Efficacy of autologous platelet-rich plasma gel in patients with hard-to-heal diabetic foot ulcers: a multicentre study in Japan.

OBJECTIVE: To evaluate the healing outcome of a platelet-rich plasma (PRP) gel prepared using TKKT01 (a wound care device to prepare the PRP gel) in patients with hard-to-heal diabetic foot ulcers (DFUs) and who showed an inadequate response to ≥4 weeks of standard of care (SoC). METHOD: This open-label, single-arm, multicentre study was conducted in 15 centres in Japan. Eligible patients received PRP gel treatment twice a week for eight weeks, followed by a final evaluation after the completion of week 8 (day 57). The primary endpoint was the percentage of patients who achieved ≥50% reduction in wound radius at the final evaluation (achievement criterion, ≥60% of patients). Secondary endpoints included: wound area and volume reduction rates; time to possible wound closure by secondary intention; time to possible wound closure using a relatively simple procedure (e.g., skin graft and suture); and safety at the final evaluation. RESULTS: A total of 54 patients were included in the full analysis set, with 47 patients included in the per protocol set; the primary endpoint was met in 38/47 (80.9%) (95% confidence interval: 66.7-90.9%) patients who achieved ≥50% wound radius reduction at the final evaluation. High rates of wound area (72.8%) and volume (92.7%) reduction were observed at the final evaluation. The median time to possible wound closure by secondary intention and by use of a relatively simple procedure was 57 and 43 days, respectively. Complete wound closure at the final evaluation was achieved in 27 (57.4%) patients. No safety concerns were raised. CONCLUSION: In this study, the efficacy and safety of PRP gel treatment with TKKT01 in patients with hard-to-heal DFUs in Japan were confirmed by our findings. DECLARATION OF INTEREST: This study was funded by Rohto Pharmaceutical Co., Ltd., Japan. NO has been paid a consulting fee by Rohto Pharmaceutical Co., Ltd. KH is the Chief Medical Officer of Rohto Pharmaceutical. Co., Ltd. The other authors have no conflict of interest to declare.

Characteristics, Antithrombotic Patterns, and Prognostic Outcomes in Claudication and Critical Limb-Threatening Ischemia Undergoing Endovascular Therapy.

PURPOSE: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study aimed to clarify differences in clinical features and prognostic outcomes between IC and CLTI, and prognostic factors in patients undergoing endovascular therapy (EVT). MATERIALS AND METHODS: A total of 692 patients with 808 limbs were enrolled from 20 institutions in Japan. The primary measurements were the 3-year rates of major adverse cardiovascular event (MACE) and reintervention. RESULTS: Among patients, 79.0% had IC and 21.0% had CLTI. Patients with CLTI were more frequently women and more likely to have impaired functional status, undernutrition, comorbidities, hypercoagulation, hyperinflammation, distal artery disease, short single antiplatelet and long anticoagulation therapies, and late cilostazol than patients with IC. Aortoiliac and femoropopliteal diseases were dominant in patients with IC and infrapopliteal disease was dominant in patients with CLTI. Patients with CLTI underwent less frequently aortoiliac intervention and more frequently infrapopliteal intervention than patients with IC. Longitudinal change of ankle-brachial index (ABI) exhibited different patterns between IC and CLTI (pinteraction=0.002), but ABI improved after EVT both in IC and in CLTI (p<0.001), which was sustained over time. Dorsal and plantar skin perfusion pressure in CLTI showed a similar improvement pattern (pinteraction=0.181). Distribution of Rutherford category improved both in IC and in CLTI (each p<0.001). Three-year MACE rates were 20.4% and 42.3% and 3-year reintervention rates were 22.1% and 46.8% for patients with IC and CLTI, respectively (log-rank p<0.001). Elevated D-dimer (p=0.001), age (p=0.043), impaired functional status (p=0.018), and end-stage renal disease (p=0.019) were independently associated with MACE. After considering competing risks of death and major amputation for reintervention, elevated erythrocyte sedimentation rate (p=0.003) and infrainguinal intervention (p=0.002) were independently associated with reintervention. Patients with CLTI merely showed borderline significance for MACE (adjusted hazard ratio 1.700, 95% confidence interval 0.950-3.042, p=0.074) and reintervention (adjusted hazard ratio 1.976, 95% confidence interval 0.999-3.909, p=0.05). CONCLUSIONS: The CLTI is characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared with IC. Also, CLTI has approximately twice MACE and reintervention rates than IC, and the underlying inflammatory coagulation disorder per se is associated with these outcomes. CLINICAL IMPACT: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study, JPASSION study found that CLTI was characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared to IC. Also, CLTI had approximately twice major adverse cardiovascular event (MACE) and reintervention rates than IC. Intriguingly, the underlying inflammatory coagulation disorder per se was independently associated with MACE and reintervention. Further studies to clarify the role of anticoagulation and anti-inflammatory therapies will contribute to the development of post-interventional therapeutics in the context of peripheral artery disease.

Endovascular Therapy Outcomes and Intravascular Ultrasound Findings in Thromboangiitis Obliterans (Buerger's Disease).

