Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　- A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study).

BACKGROUND: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5-2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer. CONCLUSIONS: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

The impact of the COVID-19 pandemic on hepatocellular carcinoma diagnosis and treatment in Japan: A multicenter collaborative observational study.

AIM: Coronavirus disease 2019 emerged in December 2019 and spread worldwide. This study aimed to clarify the impact of the coronavirus disease 2019 pandemic on the diagnosis and treatment of hepatocellular carcinoma (HCC) in Japan. METHODS: First, we collected the monthly numbers of HCC-related general medical practices from January 2019 to December 2021 at liver disease-specific medical institutions in Japan. Next, we collected individual clinical information from patients with newly diagnosed HCC during this period. RESULTS: There was a decrease in the number of HCC-related medical practices, including referrals, enhanced abdominal ultrasonography and radiofrequency ablation, in Japan's first state of emergency (SOE; April-May 2020) compared with 2019. Fewer patients were diagnosed with new HCC during the first SOE than before or after it. There was no difference in tumor diameter, number of tumors or Barcelona Clinic Liver Cancer stage between patients diagnosed before the first SOE and those diagnosed during or after the first SOE. The median waiting times for treatment of patients diagnosed during and after the first SOE were 31 and 37 days, which were significantly shorter and not longer than that of patients diagnosed before the first SOE (36 days), respectively. CONCLUSION: The number of HCC-related general medical practices decreased during the first SOE. However, the coronavirus disease 2019 pandemic did not lead to HCC progression by diagnostic delays or cause HCC treatment delays in Japan.

Risk factors for mortality after hip fracture surgery in Japan using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

We investigated the risk factors for mortality of hip fracture in the elderly using the National Database of Health Insurance Claims in Japan, and survival was significantly related to sex, age, fracture type, surgical procedure, delayed operative date, comorbidities, blood transfusions, and pulmonary embolism. PURPOSE: Hip fracture is the most common fracture in the elderly and is known to have a high mortality rate. In Japan, to the best of our knowledge, no studies have reported on mortality risk factors for hip fracture using nationwide registry databases. This study aimed to determine the number of occurrences of hip fracture and factors that increase mortality using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. METHODS: This study included extracted data from patients who were hospitalized and underwent surgical treatment for hip fracture between 2013 and 2021, using a nationwide health insurance claims database in Japan. Patient characteristics, such as sex, age, fracture type, surgical procedure, delayed operative date, comorbidities, blood transfusions, and pulmonary embolism, were tabulated to obtain 1-year and in-hospital mortality rates. RESULTS: Both 1-year and in-patient survival were significantly lower in men, older patients, patients who underwent surgery after 3 days of admission, and patients with trochanteric and subtrochanteric fractures, internal fixation, more preoperative comorbidities, blood transfusions, and pulmonary embolism. CONCLUSIONS: Survival was significantly related to sex, age, fracture type, surgical procedure, delayed operative date, comorbidities, blood transfusions, and pulmonary embolism. As the number of male patients with hip fracture will increase with the aging of society, medical staff must provide sufficient information before surgery to avoid postoperative mortality.

Pulmonary hypertension secondary to interstitial fibrosis with pulmonary venous lesions masquerading pulmonary veno-occlusive disease.

We present a 41-year-old man with idiopathic interstitial pneumonia and pulmonary hypertension (PH) in the setting of a non-autoimmune background whose clinical presentation masqueraded pulmonary veno-occlusive disease (PVOD). Because of no histological evidence of venous occlusion in his previous lung biopsy, phosphodiesterase type-5 inhibitor was given, resulting in sudden onset of pulmonary edema. At autopsy, there were histological features of interstitial fibrosis with occlusion of the lobular septal veins and venules. Clinical presentations of PH due to interstitial fibrosis with pulmonary venous lesions may simulate those of PVOD and careful diagnostic and therapeutic approaches are required.

Intracardiac Thrombosis and Systemic Embolism in a Patient with Cardiac Amyloidosis in Sinus Rhythm.

