Efficacy and safety of Vibegron for the treatment of residual overactive bladder symptoms after laser vaporization of the prostate: A single-center prospective randomized controlled trial (VAPOR TRIAL).

OBJECTIVES: This study aimed to evaluate the efficacy and safety of Vibegron for the treatment of residual overactive bladder (OAB) symptoms after laser vaporization of the prostate (photo-selective vaporization of the prostate, contact laser vaporization of the prostate, and thulium laser vaporization). METHODS: This randomized, open-label, parallel-group, single-center superiority trial with a 12-week observation (jRCTs071190040) enrolled male patients with OAB aged 40 years or older who had undergone laser vaporization of the prostate for not less than 12 weeks and not more than 1 year earlier. Patients were allocated to receive Vibegron 50 mg once daily or follow-up without treatment for 12 weeks. RESULTS: Forty-seven patients were enrolled between January 2020 and March 2023. The median age (interquartile range) was 75.5 (72.5-78.5) years for the Vibegron group and 76.5 (71.0-81.0) years for the control group. The intergroup difference in the mean change (95% confidence interval) in the 24-hour urinary frequency at 12 weeks after randomization was -3.66 (-4.99, -2.33), with a significant decrease for the Vibegron group. The Overactive Bladder Symptom Score, International Prostate Symptom Score, IPSS storage score, and Overactive Bladder Questionnaire score significantly improved for the Vibegron group. Voided volume per micturition also increased for the Vibegron group. CONCLUSIONS: The administration of 50 mg of Vibegron once daily for 12 weeks showed significant improvement compared with follow-up without treatment in bladder storage (OAB) symptoms after laser vaporization of the prostate for symptomatic benign prostatic hyperplasia.

Real-world evaluation of asthma reliever therapy among continuous users of asthma maintenance medication in Japan: A retrospective cohort study using a claims database.

BACKGROUND: The decrease in mortality rate owing to asthma has slowed in recent years. A large proportion of patients with asthma remain uncontrolled in Japan. This study aimed to determine the prevalence of short-acting beta 2 agonists (SABA) overuse and its associated factors. METHODS: This large-scale retrospective cohort study analyzed continuously treated patients with asthma aged 15-74 years between January 2017 and December 2017 using a Japanese insurance claims database. Characteristics, disease information, and prescribed drugs were extracted from the database, and treatment steps were defined according to drug combinations based on the criteria of the Japanese asthma guidelines. SABA overuse was defined as ≥3 canisters per year. Factors associated with SABA overuse were estimated using multivariable logistic regression. RESULTS: Among 7,483 patients with mild-to-moderate asthma, 7,001 (93.6%) and 482 (6.4%) had low and high SABA use, respectively. Inhaled corticosteroids (ICS)/long-acting ß-agonists (LABA) were the main asthma control treatments. The proportions of patients who overused SABA were 347 (9.9%) and 1,201 (5.6%) in the ICS and ICS/LABA groups, respectively. The factors associated with SABA overuse were male sex, ICS monotherapy, higher treatment steps, no history of allergic rhinitis, no history of chronic sinusitis, and no asthma management. CONCLUSIONS: There is a relatively low prevalence of SABA overuse among asthmatic patients in Japan. ICS/LABA therapy, treatment steps, allergic rhinitis, chronic sinusitis, and asthma management are associated with a decreased risk of SABA overuse. Further studies are needed to investigate the association between SABA overuse and asthma exacerbation and mortality.

Optimal follow-up period after switching to another inhaled corticosteroid/long-acting ß2 agonist in patients with asthma: A retrospective study using Japanese administrative claims data.