PURPOSE: To investigate outcomes of contemporary endovascular therapy and intravascular ultrasound (IVUS) findings in thromboangiitis obliterans (TAO) patients. METHODS: Between April 2007 and January 2016, 20 patients (mean age 45±8 years; 16 men) underwent endovascular therapy for TAO-related lesions in 25 consecutive limbs. Subjects exhibited a broad array of clinical symptoms, including critical limb ischemia (n=15) and claudication (10) in the lower (n=20) and upper (n=5) limbs. RESULTS: Procedure success was achieved in 24 (96%) limbs (complete success in 16 and partial success in 8), all of which exhibited improvements of at least 1 grade of the Rutherford category. Kaplan-Meier analysis showed that reintervention-free rates were 81.9% (95% CI 0.586 to 0.928) at 6 months and 71.7% at 10 months (95% CI 0.473 to 0.862). IVUS was performed in 20 limbs and revealed unique findings, including the "bull's-eye" appearance, "lotus-root" appearance, and "bunch of grapes" appearance. During a mean follow-up of 26±19 months, the limb salvage rate was 100% with no deaths. CONCLUSION: Contemporary endovascular therapy might be able to serve as a potential option for TAO patients with lower and upper limb symptoms. Liberal application of IVUS could help us understand the pathology of TAO to support endovascular therapy for TAO.

Revisiting Microsurgical Distal Bypass for Critical Limb Ischemia.

Background The purpose of this study was to investigate the efficacy of introducing microsurgical techniques to distal bypass surgery for critical limb ischemia. Methods Datasets of 83 consecutive microsurgical distal bypasses in a multicenter (SKY) study were compared with the results of the PREVENT III (PIII) study regarding the following: (1) patients' characteristics, (2) clinical severity according to the PIII risk score, (3) conduits and procedures for revascularization, (4) proximal and distal anastomosis sites, and (5) primary patency and amputation-free survival (AFS) rates at 1 year. Results The high-risk group in the SKY study was larger compared with that in the PIII study (37 vs. 9%, respectively; p < 0.0001). Although all patients underwent revascularization in the perimalleolar region (100 vs. 65.1%, respectively; p < 0.0001), the primary patency rate at 1 year was 71.8%, compared with 59.9% in the PIII study (p = 0.0227). The AFS rate at 1 year was not significantly different between the SKY and PIII studies (80.6 vs. 75.1%, respectively; p = 0.189); however, there was a significant difference between the high-risk subsets of each group: 74.1% in the SKY study and 45% in the PIII study (p < 0.0001). Conclusions Our data demonstrated that microsurgical distal bypass is an effective and durable procedure, especially for high-risk patients. We believe that microsurgical techniques should be considered for distal bypass to optimize the treatment of ischemic limbs with severe peripheral artery disease.

A hybrid therapy for Buerger's disease using distal bypass and a free temporoparietal fascial flap: a case report.

Buerger's disease presents a difficult challenge, with its uncertain etiology and lack of a standardized therapy, and is often refractory to treatment. In the present report, we have described the case of a 43-year-old male with Buerger's disease, a refractory ulcer on his right great toe, and severe pain at rest. We obtained favorable results using a hybrid therapy that combined distal bypass with a free temporoparietal fascial flap. Postoperatively, the flap healed, and the patient's pain resolved. After more than 3 years of follow-up, he had had no recurrence of the foot ulceration, and the patency of the bypass graft had been confirmed using Doppler flowmetry. We believe that the hybrid therapy we devised for the present patient (ie, combined distal bypass with a free temporoparietal fascial flap) is an effective treatment of Buerger's disease with pedal ulceration. The therapeutic strategies for this condition should not adhere to a single treatment modality; rather, they should combine available treatment modalities according to each individual patient's condition.

Subintimal angioplasty of lengthy femorotibial total occlusion in Buerger's disease.

PURPOSE: To report successful subintimal angioplasty of a lengthy femorotibial occlusion in a patient with Buerger's disease, with wound healing and limb salvage. CASE REPORT: A 38-year-old female heavy smoker was referred to our hospital for treatment of extensive infectious tissue loss, with severe foot pain 1 month after early failure of a distal bypass graft. Angiography revealed total occlusion in the femoropopliteal and infrapopliteal arteries. Endovascular recanalization was attempted in order to establish "straight-line flow" to the foot on the verge of limb loss. The subintimal angioplasty technique with a 0.014-inch hydrophilic guidewire facilitated successful crossing of the occlusive femoropopliteal and posterior tibial arteries. The lesions were serially dilated (standard and cutting balloons). Angiography demonstrated antegrade flow to the foot without flow-limiting dissection, and the serious pain dramatically disappeared. Complete wound healing was observed 5 months after initial revascularization with the assistance of repeat angioplasty for restenosis. CONCLUSION: Contemporary endovascular therapy using the subintimal angioplasty technique could represent a viable option for Buerger's disease.

A novel low-density lipoprotein/fibrinogen apheresis method for chronic limb-threatening ischemia in patients with poor options for revascularization: A multicenter, single-arm clinical trial.

