Prediction Models for Two Year Overall Survival and Amputation Free Survival After Revascularisation for Chronic Limb Threatening Ischaemia.

OBJECTIVE: The aim of this study was to create prediction models for two year overall survival (OS) and amputation free survival (AFS) after revascularisation in patients with chronic limb threatening ischaemia (CLTI). METHODS: This was a retrospective analysis of prospectively collected multicentre registry data (JAPAN Critical Limb Ischaemia Database; JCLIMB). Data from 3 505 unique patients with CLTI who had undergone revascularisation from 2013 to 2017 were extracted from the JCLIMB for the analysis. The cohort was randomly divided into development (2 861 patients) and validation cohorts (644 patients). In the development cohort, multivariable risk models were constructed to predict two year OS and AFS using Cox proportional hazard regression analysis. These models were applied to the validation cohort and their performances were evaluated using Harrell's C index and calibration plots. RESULTS: Kaplan-Meier estimates of two year OS and AFS post-revascularisation in the whole cohort were 69% and 62%, respectively. Strong predictors for OS consisted of age, activity, malignant neoplasm, chronic kidney disease (CKD), congestive heart failure (CHF), geriatric nutritional risk index (GNRI), and sex. Strong predictors for AFS included age, activity, malignant neoplasm, CKD, CHF, GNRI, body temperature, white blood cells, urgent revascularisation procedure, and sex. Prediction models for two year OS and AFS showed good discrimination with Harrell's C indexes of 0.73 (95% confidence interval [CI] 0.69 - 0.77) and 0.72 (95% CI 0.68 - 0.76), respectively CONCLUSION: Prediction models for two year OS and AFS post-revascularisation in patients with CLTI were created. They can assist in determining treatment strategies and serve as risk adjustment modalities for quality benchmarking for revascularisation in patients with CLTI at each facility.

Evaluation of paramalleolar and inframalleolar bypasses in dialysis- and nondialysis-dependent patients with critical limb ischemia.

OBJECTIVE: The aim of this study was to elucidate the efficacy of paramalleolar or inframalleolar bypass (PIMB) in hemodialysis-dependent (HD) patients with critical limb ischemia (CLI) and nonhemodialysis-dependent (NHD) patients in terms of clinical outcomes. METHODS: Between January 2000 and December 2013, there were 333 consecutive arteriosclerosis obliterans patients with CLI who underwent 401 PIMB procedures for limb salvage (LS). Of the 333 patients, 188 (56.5%) were HD patients. Vein grafts were exclusively used, and 172 paramalleolar and 229 inframalleolar bypasses were performed. Five-year primary and secondary cumulative graft patency, LS, and amputation-free survival (AFS) rates were compared between the two groups, and the independent determinants of these outcomes were identified in each group. RESULTS: The 5-year primary and secondary cumulative graft patency rates were 53% and 82% in HD patients and 69% and 92% in NHD patients (primary cumulative graft patency, P < .05; secondary cumulative graft patency, nonsignificant), respectively. The LS rates were 87% and 99% (P < .01) in HD patients and NHD patients, respectively. Overall, 48% and 70% of HD and NHD patients were ambulatory before PIMB (P < .01), and 73% and 85% of HD and NHD patients were ambulatory 12 months after PIMB (including 1-year survivors; nonsignificant), respectively, demonstrating drastic post-PIMB improvement in HD patients. The 5-year AFS rates in the HD and NHD groups were 27% and 69% (P < .01), respectively, demonstrating very poor AFS rates in HD patients. In HD patients, factors negatively associated with AFS were female gender (hazard ratio [HR], 2.102; 95% confidence interval [CI], 1.254-3.524), history of congestive heart failure (HR, 2.075; 95% CI, 1.395-3.085), and preoperative nonambulatory status (HR, 1.974; 95% CI, 1.305-2.986), whereas older age (HR, 2.601; 95% CI, 1.372-4.931) and history of congestive heart failure (HR, 2.928; 95% CI, 1.496-5.731) were identified as independent factors negatively associated with AFS in NHD patients. CONCLUSIONS: The use of PIMB for CLI was associated with excellent LS rates in both HD and NHD patients with low operative mortality and complications. However, the AFS rate observed in HD patients was significantly lower than that observed in NHD patients, indicating the necessity of a specific management program to improve AFS after LS in HD patients.

Ulcer healing after peripheral intervention-can we predict it before revascularization?