Switching inhalation devices is a reasonable option if problems with control, adherence, or inhalation technique occur in patients with asthma treated with inhaled corticosteroid (ICS)/long-acting ß2 agonist (LABA). However, evidence to determine the extent to which the carefully monitored period persists after switching is insufficient. In this study, we aimed to investigate the duration of the carefully monitored period after switching to another ICS/LABA. This retrospective study used claims data from Japanese health insurance associations from May 2014 to April 2019. A total of 1,951 patients who switched to another ICS/LABA during the study period were selected for analysis. The relative risk of the first exacerbation after switching was calculated for each four-week interval after the switch compared with that before the switch in a self-controlled case series design. We further assessed patient background associated with exacerbations during the follow-up period. In the primary analysis, the risk of asthma exacerbation compared to the control period was derived from a conditional logistic regression model, which showed a significant decrease immediately after the switch (1 to 4 weeks, Odds ratio [OR] 0.37, 95% confidence interval [CI] 0.26-0.54). Subsequently, the risk increased again and was not significantly different from the control period until week 32 (OR 0.55, 95% CI 0.29-1.04). In a sensitivity analysis among patients with a history of exacerbations, up to week 20 was the period of no continuous risk reduction (OR 0.84, 95% CI 0.41-1.70). In the secondary analysis, chronic rhinosinusitis, sleep disorders, and a history of asthma exacerbation were significantly associated with asthma exacerbation. The incidence of exacerbation remained high for approximately 4 to 7 months after patients with asthma switched to another ICS/LABA. Therefore, these patients should be carefully monitored for at least 4 to 7 months and should be re-assessed at an earlier point in time, if necessary.

Association of comorbidities and medications with risk of asthma exacerbation in pediatric patients: a retrospective study using Japanese claims data.

Asthma exacerbation impairs the quality of life of pediatric patients and negatively impacts future respiratory function and health economics. Several risk factors associated with exacerbations have been identified; however, most studies report the risk of each factor. Therefore, this study aimed to evaluate the risk of each factor and a combination of factors. We performed a retrospective cohort study using Japanese claims data and extracted factors associated with exacerbations using multivariate Cox proportional hazards regression and stepwise method. Risk scores were then calculated from the extracted factors and validated by tenfold cross validation. Of the 1,748,111 asthma patients in the database, the data of 14,980 were extracted, and 1988 (13.3%) had exacerbation. Factors associated with asthma exacerbation were age of 3-5 years, exacerbation history before cohort entry date, allergic rhinitis, chronic sinusitis, otitis externa, blepharitis, upper respiratory infections, urticaria, LTRA prescription, were determined. A four-level risk score was calculated from 9-factors and the AUC derived from cross validation was 0.700. Most factors extracted in our study are consistent with those of previous studies. We showed that combining each factor is more helpful in assessing the increased risk of asthma exacerbation than assessing each factor alone.

Exploratory research on asthma exacerbation risk factors using the Japanese claims database and machine learning: a retrospective cohort study.

OBJECTIVE: Analytical studies of risk factor assessment using machine learning have recently been reported. We performed an exploratory detection study of asthma exacerbation-related factors using health insurance claims data and machine learning to explore risk factors that have high generalizability and can be easily obtained in daily practice. METHODS: A dataset of asthma patients during May 2014-April 2019 from the Japanese insurance claims database, MediScope® (DB) was used. Patient characteristics and disease information were extracted, and association with occurrence of asthma exacerbation was evaluated to comprehensively search for exacerbation risk factors. Asthma exacerbations were defined as the co-occurrence of emergency medical procedures, such as emergency transport and intravenous steroid injections, with asthma claims, which were recorded in the database. RESULTS: In total, 5,844 (13.7%) subjects had exacerbations in 42,685 eligible cases from the DB. Information on approximately 3,300 diseases was subjected to a machine learning, and 25 variables were extracted as variable importance and targeted for risk assessment. As a result, sex, days without exacerbation from cohort entry date at look-back period, Charlson Comorbidity Index, allergic rhinitis, chronic sinusitis, acute airway disease (upper airway), acute airway disease (lower airways), Chronic obstructive pulmonary disease/chronic bronchitis, gastroesophageal reflux disease, and hypertension were significantly associated with exacerbation. Dyslipidemia and periodontitis were detected as associated factors of reduced exacerbation risk. CONCLUSIONS: A comprehensive analysis of claims data using machine learning showed asthma exacerbation risk factors mostly consistent with those in previous studies. Further examination in other fields is warranted.Supplemental data for this article is available online at https://doi.org/10.1080/02770903.2021.1923740 .

