Long-Term Clinical Outcomes of Autologous Bone Marrow Mononuclear Cell Implantation in Patients With Severe Thromboangiitis Obliterans.

BACKGROUND: Patients with severe Buerger disease, also known as thromboangiitis obliterans (TAO), are at risk of major limb amputation. It has been shown that autologous bone marrow mononuclear cell (BM-MNC) implantation improves the condition of critical limb ischemia in TAO patients. This study was conducted to further clarify the long-term (>10 years) results of autologous BM-MNC implantation in patients with TAO.Methods and Results:An observational study was conducted of the long-term results of BM-MNC implantation in 47 lower limbs of 27 patients with TAO. The mean (±SD) follow-up period was 12.0±8.6 years. There was no major amputation event up to 10 years of follow-up in patients treated with BM-MNC implantation. The overall amputation-free survival rates were significantly higher in patients who underwent BM-MNC implantation than in internal controls and historical controls. There was no significant difference in amputation-free survival rates between the historical and internal controls. There was also no significant difference in overall survival between patients who underwent BM-MNC implantation and the historical controls. CONCLUSIONS: BM-MNC transplantation successfully prevented major limb amputation over a period of >10 years in patients with severe TAO who had no other therapeutic options.

Visceral bed involvement in thromboangiitis obliterans: a systematic review.

One of the challenges of thromboangiitis obliterans (TAO) management is in the patients whose other vascular beds are involved and it remains a challenge to know whether to pursue invasive procedures or to continue medical treatment for such TAO patients. The aim of this review was to investigate reports of the involvement of the visceral vessels in TAO and the related clinical manifestations, management approaches and outcomes. According to our systematic review, the frequency of published articles, the organs most commonly involved were the gastrointestinal tract, the heart, the central nervous system, the eye, the kidneys, the urogenital system, the mucocutaneous zones, joints, lymphohematopoietic system and the ear. Notably, reports of the involvement of almost all organs have been made in relation to TAO. There were several reports of TAO presentation in other organs before disease diagnosis, in which the involvement of the extremities presented after visceral involvement. The characteristics of the visceral arteries looked like the arteries of the extremities according to angiography or aortography. Also, in autopsies of TAO patients, the vascular involvement of multiple organs has been noted. Moreover, systemic medical treatment could lead to the recovery of the patient from the onset of visceral TAO. This study reveals that TAO may be a systemic disease and patients should be aware of the possible involvement of other organs along with the attendant warning signs. Also, early systemic medical treatment of such patients may lead to better outcomes and reduce the overall mortality rate.

Long-Term Outcome and Prognostic Factors of Complications in Thromboangiitis Obliterans (Buerger's Disease): A Multicenter Study of 224 Patients.

Background Data regarding long-term outcome of patients with thromboangiitis obliterans are lacking and most series come from India and Japan. In this study, we assess long-term outcome and prognostic factors in a large cohort of thromboangiitis obliterans. Methods and Results Retrospective multicenter study of characteristics and outcomes of 224 thromboangiitis obliterans patients fulfilling Papa's criteria were analyzed. Factors associated with vascular events and amputations were identified. The median age at diagnosis was 38.5 (32-46) years, 51 (23.8%) patients were female, and 81.7% were whites. After a mean follow-up of 5.7 years, vascular events were observed in 58.9%, amputations in 21.4%, and death in 1.4%. The 5-, 10-, and 15-year vascular event-free survival and amputation-free survival were 41% and 85%, 23% and 74%, and 19% and 66%, respectively. Ethnic group (nonwhite) (hazard ratio 2.35 [1.30-4.27] P=0.005) and limb infection at diagnosis (hazard ratio 3.29 [1.02-10.6] P=0.045) were independent factors of vascular event-free survival. Factor associated with amputation was limb infection (hazard ratio 12.1 [3.5-42.1], P<0.001). Patients who stopped their tobacco consumption had lower risk of amputation ( P=0.001) than those who continued. Conclusions This nationwide study shows that 34% of thromboangiitis obliterans patients will experience an amputation within 15 years from diagnosis. We identified high-risk patients for vascular complications and amputations.

Outcomes of endovascular treatment versus bypass surgery for critical limb ischemia in patients with thromboangiitis obliterans.

