A Multicenter Prospective Interventional Trial of Therapeutic Angiogenesis Using Bone Marrow-Derived Mononuclear Cell Implantation for Patients With Critical Limb-Threatening Ischemia Caused by Thromboangiitis Obliterans.

BACKGROUND: Thromboangiitis obliterans (TAO) can lead to the development of critical limb-threatening ischemia (CLTI). Despite conventional treatments, such as smoking cessation or revascularization, young patients (<50 years) still require limb amputation. Therapeutic angiogenesis using bone marrow-derived mononuclear cell (BM-MNC) implantation has been tested and shown to have reasonable efficacy in CLTI. In this multicenter prospective clinical trial, we evaluated the safety and efficacy of BM-MNC implantation in CLTI patients with TAO.Methods and Results: We enrolled 22 CLTI patients with skin perfusion pressure (SPP) <30 mmHg. The primary endpoint of this trial is the recovery of SPP in the treated limb after a 180-day follow-up period. Secondary endpoints include the pain scale score and transcutaneous oxygen pressure (TcPO2). One patient dropped out during follow-up, leaving 21 patients (mean age 48 years, 90.5% male, Fontaine Class IV) for analysis. BM-MNC implantation caused no serious adverse events and increased SPP by 1.5-fold compared with baseline. Surprisingly, this effect was sustained over the longer term at 180 days. Secondary endpoints also supported the efficacy of this novel therapy in relieving pain and increasing TcPO2. Major amputation-free and overall survival probabilities at 3 years among all enrolled patients were high (95.5% and 89.5%, respectively). CONCLUSIONS: BM-MNC implantation showed safety and significant efficacy in CLTI patients with TAO.

Coronary anomalies associated with ventricular septal defect.

Coronary anomalies encompass different conditions in terms of anomalous origin, coursing, and branching, which are occasionally associated with congenital heart disease. This study aimed to explore coronary anomalies associated with ventricular septal defect that was a stereotypical congenital heart disease. We retrospectively reviewed angiographic findings in patients with ventricular septal defect who required corrective surgery, and identified coronary abnormalities, including anomalous origin, coursing, and branching of coronary arteries based on angiography. We studied the prevalence and types of coronary anomalies among them. A total of 998 patients with ventricular septal defect was studied. Age and weight were 2.0 (2.1-15.2) months and 5.7 (4.1-8.7) kg, respectively. There were 115 patients (12%) with syndrome or genetic disorder, and 34 patients (3%) with extracardiac major organ anomalies. The overall prevalence of coronary anomalies was 6.2%. All coronary anomalies were anomalous origin and coursing, among 3 patients accompanied anomalous intrinsic coronary anatomy. Originating within aortic root above the Valsalva sinus was the most common coronary anomaly. Coronary anomalies were independently correlated with bicuspid aortic valve (odds ratio [OR]: 8.02, 95% confidence interval [CI]: 2.34-23.4) and persistent left superior caval vein (OR: 5.02, 95% CI: 1.93-11.7). We showed the possibility that minor cardiac variants, such as bicuspid aortic valve and persistent left superior caval vein, contribute to higher prevalence of coronary anomalies in patients with ventricular septal defect.

Clot-regression effects of rivaroxaban in venous thromboembolism treatment in cancer patients-a prospective interventional study.

Rivaroxaban, a direct oral anticoagulant, is effective against venous thromboembolism (VTE) recurrence without increasing the risk of major bleeding in patients with cancer-associated venous thromboembolism (CAT). However, its clot regression effects are poorly understood. This single-arm, prospective interventional study aimed to investigate the clot regression effects of rivaroxaban in 40 CAT patients, through a contrast-enhanced computed tomography at baseline, 3 weeks, and 3 months of rivaroxaban treatment. The primary endpoint was the clot-regression ratio calculated from the thrombus volumes at 3 weeks and 3 months. Compared with baseline, the total clot volume was significantly reduced at both 3 weeks and 3 months after initiation (p < 0.01). The clot-regression rates were statistically significant with 83.1% (95% confidence interval [CI], 73.8-92.3%) at 3 weeks and 98.7% (95% CI, 97.1-100.2%) at 3 months, with complete resolution in 36.1% and 80.8% of patients at 3 weeks and 3 months, respectively. One patient had recurrent VTE after dose reduction, and seven had non-fatal major bleeding. Therefore, rivaroxaban had a sufficient clot-regression effect against CAT with caution of bleeding complication.

Microwave focal therapy of prostate cancer: a non-clinical study and exploratory clinical trial.