Fatty liver index as a predictive marker for the development of diabetes: A retrospective cohort study using Japanese health check-up data.

BACKGROUND & AIMS: Fatty liver is associated with incident diabetes, and the fatty liver index (FLI) is a surrogate marker for non-alcoholic fatty liver disease (NAFLD). We aimed to determine whether or not FLI was associated with incident diabetes in relation to obesity and prediabetic levels in the general Japanese population. METHODS: This was a retrospective study using the Japanese health check-up database of one health insurance from FY2015 to FY2018. This study included 28,991 individuals with prediabetes. First, we stratified all participants into two groups: "high-risk," comprising patients with HbA1c >6.0%, and "standard," comprising the rest. Subsequently, we divided them into four groups according to FLI (<30 or not) and obesity (BMI <25 kg/m2 or not). Subsequently, the incidence rate of diabetes was compared among the groups after 3 years of follow-up using multiple logistic regression models after adjusting for potential confounders. RESULTS: After 3 years of follow-up, 1,547 new cases of diabetes were found, and the cumulative incidence was 2.96% for the standard group and 26.1% for the high-risk group. In non-obese individuals, odds ratios (95% confidence interval) for FLI ≥30 versus FLI <30 were: 1.44 (1.09-1.92) for the standard group and 1.42 (0.99-2.03) for the high-risk group. In the high-risk group, obesity (BMI ≥25 kg/m2) but FLI <30 was not a risk factor for developing diabetes. CONCLUSION: Although high FLI is generally considered to be a risk factor for developing diabetes, obesity might have been a confounding factor. However, the present study showed that high FLI is a risk factor for the development of diabetes, even in non-obese individuals. Our results include suggestion to develop a screening tool to effectively identify people at high risk of developing diabetes from the population (especially non-obese prediabetes) who are apparently at low health risk and are unlikely to be targeted for health guidance.

Correlation of indoleamine-2,3-dioxigenase 1 inhibitory activity of 4,6-disubstituted indazole derivatives and their heme binding affinity.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that acts on the first and rate-limiting step of the tryptophan/kynurenine pathway. Since the pathway is one of the means of cancer immune evasion, IDO1 inhibitors have drawn interest as potential therapeutics for cancers. We found a 4,6-disubstituted indazole 1 as a hit compound that showed both IDO1 inhibitory activity and binding affinity for IDO1 heme. Structural modification of 1 yielded compound 6, whose relatively large substituent at the 4-position and proper size substituent at the 6-position were found to be important for the enhancement of IDO1 inhibitory activity and heme affinity. A series of compounds synthesized in this work were evaluated by in silico docking simulations and by in vitro experiments using a C129Y mutant of the pocket-A of IDO1. Our results revealed that proper substituents at the 6- and 4-positions of the compounds interact with pockets A and B, respectively, and that, in particular, a good fit in pocket-A is important for the compounds' biological activities. Absorption spectral analysis of these compounds showed that they strongly bound to the ferrous heme rather than its ferric heme. Furthermore, we observed that the heme affinities of these compounds strongly correlate with their IDO1 inhibitory activities.

Cardiac angiosarcoma diagnosed by transvenous endomyocardial biopsy with the aid of transesophageal echocardiography and intra-procedural consultation.