We aimed to compare the clinical outcomes between endovascular treatment and inframalleolar bypass surgery for critical limb ischemia (CLI) in patients with thromboangiitis obliterans (TAO) and to assess the role of bypass surgery in the era of innovative endovascular treatment. Between January 2007 and December 2017, a total of 33 consecutive patients with the diagnosis of TAO presenting with CLI who underwent endovascular treatment (endovascular group, n = 22) or bypass surgery to the pedal or plantar vessels (bypass group, n = 11) were included and analyzed retrospectively. The primary endpoint was defined as a major amputation of the index limb, and the secondary endpoint was defined as graft occlusion, regardless of the number of subsequent procedures. In the bypass group, six patients (55%) had undergone previous failed endovascular procedures and/or arterial bypass surgery to the index limb before inframalleolar bypass, and two patients (18%) received microvascular flap reconstruction after bypass surgery. During the median follow-up period of 32 months (range 1-115 months), there were no significant differences in primary and secondary endpoints between the two groups although the bypass group had a higher Rutherford class than the endovascular group. Kaplan-Meier survival analysis showed that there were similar limb salvage (P = 0.95) and graft patency rates (P = 0.39). In conclusion, endovascular treatment is a valid strategy leading to an acceptable limb salvage rate for TAO patients, and surgical bypass to distal target vessels could play a vital role in cases of previous failed endovascular treatment or extensive soft tissue loss of the foot.

Autologous bone marrow-derived mononuclear cell therapy in Chinese patients with critical limb ischemia due to thromboangiitis obliterans: 10-year results.

BACKGROUND: For patients with thromboangiitis obliterans (TAO), revascularization with bypass or angioplasty is frequently not feasible due to the poor outflow of the distal small vessels. We evaluated the long-term results of our experience treating patients with TAO with autologous bone marrow-derived mononuclear cells (ABMMNCs) to determine the safety and efficacy of ABMMNC therapy in patients with critical limb ischemia due to TAO. METHODS: This was a retrospective chart review from a single university hospital vascular surgery center between January 2005 and July 2006. Patients were treated with smoking cessation and either aspirin (100 mg/day) alone or aspirin and ABMMNC injection according to patient preference. Groups were compared for demographics, clinical characteristics, and short-term and long-term results. RESULTS: Of 59 patients with TAO who were treated, 19 patients elected aspirin alone and 40 patients elected aspirin and ABMMNC injection. No patients suffered perioperative complications and 49 (83%) patients remained smoke-free for 10 years. The 10-year amputation-free survival was 85.3% (29/34) in patients treated with ABMMNCs compared to 40% (6/15) in patients treated with aspirin alone (p = 0.0019). Ulcer area (p < 0.0001), toe-brachial index (TBI; p < 0.0001), transcutaneous oxygen pressure (TcPO2; p < 0.0001), and pain score (p < 0.0001) were also significantly improved with ABMMNC treatment, although there was no difference in mean ankle-brachial index (ABI; p = 0.806). CONCLUSIONS: In patients with critical limb ischemia due to TAO, ABMMNC treatment was safe and effective. ABMMNC treatment significantly improved amputation-free survival, ulcer healing, and pain, although there is no difference in ABI compared to treatment with aspirin alone.

Long-term follow-up evaluation of results from clinical trial using hepatocyte growth factor gene to treat severe peripheral arterial disease.

OBJECTIVE: As angiogenic growth factors can stimulate the development of collateral arteries, a concept called therapeutic angiogenesis, we performed a phase I/IIa open-label clinical trial using intramuscular injection of naked plasmid DNA encoding hepatocyte growth factor (HGF). We reported long-term evaluation of 2 years after HGF gene therapy in 22 patients with severe peripheral arterial disease. METHODS AND RESULTS: Twenty-two patients with peripheral arterial disease or Buerger disease staged by Fontaine IIb (n=7), III (n=4), and IV (n=11) were treated with HGF plasmid, either 2 mg or 4 mg ×2. Increase in ankle-branchial pressure index >0.1 was observed in 11 of 14 patients (79 %) at 2 years after gene therapy and in 11 of the 17 patients (65%) at 2 months. Reduction in rest pain (>2 cm in visual analog scale) was observed in 9 of 9 patients (100%) at 2 years and in 8 of 13 (62%) patients at 2 months. At 2 years, 9 of 10 (90%) ischemic ulcers reduced by >25%, accompanied by a reduction in the size of ulcer. Severe complications and adverse effects caused by gene transfer were not detected in any patient throughout the period up to 2 years. CONCLUSIONS: Overall, the present study demonstrated long-term efficacy of HGF gene therapy up to 2 years. These findings may be cautiously interpreted to indicate that intramuscular injection of naked HGF plasmid is safe, feasible, and can achieve successful improvement of ischemic limbs as sole therapy.

Long-term clinical outcome after intramuscular transplantation of granulocyte colony stimulating factor-mobilized CD34 positive cells in patients with critical limb ischemia.