Intracardiac thrombosis formation in patients in sinus rhythm is a rare phenomenon. An 84-year-old woman was admitted because of worsening dyspnea on exertion. An electrocardiogram showed sinus rhythm, left atrial overload, marked left axis deviation, low voltage, and poor r-wave progression in leads V1-4. An echocardiogram showed relatively preserved left ventricular ejection fraction with minimal wall thickening. Her serum level of B-type natriuretic peptide (931 pg/mL) was markedly elevated and a diagnosis of worsening heart failure was made. During the course of treatment for heart failure, she was complicated by acute abdominal aortic thromboembolism together with left atrial thrombus. An emergency abdominal aortic thrombectomy was followed by the removal of a left atrial thrombus 2 days later. Left ventricular biopsy performed during the surgery revealed amyloid deposits in the myocardial interstitium. Immunohistochemical study confirmed the diagnosis of transthyretin cardiac amyloidosis. It is postulated that the risk of intracardiac thrombosis and systemic embolism is increased even in sinus rhythm in patients with cardiac amyloidosis.

Seronegative rheumatoid arthritis after combination therapy with ipilimumab and nivolumab for postoperative pancreatic and liver metastases from renal cell carcinoma.

Introduction: Since the approval of immune checkpoint inhibitors for renal cell carcinoma treatment, therapeutic efficacy has been enhanced. However, although autoimmune-related side effects may occur, rheumatoid immune-related adverse events seldom develop. Case presentation: A 78-year-old Japanese man with renal cell carcinoma developed pancreatic and liver metastases after bilateral partial nephrectomy and was treated with ipilimumab and nivolumab. After 22 months, he developed arthralgia in limbs and knee joints, accompanied by limb swelling. The diagnosis was seronegative rheumatoid arthritis. Nivolumab was discontinued, and prednisolone was initiated, quickly improving symptoms. Although nivolumab was resumed after 2 months, arthritis did not recur. Conclusion: Immune checkpoint inhibitors may cause a wide variety of immune-related adverse events. When arthritis is encountered during immune checkpoint inhibitor administration, seronegative rheumatoid arthritis should be differentiated from other types of arthritis, despite being less frequent.

A study of 95 infantile hemangiomas treated with propranolol: A potentially efficacious combination with laser therapy.

We studied 95 patients with infantile hemangioma (IH) treated with propranolol at the Department of Dermatology, Kumamoto University Hospital, from November 2016 to January 2022, based on sex, site, clinical classification, duration of treatment, and residual lesions after treatment. Four of the 95 patients discontinued propranolol due to side effects, and 55 completed follow-ups at our hospital. We observed that 30.1% showed complete resolution of the skin rash, while the remaining 69.8% had erythema or atrophic scarring. Complete resolution occurred in 70% of the cases with the subcutaneous type but only in 15% with the tumor type. Seventeen of the 55 patients who completed follow-ups were treated with propranolol combined with laser therapy. Combined use of propranolol and laser therapy significantly reduced severe erythema compared to the propranolol monotherapy. These results suggest that propranolol therapy in IH often leaves erythema except in the subcutaneous type and that an improvement in erythema can be expected when propranolol is combined with laser therapy.

YAP1::MAML2 fusions in poromatosis: A report of two patients.

Poromatosis is a rare condition characterized by the development of multiple poromas, mainly reported in patients with a history of malignancy. Recently, frequent YAP1::MAML2 and YAP1::NUTM1 fusions have been described in poromas and porocarcinomas. To date, the molecular features of poromatosis have been investigated in one patient only, wherein the poromas harbored YAP1::MAML2 fusions. Herein, we present two additional cases of poromatosis with YAP1::MAML2 fusions. Case 1: An 81-year-old woman presented with nine papules on the scalp, trunk, and extremities persisting for a year. She had a history of breast cancer, with no information on the treatment. Seven papules were excised. Case 2: A 65-year-old woman presented with 21 lesions on her trunk and lower extremities persisting for 2 years. She had been diagnosed with breast cancer 11 years prior and had undergone partial mastectomy, radiotherapy, chemotherapy, and endocrine therapy. Four lesions were excised. All 11 lesions in both patients were histopathologically similar: anastomosing cords and strands extending from the epidermis, and poroid and cuticular cell proliferation with interspersed small ducts. The tumors showed diffuse nuclear expression of YAP1 N-terminus and loss of YAP1 C-terminus expression. No lesions showed NUT immunopositivity. Sanger sequencing identified YAP1::MAML2 fusions in the poromas of both patients.