We report a case who had confirmed tumor cells in the biopsy specimens by transvenous endomyocardial biopsy with intra-procedural consultation and fast smear cytology. A 57-year-old female was admitted to our hospital because of shortness of breath and left back pain. Transthoracic echocardiography (TTE) and contrast-enhanced computed tomography (CT) scans demonstrated a large mass in the right atrium and multiple liver tumors thought to be due to spread of the disease. Coronary angiography showed the right coronary artery was involved in the mass. In order to confirm the histological diagnosis, we attempted transvenous endomyocardial tumor biopsy under fluoroscopic guidance. However, we failed to obtain adequate tissue material. Due to several risks associated with a surgical procedure such as an open surgical biopsy, transvenous endomyocardial tumor biopsy was again attempted with the aid of transesophageal echocardiography (TEE). Intra-procedural consultation and fast smear cytology enabled us to finish the procedure. Hematoxylin-eosin stained sections demonstrated spindle-shaped cells. Immunohistochemical stains of these cells were positive for anti-factor VIII antigen, CD31, and CD34. These findings indicated a definite diagnosis of angiosarcoma. Since there was no surgical indication for this tumor, the patient underwent chemotherapy with docetaxel and radiotherapy. Three months later, CT scans showed a reduction in the size of the cardiac tumor.

[Cytology of soft tissue tumors].

In the diagnosis of soft tissue tumors, an incomplete biopsy for malignancy interferes with subsequent therapy. Therefore, we perform fine needle aspiration cytology (FNAC) for soft tissue tumors and consider the following four issues: 1) Is the tumor benign or malignant?; 2) In malignancy, is the tumor primary or metastatic? Furthermore, if possible; 3) In a primary malignant tumor, the histological type and degree of malignancy; 4) In a metastatic malignant tumor, the histological type and the primary site. In FNAC, we diagnose soft tissue tumors based on the pattern of cytological findings, such as small round cells, pleomorphic cells, spindle cells, and epithelioid cells, and furthermore based on the findings of the background, such as mucin, vessels, multinucleated giant cells, and inflammatory cells while referring to clinical information. In soft tissue tumors that are difficult to diagnose only by cytology, immunochemical staining for multiple antibodies using the cell block method and/or cell transfer method is useful to make a definitive diagnosis. If necessary, rapid cytological diagnosis is currently performed for soft tissue tumors in our department.

Malignant granular cell tumor in the gluteal region with unusual pathologic features.

Malignant granular cell tumors (MGCTs) are very rare soft tissue sarcomas. Definite criteria for pathologic diagnosis and the optimal treatment strategy have not been fully established. Here, we describe a 76-year-old woman with a huge MGCT in the right gluteal region, who developed a local recurrence and died from that tumor 14 months after undergoing an operation for the primary tumor. Although microscopic examination revealed that round and granular tumor cells staining for S-100 protein were dominant, components of the spindle cell sarcoma reacting with alpha smooth muscle actin were partially observed. MGCT is believed to originate from Schwann cells; however, pathologic findings in our case showed both Schwannian and non-Schwannian features. This is the first report on MGCT with these 2 features appearing simultaneously.

Pathologic complete response confirmed by surgical resection for liver metastases of gastrointestinal stromal tumor after treatment with imatinib mesylate.

A 39-year-old male underwent distal gastrectomy for a high grade gastrointestinal stromal tumor (GIST). Computed tomography (CT) and magnetic resonance imaging (MRI) 107 mo after the operation, revealed a cystic mass (14 cm in diameter) and a solid mass (9 cm in diameter) in the right and left lobes of the liver, respectively. A biopsy specimen of the solid mass showed a liver metastasis of GIST. The patient received imatinib mesylate (IM) treatment, 400 mg/day orally. Following the IM treatment for a period of 35 mo, the patient underwent partial hepatectomy (S4 + S5). The effect of IM on the metastatic lesions was interpreted as pathologic complete response (CR). Pathologically verified cases showing therapeutic efficacy of IM have been rarely reported.

Hirschsprung's disease in adults: report of a case and review of the literature.