INTRODUCTION: Low-density lipoprotein (LDL) apheresis is a treatment option for patients with unhealed chronic limb-threatening ischemia (CLTI) after revascularization. The newly developed AS-25 is a direct hemoperfusion-type apheresis device that differs from conventional LDL apheresis therapy and is designed to specifically adsorb both LDL-C and fibrinogen. We evaluate the efficacy and safety of AS-25. METHODS: This study included 61 patients whose ulcers failed to heal after revascularization or were ineligible for revascularization. Of these, 50 were undergoing hemodialysis. The primary endpoint was the healing rate of a target lesion of interest (ulcer), using historical data as control. RESULTS: The ulcer healing rate of 45.9% was significantly higher than the historical data. No significant safety concerns were observed. CONCLUSIONS: AS-25 was effective in healing ulcers and preventing major amputation even in CLTI refractory patients on hemodialysis, thus showing potential clinical applicability and high significance. CLINICAL TRIAL REGISTRATION: UMIN study ID UMIN000020336.

The Simultaneous Application of OASIS and Skin Grafting in the Treatment of Tendon-exposed Wound.

In the present case, we successfully applied the OASIS extracellular matrix to a tendon-exposed wound and simultaneously performed skin grafting. In the future, this approach can be used to further reduce a patient's burden, as it is more effective than PAT transplantation for wounds with exposed tendons.

Successful use of last-option infrapopliteal rotational atherectomy despite microembolisation: Peripheral rotational atherectomy and microembolisation.

Calcified lesions pose a technical challenge even in contemporary endovascular intervention. A 71-year-old man who had been receiving haemodialysis required infrapopliteal revascularisation for the treatment of ischaemic infectious gangrene of the right toes. Baseline angiography suggested that the multiple stenotic lesions in the anterior tibial artery were amenable to endovascular therapy for the purpose of establishing one straight-line flow to the foot. However, even a 1.25×15 mm semi-compliant balloon catheter failed to cross and dilate the focal lesion because of the underlying severe calcification in the mid segment of the anterior tibial artery. We adjunctively used high-speed rotational atherectomy with the ROTABLATOR device (1.5 mm burr) to ablate the focal calcified lesion while paying attention to minimise the ablation length and the ablation time. Subsequent balloon angioplasty with a 2.0×40 mm balloon catheter was successful. The skin perfusion pressure in the right foot increased from 32 to 48 mmHg, suggesting a high probability of wound healing. Pathological examination of the right toe amputated on schedule found non-clinically relevant microembolisation involving a couple of cholesterol crystals (20-30 µm) located in the arterioles and capillaries of the necrotic tissue. As an adjunctive device, the ROTABLATOR could provide a last resort for limb salvage, albeit that microembolisation can occur.

Contemporary critical limb ischemia: Asian multidisciplinary consensus statement on the collaboration between endovascular therapy and wound care.

The burden of peripheral artery disease (PAD) and diabetes in Asia is projected to increase. Asia also has the highest incidence and prevalence of end-stage renal disease (ESRD) in the world. Therefore, most Asian patients with PAD might have diabetic PAD or ESRD-related PAD. Given these pandemic conditions, critical limb ischemia (CLI) with diabetes or ESRD, the most advanced and challenging subset of PAD, is an emerging public health issue in Asian countries. Given that diabetic and ESRD-related CLI have complex pathophysiology that involve arterial insufficiency, bacterial infection, neuropathy, and foot deformity, a coordinated approach that involves endovascular therapy and wound care is vital. Recently, there is increasing interaction among cardiologists, vascular surgeons, radiologists, orthopedic surgeons, and plastic surgeons beyond specialty and country boundaries in Asia. This article is intended to share practical Asian multidisciplinary consensus statement on the collaboration between endovascular therapy and wound care for CLI.

Reconstruction Using Locoregional Flaps for Large Skull Base Defects.

We present a modified locoregional flap for the reconstruction of large anterior skull base defects that should be reconstructed with a free flap according to Yano's algorithm. No classification of skull base defects had been proposed for a long time. Yano et al suggested a new classification in 2012. The lb defect of Yano's classification extends horizontally from the cribriform plate to the orbital roof. According to Yano's algorithm for subsequent skull base reconstructive procedures, a lb defect should be reconstructed with a free flap such as an anterolateral thigh free flap or rectus abdominis myocutaneous free flap. However, our modified locoregional flap has also enabled reconstruction of lb defects. In this case series, we used a locoregional flap for lb defects. No major postoperative complications occurred. We present our modified locoregional flap that enables reconstruction of lb defects.

Tranilast as an additional treatment with conservative therapy for concave deformity following traumatic hematoma.

Fibrotic scar tissue resulting from a cheek hematoma sometimes seriously contracts to form a concave deformity, despite conservative therapy. We used Tranilast as an additional treatment with conservative therapy for four patients who were resistant to massage and compression therapy. Four months after oral administration of Tranilast, all the deformities were resolved. Tranilast is used for the treatment of allergic diseases and keloids. It inhibits the release of transforming growth factor b-1, interleukin-1 b, and prostaglandin E2. It also suppresses collagen synthesis by fibroblasts.