Short-term administration of Polypodium leucotomos extract does not inhibit CYP3A4-mediated metabolism of midazolam in healthy subjects: an open-label, two-period, fixed-sequence study.

The extract of Polypodium leucotomos is used as a dietary supplement for its ultraviolet radiation-protective properties. Polypodium leucotomos extract reportedly inhibits CYP3A, which is important for drug metabolism in vitro in human microsomes and in vivo in rats. In this study, we explored the inhibitory effect of the P. leucotomos extract on CYP3A4-mediated midazolam metabolism in humans. This open-label, two-period, fixed-sequence study was performed on six healthy, Japanese, male volunteers. During period 1 (control), midazolam (1 mg) was orally administered. After a wash-out period of at least 5 days, period 2 was initiated. Subjects ingested P. leucotomos extract (240 mg) once in the morning and once at noon on the day before midazolam administration, and once the next morning (thrice overall). Midazolam was administered as in period 1. Blood samples were regularly collected for 8 hours after drug administration, and serum midazolam concentration was determined by ultra-fast liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters of midazolam were calculated and compared between the two periods. The area under the concentration-time curve was 19.18 ± 3.65 ng h/ml, maximum serum concentration was 7.81 ± 1.25 ng/ml, and half-life was 2.32 ± 0.35 hours during period 2. These parameters did not differ from those recorded in period 1 (area under the concentration-time curve: 18.74 ± 2.97 ng h/ml, maximum serum concentration: 8.78 ± 1.67 ng/ml, half-life: 2.52 ± 0.52 h). Therefore, short-term oral administration of P. leucotomos extract did not cause food-drug interactions mediated by CYP3A4 inhibition in humans.

A Japanese case of melanoma of unknown origin with a rare BRAFV600R mutation was successfully treated with BRAF/MEK inhibitors.

Combination therapy with BRAF and MEK inhibitors (BRAF/MEKi) has shown significantly prolonged progression-free survival (PFS) and overall survival (OS) for BRAF mutated melanoma. Over 90% of the activating mutations are BRAFV600E or BRAFV600K changes. There are no reports of BRAFV600R in Japanese patients with melanoma. The third most common BRAF mutation is BRAFV600R. In this case, we detected the BRAFV600R mutation with FoundationOne CDx in a Japanese patient with melanoma.. The patient was treated with BRAF/MEKi and maintained stable disease status for 1 year.

Dephospho-Coenzyme A Kinase Is an Exploitable Drug Target against Plasmodium falciparum: Identification of Selective Inhibitors by High-Throughput Screening of a Large Chemical Compound Library.

Malaria is a mosquito-borne fatal infectious disease that affects humans and is caused by Plasmodium parasites, primarily Plasmodium falciparum. Widespread drug resistance compels us to discover novel compounds and alternative drug discovery targets. The coenzyme A (CoA) biosynthesis pathway is essential for the malaria parasite P. falciparum. The last enzyme in CoA biosynthesis, dephospho-CoA kinase (DPCK), is essential to the major life cycle development stages but has not yet been exploited as a drug target in antimalarial drug discovery. We performed a high-throughput screen of a 210,000-compound library using recombinant P. falciparum DPCK (PfDPCK). A high-throughput enzymatic assay using a 1,536-well platform was developed to identify potential PfDPCK inhibitors. PfDPCK inhibitors also inhibited parasite growth in a P. falciparum whole-cell asexual blood-stage assay in both drug-sensitive and drug-resistant strains. Hit compounds were selected based on their potency in cell-free (PfDPCK) and whole-cell (Pf3D7 and PfDd2) assays, selectivity over the human orthologue (HsCOASY) and no cytotoxicity (HepG2). The compounds were ranked using a multiparameter optimization (MPO) scoring model, and the specific binding and the mechanism of inhibition were investigated for the most promising compounds.

[Fatal primary influenza virus pneumonia in a patient with secondary myelofibrosis during ruxolitinib therapy].