Hirschsprung's disease in the adult is a rare and frequently misdiagnosed cause of long-standing refractory constipation. We report a case of Hirschsprung's disease in a 23-year-old man and review the literature. The patient had a history of chronic constipation that required daily enemas, since early infancy, but he had remained in good health until intestinal obstruction developed. As a subemergency operation, right transverse colostomy was performed, to relieve the constipation. Histological examination, by a biopsy, showed absence of ganglion cells in the myenteric plexus in the rectum. One year later, Ikeda's modification of the Duhamel procedure was successfully performed as definitive surgery. The postoperative course was uneventful, and complete resolution of the symptoms without complications has been confirmed by a 22-year follow-up. A review of 229 cases of adult Hirschsprung's disease in the literature suggested that the Duhamel procedure is the operation of choice because of the lower postoperative morbidity rate and better functional outcome.

Epithelioid hemangioendothelioma of the phalanx: a case report.

Epithelioid hemangioendothelioma (EH) of a hand bone is extremely rare. We describe a patient with a phalangeal EH. This was treated by resection of the entire middle phalanx with no recurrence within a 10-year postsurgical follow-up period. We recommend wide resection as the safest treatment for EH of the hand phalanx.

Cytological interface of diffusely infiltrating astrocytoma and its marginal tissue.

Cytological differences between infiltrating lesions of the diffusely infiltrating astrocytoma (DIA) and reactive gliosis at its periphery have not yet been established. We compared histological specimens from cytological crush preparations of 200 brain tumors to characterize the cytology of the DIA and to discriminate it from reactive gliosis. First, the cytological findings of the backgland brain parenchyma were assessed. Second, we looked at the nuclear characteristics of the DIA, comparing them with those of other brain tumors. Third, the cytology of the infiltrating DIA was assessed together with brain parenchymal elements. Finally, we characterized discriminative points of the area of infiltration of the DIA versus those of the reactive gliosis. In addition, we assessed the relations between the cytological findings of the DIA and its MRI images. The cytological findings of this area are important because the surgeon may have to make a rapid diagnosis regarding the existence of the tumor.

Fine needle aspiration cytology of primary epithelioid sarcoma. A report of 2 cases.

BACKGROUND: Epithelioid sarcoma is a rare soft part tumor, the cytologic features of which have not been fully elucidated to date. We describe the cytologic features in 2 cases of primary epithelioid sarcoma with samples obtained by fine needle aspiration (FNA). CASES: Case 1 was a 50-year-old male who complained of a small mass in his left palm. Case 2 was a 56-year-old female who presented with a mass on the medial aspect of her right forearm. Preoperative FNA smears in both cases showed loose, aggregated and isolated tumor cells that were round to polygonal, with eccentrically located nuclei, against a background of inflammation and necrosis. The tumor cells showed moderate atypia, irregularity in size and many mitoses. In case 1 a presumptive diagnosis of epithelioid sarcoma was made by FNA cytology, while in case 2, FNA cytology revealed a high grade sarcoma with abundant matrix mimicking osteoids, difficult to differentiate from an extraskeletal osteosarcoma. CONCLUSION: Epithelioid sarcoma may be difficult to differentiate from an extraskeletal osteosarcoma in cases with abundant hyalinized collagen on FNA cytology.

Intracranial osteosarcoma after radiosurgery--case report.

A 56-year-old woman presented with an intracranial osteosarcoma at the site of previous radiosurgery, manifesting as sudden onset of headache and left hemiparesis with aphasia. She had a previous history of stereotactic radiosurgery for an intracranial tumor under a diagnosis of falx meningioma. Computed tomography showed intratumoral and peritumoral hemorrhage at the right parietofrontal region. Gross total resection of the tumor with hematoma was performed. The histological diagnosis was osteosarcoma. Sarcomatous change is a rare complication of radiotherapy. This case illustrates that osteosarcoma may develop years after radiosurgery for benign brain neoplasm.

Deciduoid mesothelioma in the pelvic cavity.