Complete ulcer healing is one of the most important goals of treatment for critical limb ischemia; however, it is still difficult to inform patients of the time to ulcer healing before performing revascularization. The time to ulcer healing has a great impact on the cost of treatment and patient's quality of life. To predict it, the factors that influence delayed ulcer healing should be explored. According to a review of the literature investigating ulcer healing after revascularization, the influential factors can be classified into 5 categories: (1) systemic factors; (2) clinical state of tissue defect; (3) infection; (4) wound management strategy; and (5) revascularization strategy (endovascular or open repair, the angiosome concept). It is also important to ensure sufficient blood supply to predict ulcer healing probability in the individual patient. Several new methodologies, such as measuring tissue circulation around the tissue defect and intraoperative imaging techniques, have been reported. Because the status of ischemic tissue loss and wound healing ability can affect the decision-making process in selecting the revascularization strategy, understanding the many factors that influence ulcer healing after revascularization is indispensable for physicians performing revascularization. Accumulating ulcer healing data via well-designed clinical research can help to establish a new paradigm for the revascularization strategy from the viewpoint of ulcer healing.

Clinical results of cystic excision for popliteal artery cystic adventitial disease: long-term benefits of preserving the intact intima.

Surgical treatment for popliteal artery cystic adventitial disease (PACAD) is still controversial. PACAD often occurs in young or middle-aged adults. Therefore, the maintenance of graft patency for very long periods is a concern if a prosthesis is used. Because the intima is intact in PACAD patients with popliteal artery stenosis, a treatment that preserves the healthy intima is ideal. We describe the cases of 3 patients who underwent cystic excision for PACAD with severe stenosis. No recurrence was observed for up to 11 years, and these long-term results revealed that cystic excision could be reconsidered as one of the first-line therapeutic methods.

The Association between Severity of Atherosclerosis and Lower Urinary Tract Function in Male Patients with Lower Urinary Tract Symptoms.

OBJECTIVES: The present study was undertaken to investigate the association between the severity of atherosclerosis and lower urinary tract function in male patients with lower urinary tract symptoms. METHODS: Male patients with lower urinary tract symptoms were examined with routine investigation. The severity of atherosclerosis was assessed by ultrasound examination of carotid artery. Patients were divided into two groups: control group and atherosclerosis group. The voiding function and storage function were compared between the two groups. RESULTS: A total of 50 men (69.9 ± 9.1 years [mean ± standard deviation]) entered the study. There was no significant difference in age distribution (control group: 68.7 ± 7.6 years; atherosclerosis group: 72.5 ± 9.7 years) and prostate volume (control group: 26.5 ± 17.3 mL; atherosclerosis group: 22.2 ± 11.0 mL) between the two groups. In the voiding parameters, maximum flow rate in the atherosclerosis group (13.4 ± 5.5 mL/s, P < 0.05) was significantly lower than that in the control group (16.7 ± 7.7 mL/s). Postvoid residual urine volume showed no significant difference between the two groups. In the storage parameters, voided volume was significantly reduced in the atherosclerosis group (161.8 ± 46 mL, P < 0.05), as compared to control group (201.1 ± 78 mL). Moreover, daytime frequency was 7.13 ± 3.02 times in the control group, and significantly higher in the atherosclerosis group (8.75 ± 2.50 times, P < 0.05). CONCLUSION: Development of atherosclerosis impairs both voiding and storage function independently of age, suggesting atherosclerosis leads to lower urinary dysfunction.

Combined distal venous arterialization and free flap for patients with extensive tissue loss.

BACKGROUND: We evaluated the mid-term outcome of distal venous arterialization (DVA) and the role of a combined free flap as a bridgehead for blood supply. METHODS: In the past 5 years, nine patients with extensive tissue loss and lacking graftable distal arteries underwent DVA. These consisted of four primary DVAs, three combined DVA and free flap procedures, and two adjuvant DVAs for hemodynamically failed distal bypasses. After nine primary DVAs, three redo DVAs were performed for early failure. Etiologies were four Buerger disease and five arteriosclerosis obliterans, including three dialysis patients. RESULTS: Among the nine DVA cases, there were five primary failures: two underwent amputation, two had successful redo DVA, and the remaining one did not require redo DVA. Primary patency, secondary patency, and limb salvage rates were 44.4%, 55.6%, and 77.8%, respectively. The postoperative period was 1-36 months (median 12). Angiography demonstrated DVA was effective in the early period, and development of collaterals or a capillary network from the free flap replaced the DVA function in the intermediate period. CONCLUSION: DVA can be effective as a procedure for limb salvage in patients without graftable distal arteries, and a combined free flap is effective and functions as a bridgehead for blood supply to the ischemic zone.

CKD accelerates development of neointimal hyperplasia in arteriovenous fistulas.