OBJECTIVE: To examine the safety and efficacy of microwave tissue coagulation (MTC) for prostate cancer and assess its use in lesion-targeted focal therapy in a non-clinical study and a clinical phase II trial. METHODS: In the non-clinical study using Microtaze® -AFM-712 (Alfresa Pharma Corporation, Osaka, Japan) with an MTC needle, MTC was performed using a transperineal approach to targeted canine prostatic tissue under real-time ultrasonography guidance. Using various MTC output and irradiation time combinations, the targeted and surrounding tissues (rectum, bladder and fat) were examined to confirm the extent of coagulative necrosis or potential cell death, and to compare intra-operative ultrasonography and pathology findings. The exploratory clinical trial was conducted to examine the safety and efficacy of MTC. Five selected patients underwent transperineal MTC to clinically single lesion magnetic resonance imaging (MRI)-visible lesions with Gleason score 3 + 4 or 4 + 4. Prostate-specific antigen (PSA), MRI and Expanded Prostate Cancer Index Composite questionnaire findings were compared before and 6 months after surgery. RESULTS: The region of coagulative necrosis was predictable by monitoring of ultrasonically visible vaporization; thus, by placing the MTC needle at a certain distance, we were able to perform a safe procedure without adverse events affecting the surrounding organs. Based on the non-clinical study, which used various combinations of output and irradiation time, MTC with 30-W output for 60-s irradiation was selected for the prostate. Based on the predictable necrosis, the therapeutic plan (where to place the MTC needle to achieve complete ablation of the target and how many sessions) was strictly determined per patient. There were no serious adverse events in any patient and only temporary urinary symptoms related to MTC therapy were observed. Furthermore, post-treatment satisfaction was very high. All preoperative MRI-visible lesions disappeared, and PSA decreased by 55% 6 months after surgery. CONCLUSION: Microwave tissue coagulation may be an option for lesion-targeted focal therapy for prostate cancer.

Therapeutic Angiogenesis Using Bone Marrow-Derived Mononuclear Cell Implantation for Patients With Critical Limb-Threatening Ischemia Caused by Thromboangiitis Obliterans　- Study Protocol for a Multicenter Prospective Interventional Trial.

Background: Patients with thromboangiitis obliterans (TAO) can develop critical limb-threatening ischemia (CLTI) and require limb amputation. Smoking cessation and exercise therapy are recommended as standard treatments, and revascularization by bypass surgery or endovascular therapy (EVT) is required for patients with CLTI. However, there are many cases in which revascularization is difficult because of vascular characteristics, and the patency rate after revascularization remains unsatisfactory. Therapeutic angiogenesis using bone marrow-derived mononuclear cell (BM-MNC) implantation is used clinically, with many trials demonstrating long-term efficacy and safety of the technique in patients with CLTI, especially that caused by TAO. To expand the use of BM-MNCs implantation in clinical practice, further evidence is required in patients with CLTI caused by TAO. Methods and Results: This trial is a multicenter, prospective, non-randomized interventional trial of an Advanced Medicine B treatment approach. We aim to enroll 25 patients aged 20-80 years with Fontaine classification Stage III or IV, who will undergo BM-MNC implantation. The primary endpoint is the improvement in skin perfusion pressure of the target limb 180 days after BM-MNC implantation, whereas secondary endpoints are improvements in rest pain or ulcer size. We will also investigate rates of major or minor amputation, survival, and adverse events during follow-up. Conclusions: BM-MNC implantation is expected to be an efficacious and feasible treatment for patients with CLTI caused by TAO.

Clot regression effects of rivaroxaban in the treatment of venous thromboembolism in patients with cancer (CRERIT-VTE cancer): study protocol.

INTRODUCTION: Anticoagulant therapy in patients with cancer with venous thromboembolism (VTE) increases the risk of both VTE recurrence and haemorrhagic complication. Direct oral anticoagulants (DOACs) have been shown to be effective in preventing VTE recurrence, and comparable to conventional therapy in preventing VTE recurrence in patients with advanced cancer. Rivaroxaban is a DOAC that causes thrombus regression, possibly through a profibrinolytic effect. Thrombus regression with initial treatment is essential for VTE patients. However, the thrombolytic effect of DOAC for VTE patients with cancer has not been fully examined. Therefore, in this study, we investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE. METHODS AND ANALYSIS: This study is a single-arm, open-label, prospective interventional study. Forty patients aged from 20 to 75 years old at the time of consent who have been diagnosed with acute VTE and have active cancer are included. Patients are excluded if they have received thrombolytic therapy, have creatinine clearance of less than 30 mL/min, have expected a life expectancy of less than 6 months or have deep vein thrombosis limited to the distal lower leg. Eligible patients receive standard treatment with rivaroxaban (15 mg two times daily for 3 weeks, followed by 15 mg QD). The primary study endpoint is clot regression ratio as evaluated by contrast-enhanced CT imaging. CT imaging is obtained at baseline, 21±4 and 90±14 days after the start of rivaroxaban treatment. Secondary endpoints are the recurrence of VTE and haemorrhagic complications. ETHICS AND DISSEMINATION: This study was approved by the institutional review board of the Kyoto Prefectural University of Medicine. Study results will be disseminated through peer-reviewed journals.Trial registration numberUMIN000027793.