and these multiple rare mutations alone or a combination with each of prevalent mutations is responsible for mild-to-moderate or marked HALP, respectively.

Emergent thoracic aortic angioplasty and stenting for middle aortic syndrome in non-specific aortitis.

A 61-year-old Japanese male was admitted to hospital due to severe congestive heart failure and pre-renal failure with middle aortic syndrome. The patient was successfully treated with emergent aortic angioplasty and kissing stents implantation whilst in a hemodynamically unstable state. Our experience confirms that stenosis of the descending aorta when treated with catheter intervention may be palliative, however, it was a very effective method for life threatening clinical conditions in the short and mid-term and may be an alternative to surgery.

Survey of the vectorial competence of ticks in an endemic area of spotted fever group rickettsioses in Fukui Prefecture, Japan.

The prevalence of SFGR in ixodid ticks in the Mt. Arashima-dake area in the northern part of Fukui Prefecture was surveyed, because of strong suspicions that the first case identified in this Prefecture had become infected with R. helvetica in this region. The ticks identified consisted of three genera and six species; I.ovatus, I. persulcatus, I. monospinosus, H. flava, H. japonica and D. taiwanensis. Of all 222 ticks collected, only I. monospinosus ticks (8 of 32 examined) were positive for SFGR isolates, which were genetically identified as R. helvetica. Ticks (157 of all 222) positive for SFGR-DNA fragments consisted of I. monospinosus (14 of 32), I. persulcatus (11 of 55), I. ovatus (3 of 38), H. flava (5 of 21) and H. japonica (2 of 9). Of these, thirteen I. monospinosus, eight I. persulcatus, three I. ovatus, two H. flava and one H. japonica were identified by nucleotide sequences as positive for R. helvetica. DNA fragments from three H. flava and one H. japonica showed greater homology to R. japonica than to R. helvetica or R. asiatica. The present results indicate that it is most likely that the vector tick of R. helvetica infection in Fukui Prefecture is I. monospinosus.

The first reported case of spotted fever in Fukui Prefecture, the northern part of central Japan.

A 53-year-old man visited Mt. Arashima-dake in Fukui Prefecture, and was infested by a tick-like organism. He visited a local clinic on July 12, 2004, complaining of high fever, general fatigue and rash. After several days without definite diagnosis, he was admitted to the Fukui Prefectural Hospital, where he was treated with minocycline hydrochloride for 10 days until recovery. His clinical symptoms on admission were high fever (39.6 degrees C), erythematous eruption, eschar on the right upper arm, and regional lymphoadenopathy. The epidemiological status and some clinical findings strongly suggested spotted fever (SF), and SF was confirmed based on the finding that his sera were reactive only to antigens of the SF group rickettsiae in the indirect immunoperoxidase analysis. This case is the first official report of SF rickettsiosis in Fukui Prefecture, the northern part of central Japan.

Cutoff point separating affected and unaffected familial hypercholesterolemic patients validated by LDL-receptor gene mutants.

Familial hypercholesterolemia (FH) results from low-density lipoprotein (LDL) receptor gene mutations. Heterozygotes have twice normal LDL-cholesterol concentrations in early childhood, and experience early myocardial infarction. We demonstrated bimodal cholesterol frequency distributions, independently confirming existence of an identifiable hypercholesterolemic subpopulation. We assayed blood lipids in 181 FH patients genetically diagnosed and 100 unaffected relatives. Receiver operating characteristics curves were constructed. Total cholesterol and LDL-cholesterol concentrations showed bimodality. A total cholesterol cutoff of 225 mg/dl produced results agreeing with DNA testing (specificity, 98.5%; sensitivity, 99.4%). An LDL-cholesterol cutoff of 161-163 mg/dl produced 98.5% specificity and 98.3% sensitivity. Areas under curves were 0.9826 +/- 0.0058 for total cholesterol, and 0.9852 +/- 0.0043 for LDL-cholesterol. In conclusion, we define total cholesterol and LDL-cholesterol levels of 225 and 160 mg/dl, respectively, as cutoff points of normal subjects and FH patients.

Increased circulating matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction.