BACKGROUND: Our phase I/IIa clinical trial revealed that intramuscular transplantation of autologous, GCSF-mobilized CD34+ cells was safe, feasible and potentially effective at week 4 and 12 post cellular therapy in 17 patients with chronic critical limb ischemia (CLI) (5 patients with atherosclerotic peripheral arterial disease (PAD) and 12 with Buerger's disease). However, long-term outcome of the cell therapy has yet to be reported. METHODS AND RESULTS: Incidence of major clinical events and physiological parameters of limb ischemia were evaluated at week 52, 104, 156 and 208 post CD34+ cell therapy. No patients died by week 104, whereas 3 patients with PAD died by week 156 and 1 patient with Buerger's disease died by week 208 due to cardiac complications. No patients underwent major amputation, whereas 1 patient with Buerger's disease underwent unplanned minor amputation by week 104. CLI-free ratio was 88.2% at week 52 and 104, 92.3% at week 156 and 84.6% at week 208 in all patients. Significant improvement of toe brachial pressure index versus baseline was sustained up to week 208 and that of transcutaneous partial oxygen pressure was kept up to week 156. The Wong-Baker FACES pain rating scale, ulcer size and exercise tolerance significantly improved at week 52, the final evaluation time point, compared with baseline. Subgroup analysis revealed the similar outcome in patients with Buerger's disease. CONCLUSIONS: Favorable clinical outcomes as well as physiological evidences strongly indicate the long-term benefit of GCSF-mobilized CD34+ cell transplantation for retrieval from CLI, especially in patients with Buerger's disease.

Natural history definition and a suggested clinical approach to Buerger's disease: a case-control study with survival analysis.

The aim of this study was first to describe the natural history of Buerger's disease (BD) and then to discuss a clinical approach to this disease based on multivariate analysis. One hundred eight patients who corresponded with Shionoya's criteria were selected from 2000 to 2007 for this study. Major amputation was considered the ultimate adverse event. Survival analyses were performed by Kaplan-Meier curves. Independent variables including gender, duration of smoking, number of cigarettes smoked per day, minor amputation events and type of treatments, were determined by multivariate Cox regression analysis. The recorded data demonstrated that BD may present in four forms, including relapsing-remitting (75%), secondary progressive (4.6%), primary progressive (14.2%) and benign BD (6.2%). Most of the amputations occurred due to relapses within the six years after diagnosis of BD. In multivariate analysis, duration of smoking of more than 20 years had a significant relationship with further major amputation among patients with BD. Smoking cessation programs with experienced psychotherapists are strongly recommended for those areas in which Buerger's disease is common. Patients who have smoked for more than 20 years should be encouraged to quit smoking, but should also be recommended for more advanced treatment for limb salvage.

Long-term clinical outcomes for patients with lower limb ischemia implanted with G-CSF-mobilized autologous peripheral blood mononuclear cells.

BACKGROUND: Many studies have described the clinical effects of treating critical limb ischemia with granulocyte colony-stimulating factor-mobilized autologous peripheral blood mononuclear cells (M-PBMNC); however, there are no long-term data available on survival, limb salvage, or prognostic factors. METHODS: To investigate the long-term clinical outcomes of M-PBMNC implantation, we reviewed data for 162 consecutive patients with limb ischemia who were treated with M-PBMNC implantation at 6 hospitals between 2001 and 2006. A subset of 123 patients with homogenous clinical profiles was selected for prognostic factor analysis. RESULTS: Of the 162 patients, 50 died during the follow-up period. The median follow-up time for surviving patients was 26.4 months. The 2-year survival rate was 65% for the 140 patients with arteriosclerosis obliterans (ASO), and 100% for the 11, 4 and 7 patients with thromboangiitis obliterans (TAO), diabetic gangrene (DG) and connective tissue disease (CTD), respectively. The 1-year amputation-free rates for ASO, TAO, DG and CTD were 70%, 79%, 75% and 83%, respectively. Common serious adverse events included heart failure (15 cases), myocardial infarction (15 cases), serious infection (13 cases), stroke (10 cases), and malignant tumor (9 cases). Significant negative prognostic factors associated with overall survival were ischemic heart disease and collection of a small number of CD34-positive cells. Factors associated with time-to-amputation and amputation-free survival were a combination of Fontaine classification and lower limb gangrene, and history of dialysis. CONCLUSIONS: Collection of a small number of CD34-positive cells and ischemic heart disease were associated with a reduction in overall survival.

Unblinded pilot study of autologous transplantation of bone marrow mononuclear cells in patients with thromboangiitis obliterans.