Arteriovenous (AV) access failure resulting from venous neointimal hyperplasia is a major cause of morbidity in patients with ESRD. To understand the role of chronic kidney disease (CKD) in the development of neointimal hyperplasia, we created AV fistulae (common carotid artery to jugular vein in an end-to-side anastomosis) in mice with or without CKD (renal ablation or sham operation). At 2 and 3 wk after operation, neointimal hyperplasia at the site of the AV anastomosis increased 2-fold in animals with CKD compared with controls, but cellular proliferation in the neointimal hyperplastic lesions did not significantly differ between the groups, suggesting that the enhanced neointimal hyperplasia in the setting of CKD may be secondary to a migratory phenotype of vascular smooth muscle cells (VSMC). In ex vivo migration assays, aortic VSMC harvested from mice with CKD migrated significantly greater than VSMC harvested from control mice. Moreover, animals with CKD had higher serum levels of osteopontin, which stimulates VSMC migration. When we treated animals with bone morphogenic protein-7, which promotes VSMC differentiation, before creation of the AV anastomosis, the effect of CKD on the development of neointimal hyperplasia was eliminated. In summary, CKD accelerates development of neointimal hyperplasia at the anastomotic site of an AV fistula, and administration of bone morphogenic protein-7 neutralizes this effect.

[A case of long-term survival of advanced penile carcinoma treated with combination therapy].

A 72-year-old man with genital ulcerative tumor was introduced to our hospital in December 1997. The pathological examination revealed well differentiated squamous cell carcinoma. A diagnosis by computed tomography and magnetic resonance imaging indicated that a locally advanced penile carcinoma had infiltrated the urethra, prostate, pubic bone and there was also bilateral inguinal lymphoadenopathy. Linac irradiation (40Gy/4 weeks) combined with once-a-week administration of THP-ADM were indicated. One month after the combination therapy, the tumor size had become small enough to allow curative surgical treatment. Pathological examination revealed no positive margin. For eight years since this radical treatment, the patient has been healthy with no local recurrence and no distant metastatic lesion.

Integrin alpha(v)beta(3) as a target in the prevention of neointimal hyperplasia.

Although major advances have been made in the prevention and treatment of restenosis following coronary and peripheral interventions, the persistent complications of thrombosis and reintervention remain a mainstay for repeat hospitalizations in this patient population. For many years, a ubiquitous cell surface receptor called alpha(v)beta(3) integrin was the target of investigators in the prevention of restenosis because its interaction with the extracellular matrix was believed to coordinate the migration of smooth muscle cells (SMCs) from the media to the intima, the seminal event in the formation of intimal occlusive lesion. After the publication of uniformly positive animal studies demonstrating that alpha(v)beta(3) integrin blockade led to a significant reduction in new intimal (neointimal) lesion formation, early clinical trials supported the association of avoidance of target lesion revascularization and the use of antagonists to the SMC integrin alpha(v)beta(3) and its related platelet integrin alpha(IIb)beta(3). However, a series of clinical trials subsequently demonstrated that these antagonists did not necessarily prevent revascularizations by inhibiting intimal hyperplasia per se. Additional animal studies subsequently showed that, indeed, in the setting of pre-existing SMCs in the intimal lesion (ie, atherosclerotic plaque, fatty streaks), inhibiting SMC migration by way of beta(3) integrin blockade was an ineffective approach in the prevention of intimal hyperplasia and restenosis. However, given the wealth of basic and clinical information on the alpha(v)beta(3) integrin and its antagonists, we discuss in this article our new approach to this old solution by targeting a new clinical problem of early failure arteriovenous access for hemodialysis. Given the uniqueness of arteriovenous access in that there are essentially no significant atherosclerotic lesions in the artery and vein prior to the anastomosis, the seminal event of the migration of SMCs from the media to the neointima could by targeted once again with beta(3) integrin antagonists.

Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function.

We evaluated the pharmacological characteristics of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]-ethyl} acetanilide (YM178). YM178 increased cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing human beta3-adrenoceptor (AR). The half-maximal effective concentration (EC50) value was 22.4 nM. EC50 values of YM178 for human beta1- and beta2-ARs were 10,000 nM or more, respectively. The ratio of intrinsic activities of YM178 versus maximal response induced by isoproterenol (nonselective beta-AR agonist) was 0.8 for human beta3-ARs, 0.1 for human beta1-ARs, and 0.1 for human beta2-ARs. The relaxant effects of YM178 were evaluated in rats and humans bladder strips precontracted with carbachol (CCh) and compared with those of isoproterenol and 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP-12177A) (beta3-AR agonist). EC50 values of YM178 and isoproterenol in rat bladder strips precontracted with 10(-6) M CCh were 5.1 and 1.4 microM, respectively, whereas those in human bladder strips precontracted with 10(-7) M CCh were 0.78 and 0.28 microM, respectively. In in vivo study, YM178 at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. These findings suggest the suitability of YM178 as a therapeutic drug for the treatment of symptoms of overactive bladder such as urinary frequency, urgency, and urge incontinence.

Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors.