BACKGROUND: Some patients with hypertrophic cardiomyopathy (HCM) develop left ventricular (LV) wall thinning associated with LV dilatation and systolic dysfunction. Recently, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were reported to be involved in ventricular remodeling, however, little is known about MMPs and TIMPs in patients with HCM. METHODS AND RESULTS: Enzyme-linked immunoassays were used to measure the plasma concentrations of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 in 11 patients with HCM accompanied by systolic dysfunction (fractional shortening (FS) <25%, group A), 17 patients with HCM who had preserved systolic function (FS> or =25%, group B), and 50 age-matched clinically healthy control subjects (mean age: 57 years). The concentration of MMP-2 in group A was significantly higher than in group B and the control subjects (1,124 +/- 84, 792 +/- 49, 809 +/- 26 ng/ml, respectively), whereas there was no significant difference between group B and the control subjects. MMP-2 concentrations significantly increased as the New York Heart Association functional class increased in patients with HCM. TIMP-2 was also significantly higher in group A patients than in group B and the control subjects (45.3 +/- 4.7, 34.6 +/- 2.2, 33.7 +/- 1.8 ng/ml, respectively), but there was no difference between group B and control subjects. TIMP-1 was significantly higher in HCM patients than in control subjects. MMP-3 and MMP-9 concentrations did not differ among the 3 groups. Both MMP-2 and TIMP-2 correlated significantly with FS and LV dimension, negatively and positively, respectively. CONCLUSIONS: These results suggest that changes in the release and activity of MMP-2 and TIMP-2 may be associated with the mechanisms responsible for cardiac remodeling in patients with HCM.

Identification of two novel missense mutations (p.R1221C and p.R1357W) in the ABCC6 (MRP6) gene in a Japanese patient with pseudoxanthoma elasticum (PXE).

Pseudoxanthoma elasticum (PXE) is a rare, inherited, systemic disease of elastic tissue that in particular affects the skin, eyes, and cardiovascular system. Recently, the ABCC6 (MRP6) gene was found to cause PXE. A defective type of ABCC6 gene (16pl3.1) was determined in two Japanese patients with PXE. In order to determine whether these patients have a defect in ABCC6 gene, we examined each of 31 exons and flanking intron sequences by PCR methods (SSCP screening and direct sequencing). We found two novel missense variants in exon 26 and 29 in a compound heterozygous state in the first patient. One is a missense mutation (c.3661C>T; p.R1221C) in exon 26 and the other is a missense mutation (c.4069C>T; p.R1357W) in exon 29. These mutations have not been detected in our control panel of 200 alleles. To our knowledge, this is the first report of mutation identification in the ABCC6 gene in Japanese PXE patients. The second patient was homozygous for 2542_2543delG in ABCC6 gene and heterozygous for 6 kb deletion of LDL-R gene. This case is the first report of a genetically confirmed case of double mutations both in PXE and FH loci.

Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients with heterozygous familial hypercholesterolemia.

The clinical efficacy and safety of pitavastatin (NK-104), a novel HMG-CoA reductase inhibitor, during long-term treatment, were examined in 25 patients (male/female=11/14, mean age=53+/-13 (mean+/-SD) years) with heterozygous familial hypercholesterolemia (FH). After a period on placebo of >4 weeks, 2 mg/day of pitavastatin was administered for 8 weeks, and the dose was increased to 4 mg/day for up to 104 weeks. Total cholesterol (TC) decreased by 31% from the initial value of 340+/-57 to 237+/-40 mg/dl (P<0.0001) at week 8. During treatment with the higher dose, TC decreased even further to 212+/-35 mg/dl at week 12; it decreased by 37% from the initial value (P<0.0001). Similarly, the baseline low-density lipoprotein (LDL)-cholesterol (LDL-C) decreased by 41% at week 8, and by 49% at week 12, from 267+/-61 mg/dl at baseline. These findings indicate a dose-dependent effect of the drug on TC and LDL-C concentrations. To examine whether the levels of circulating matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases: TIMPs) are altered during lipid-lowering therapy, we also measured their plasma levels. The mean levels of MMP-2 and -3 were significantly increased. No significant alteration was found in MMP-9, TIMP-1 and -2 levels. As for the safety of pitavastatin, adverse reactions were observed in one case (4%) of subjective and objective symptoms. The effects of pitavastatin on TC and LDL-C were stable during long treatment of patients with heterozygous FH.