BACKGROUND: The short-term clinical benefits of bone marrow mononuclear cell transplantation have been shown in patients with critical limb ischemia. The purpose of this study was to assess the long-term safety and efficacy of bone marrow mononuclear cell transplantation in patients with thromboangiitis obliterans. METHODS AND RESULTS: Eleven limbs (3 with rest pain and 8 with an ischemic ulcer) of 8 patients were treated by bone marrow mononuclear cell transplantation. The patients were followed up for clinical events for a mean of 684+/-549 days (range 103 to 1466 days). At 4 weeks, improvement in pain was observed in all 11 limbs, with complete relief in 4 (36%). Pain scale (visual analog scale) score decreased from 5.1+/-0.7 to 1.5+/-1.3. An improvement in skin ulcers was observed in all 8 limbs with an ischemic ulcer, with complete healing in 7 (88%). During the follow-up, however, clinical events occurred in 4 of the 8 patients. The first patient suffered sudden death at 20 months after transplantation at 30 years of age. The second patient with an incomplete healing of a skin ulcer showed worsening of the lesion at 4 months. The third patient showed worsening of rest pain at 8 months. The last patient developed an arteriovenous shunt in the foot at 7 months, which spontaneously regressed by 1 year. CONCLUSIONS: In the present unblinded and uncontrolled pilot study, long-term adverse events, including death and unfavorable angiogenesis, were observed in half of the patients receiving bone marrow mononuclear cell transplantation. Given the current incomplete knowledge of the safety and efficacy of this strategy, careful long-term monitoring is required for future patients receiving this treatment.

Clinical and social consequences of Buerger disease.

PURPOSE: This study was undertaken to assess the clinical course of Buerger disease and to analyze the social problems that influence quality of life of affected patients. PATIENTS AND METHODS: One hundred ten patients with Buerger disease (106 men, 4 women; mean age, 40.0 years) for whom complete data since onset of disease were available were included in this retrospective study (mean follow-up, 10.6 years). Data were obtained by means of direct interview, written reports, or telephone. Data for deceased subjects were gathered from their families via written report or telephone. Graft patency was evaluated by means of ankle pressure measurement; and in all patients with decreased ankle pressure arteriography was performed. RESULTS: Seven of 110 study patients (6%) died during follow-up. Cumulative survival rate was 84% up to 25 years after the initial consultation. Results of bypass operations (n = 46) were not satisfactory. Primary graft patency was 41% at 1 year after operation, 32% at 5 years, and 30% at 10 years. Secondary graft patency was 54% at 1 year of follow-up, 47% at 5 years, and 39% at 10 years. However, major amputation was necessary in only 5 of 35 limbs (14%) with failed grafts. Forty-seven patients (43%) underwent 108 amputation procedures, either major amputation (13 patients) or minor amputation (34 patients), of an upper or lower limb. No ischemic ulcers occurred or recurred in patients older than 60 years. Forty-one patients who stopped smoking did not undergo major amputation. Furthermore, of 69 patients who continued smoking, 13 patients (19%) underwent major amputation. There was a correlation between incidence of continued smoking and limb amputation (P =.0070). In addition, 11 of 13 patients who underwent major lower limb amputation (85%) lost their job, compared with 9 of 97 patients without major amputation (9%). There was an association between limb amputation and job loss (P <.0001). All patients who lost their jobs were engaged in manual labor. CONCLUSION: The natural course of life and limb is favorable in many patients with Buerger disease. Occurrence or recurrence of necrotic lesions usually is arrested in patients older than 60 years. To avoid factors that markedly influence quality of life, early treatment and strict instruction to prohibit smoking are mandatory. Arterial reconstruction shortens the healing process of ischemic ulcers, despite poor long-term results. However, bypass surgery to treat intermittent claudication should be limited.

[Smoking and peripheral vascular disorders]. / Rauchen und periphere Gefässleiden.

Smoking is a major risk factor for peripheral arterial occlusive disease (PAOD) and plays a crucial role in the pathogenesis of the thrombangiitis obliterans (TAO), nicotine and carboxyhemoglobin cause functional disturbances and structural damage of the endothelial cells which may initiate arteriosclerosis. Additional effects of smoking are hyperfibrinogenemia, lowering of HDL-cholesterol and increased oxidation of LDL-cholesterol. By these mechanisms, smoking influences other primary risk factors for arteriosclerosis. Patients with PAOD, who continue to smoke, have a worse clinical prognoses with higher amputation and mortality rates than those who quit smoking. The most urgent goal in the therapy of PAOD and TAO should be an immediate and complete smoking cessation. However most patients continue to smoke despite the knowledge of the hazards to their health. An appropriate approach to this addiction may be an alternative application of nicotine temporarily (transdermal by patches or chewing gum) and behavioral treatment. This combined therapy results in better success rates in terms of smoking cessation.