A very rare case of deciduoid mesothelioma in the pelvic cavity is presented. A 24-year-old woman (gestational stage: 28 weeks and 6 days) was admitted because of a tumor mass in the abdominal cavity. A well-circumscribed and fibrously encapsulated tumor mass was revealed in the Douglas cavity. Histologically, tumor cells were arranged in a solid sheet with deciduoid appearance and showed partial glandular and papillary structures. The tumor cells contained PAS positive and diastase-digested granules in the cytoplasm as well as alcian-blue positive and hyaluronidase-digested substances in the stroma. The cellularity of the tumor cells was moderate and mitoses were rare. There was partial tumor necrosis and tumor cells had infiltrated through the fibrous capsule. Immunohistochemically, the tumor cells were reactive for pancytokeratin, cytokeratin5/6, vimentin, HBME-1, calretinin and thrombomodulin. Ultrastructurally, numerous, long microvilli, tonofilaments and desmosome junctions could be seen. Consequently, this case was diagnosed as deciduoid mesothelioma and 2 years and 4 months after operation, the patient's clinical course has been good. This case is considered to be the first reported in Japan.

Prognostic significance of Ki-67 antigen immunostaining (MIB-1 monoclonal antibody) in ovarian cancer.

OBJECTIVE: To assess the potential usefulness of Ki-67 antigen expression as a predictor of outcome in ovarian cancer through the analysis of MIB-1 monoclonal antibody reactivity. METHODS: Cell proliferation and clinicopathologic variables were assessed in 26 patients with primary epithelial ovarian cancer who had undergone exploratory laparotomy. The expression of primary tumor proliferation related to Ki-67 antigen was immunohistochemically evaluated by MIB-1 monoclonal antibody. RESULTS: The value of Ki-67 labeling index (LI) ranged between 0 and 92.6% with a mean of 48.9%. Ki-67 LI correlated well with the mitotic index, but not the histological subtype. Ki-67 LI of more than 40%was defined as a higher proliferating tumor by a receiver operating characteristic curve analysis. Higher proliferating tumors were identified in 14 patients (54% of all subjects). The patients with higher proliferating tumors had a statistically significantly worse prognosis compared with those with lower proliferating tumors (p<0.001). CONCLUSIONS: The present study demonstrates that the proliferating index detected by Ki-67 antigen immunostaining is a useful factor for predicting the survival of patients with ovarian cancer.

Basic FGF and Ki-67 proteins useful for immunohistological diagnostic evaluations in malignant solitary fibrous tumor.

Solitary fibrous tumor (SFT) is an uncommon soft tissue tumor initially reported in the pleura but recently described in other sites in the body. Morphological distinction between benign and malignant SFT is often difficult. An immunohistochemical study was performed in pleural and extrapleural sites. The aim of this study was to determine if an immunohistochemical method is helpful in distinguishing benign SFT from malignant SFT, and providing valid information to predict the prognosis associated with malignant SFT. Twenty-four cases of benign (14 patients) and malignant (10 patients) SFT in the pleura, pelvic space, prostate and other sites of soft tissue were analyzed. Tumors from 10 patients were diagnosed as malignant on the basis of markedly increased cellularity, mitotic activity (>4/10 high-power fields), nuclear pleomorphism and areas of necrosis. Immunohistochemically, we found a mean basic fibroblast growth factor (bFGF) labeling index of 48.67% (48.67 +/- 8.52%) for benign SFT and 74.5% (74.5 +/- 6.92%) for malignant SFT (P < 0.05). We also found a mean Ki-67 labeling index of 1.9% (1.9 +/- 0.43%) for benign SFT and 6.11% (6.11 +/- 1.05%) for malignant SFT (P < 0.05). Our results suggest that bFGF and Ki-67 are diagnostically relevant to the evaluation of malignant SFT and these proteins are thought to be potentially useful markers for prognosis of SFT.