In recent years, fatal cases of primary influenza virus pneumonia have been rare. A 67-year-old woman with secondary myelofibrosis, who had been diagnosed with polycythemia vera 25 years prior, died of primary influenza virus pneumonia. She was immunocompromised due to the underlying disease and ruxolitinib therapy, but she was not vaccinated against influenza. She might have caught the flu from an infected family member. This case reminds us of the importance of infection control measures such as preventing familial infection during ruxolitinib therapy in severely immunocompromised patients.

Intertumor and intratumor heterogeneity of PIK3CA mutations in extramammary Paget's disease.

Although the prognosis of patients with extramammary Paget's disease (EMPD) treated with radical resection is good, the prognosis of EMPD with distant metastasis is very poor. PIK3CA mutations predict a good response to PIK3CA inhibitors. The aim of this study was to investigate the occurrence rate of PIK3CA mutations (including multiple mutations [MM]) related to the intertumor and intratumor heterogeneity in EMPD and to evaluate the correlation between these mutations and clinical parameters of EMPD. We performed droplet digital polymerase chain reaction to detect PIK3CA mutations (E542K, E545K, H1047R, and MM) in 68 patients with EMPD. In addition, we investigated the presence of PIK3CA mutations at multiple sites in 16 patients with PIK3CA mutations to assess the intratumor heterogeneity of PIK3CA mutations in EMPD. The frequency of one or more PIK3CA mutations in patients with EMPD was 30.8% (21/68). The frequency of E542K, E545K, H1047R, and MM were 10.2% (7/68), 13.2% (9/68), 11.7% (8/68), and 4.4% (3/68), respectively. No significant correlation was found between PIK3CA mutation patterns and clinical parameters. Of the 21 patients with PIK3CA mutations, 16 with tissue samples that could be analyzed at multiple sites were examined. The proportion of patients with the same PIK3CA mutations at all sites was 12.5% (2/16). The proportion of patients with the same PIK3CA mutations at least two or more sites, but not at all sites, was 31.2% (5/16). The proportion of patients with no PIK3CA mutations at other sites was 37.5% (6/16). The proportion of patients with other PIK3CA mutations at other sites was 18.7% (3/16). There is intertumor and intratumor heterogeneity of PIK3CA mutations. PIK3CA mutations in EMPD may be progressor mutations in EMPD.

Analysis of microsatellite instability using Promega panel in dermatofibrosarcoma protuberans.

Dermatofibrosarcoma protuberans (DFSP) is a rare neoplasm derived from fibroblasts. Although the frequency of microsatellite instability (MSI) in skin cancer is reported to be less than 5%, there is only one report of the status of MMR in DFSP. The only analytical report of microsatellite stability in which Promega panel is not used, showed that the frequency of MSI-high, MSI-low and microsatellite stable (MSS) cases was 13.9% (5/36), 16.7% (6/36) and 69.4% (25/36), respectively. Thus, the aim of this study was to evaluate the status of MMR in 36 patients with DFSP diagnosed at Kumamoto University. MSI analysis using the Promega panel showed that all cases were MSS, which indicated the absence of MSI in DFSP. This result indicates that the status of MMR may not be useful for the potential therapeutic application of pembrolizumab and the pathogenesis of DFSP may not involve MSI.

Genomic landscape of circulating tumour DNA in metastatic extramammary Paget's disease.

Although cancer personalized profiling by deep sequencing (CAPP-Seq) of cell-free DNA (cfDNA) has gained attention, the clinical utility of circulating tumour DNA (ctDNA) in extramammary Paget's disease (EMPD) has not been investigated. In this study, genomic alterations in the cfDNA and tumour tissue DNA were investigated in seven patients with metastatic EMPD. CAPP-Seq revealed mutations in 18 genes, 11 of which have not yet been reported in EMPD. The variant allele frequency of some of the mutated genes reflected the disease course in patients with EMPD. In one patient, the mutation was detected even though imaging findings revealed no metastasis. In another patient with triple EMPD (genital area and both axilla), cfDNA sequencing detected the mutation in a rib metastatic lesion, which was also detected in both axilla lesions but not the genital region. Investigations of the ctDNA may be useful towards the elucidation of clonal evolution in EMPD.