We investigated the cAMP-dependent and -independent mechanisms of relaxation via beta-adrenoceptor in rat detrusor muscle with and without pre-contraction. A microdialysis technique was used to measure detrusor tension and cAMP level on the same detrusor tissue. In non-contracted tissue, isoproterenol, clenbuterol (beta2-adrenoceptor agonist) and FR165101, ((8S)-8-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)oxy]acetic acid hydrochloride (beta3-adrenoceptor agonist) relaxed detrusor muscle and cAMP levels also increased in a concentration dependent manner. SQ22536 (adenylyl cyclase inhibitor) markedly suppressed relaxation, suggesting that beta-adrenoceptor-mediated relaxation may be attributed mainly to cAMP-dependent mechanism. In high K+ pre-contracted tissue, although relaxation advanced in a concentration dependent manner, cAMP production reached a plateau at concentrations of more than 10(-7) M. SQ22536 had only a small inhibitory effect. However, large-conductance, Ca2+-activated K+ (BK(Ca)) channel inhibitors, charybdotoxin and iberiotoxin markedly suppressed relaxation. These results suggest that in addition to cAMP-dependent pathway, BK(Ca) channels are involved in the beta-adrenoceptor agonists-induced relaxation in pre-contracted detrusor muscle.

Matrix metalloproteinase-9 modulation by resident arterial cells is responsible for injury-induced accelerated atherosclerotic plaque development in apolipoprotein E-deficient mice.

OBJECTIVE: Although matrix metalloproteinase-9 (MMP-9) has been implicated in atherosclerotic plaque instability, the exact role it plays in the plaque development and progression remains largely unknown. We generated apolipoprotein E (apoE)-deficient (apoE-/-) MMP-9-deficient (MMP-9-/-) mice to determine the mechanisms and the main cell source of MMP-9 responsible for the plaque composition during accelerated atherosclerotic plaque formation. METHODS AND RESULTS: Three weeks after temporary carotid artery ligation revealed that while on a Western-type diet, apoE-/- MMP-9-/- mice had a significant reduction in intimal plaque length and volume compared with apoE-/- MMP-9+/+ mice. The reduction in plaque volume correlated with a significantly lower number of intraplaque cells of resident cells and bone marrow-derived cells. To determine the cellular origin of MMP-9 in plaque development, bone marrow transplantation after total-body irradiation was performed with apoE-/- MMP-9+/+ and apoE-/- MMP-9-/- mice, which showed that only MMP-9 derived from resident arterial cells is required for plaque development. CONCLUSIONS: MMP-9 is derived from resident arterial cells and is required for early atherosclerotic plaque development and cellular accumulation in apoE-/- mice.

[Correlation between re-biopsy one year after endocrine therapy and long-term prognosis in localized prostate cancer].

PURPOSE: Even in the cases of localized prostate cancer, there are a substantial number of patients who undergo endocrine therapy, and their prognosis is affected by the treatment. We evaluated the histological effect of endocrine therapy and analyzed its correlation with prognosis. METHODS AND SUBJECTS: Seventy-seven cases with localized prostate cancer who underwent maximal androgen blockade (MAB) therapy 1 year or longer were pathologically evaluated using repeat biopsy specimens from November 1994 to October 2001. The relationship between clinical parameters and histological effect in repeat biopsy specimens was examined. Biopsy was conducted mainly by the 6-site systematic method, and the histological effect was judged in accordance with the General Rules for Clinical and Pathological Study of Prostate Cancer (3rd edition). The median re-biopsy and follow-up periods were 13 months and 41 months, respectively. RESULTS: Using this criteria for the histological effects of anti-cancer treatment, the histological effect of endocrine therapy was most frequently observed in class G3b with 61.0%, and correlations with PSA nadir and initial biopsy positive number before endocrine therapy were observed. After biopsy, radical prostatectomy was performed on 9 patients (endocrine therapy was concurrently performed on 4), endocrine therapy on 67 (intermittent administration on 21), and radiation therapy on 1 (MAB was concurrently performed). Outcomes included PSA failure in 14, of whom 2 died of cancer. Three-year and 5-year PSA-failure free survival rates were 91.1% and 76.3%, respectively. Pathological disease stage in radical prostatectomy specimens was examined by dividing it into class G0-2 and class G0-3. This revealed a significant correlation between histological effect and pathological disease stage (pT2-3). PSA-failure free survival was analyzed in 67 of the 77 patients who underwent endocrine therapy. A significantly large number of PSA-failures occurred in class G0-2. Multivariate analysis revealed that the histological effect alone was the influencing factor in PSA-failure. CONCLUSION: A strong histological effect by MAB 1 year or longer after treatment was observed on localized prostate cancer. Evaluation of the histological effect by the present method was considered to be a useful predictor for organ-confined disease after radical prostatectomy and endocrine therapy for PSA-failure.

Isolated iliac artery aneurysm caused by fibromuscular dysplasia: report of a case.

Fibromuscular dysplasia (FMD) can develop in many different arteries, but iliac artery aneurysms are rare. A 69-year-old Japanese woman was admitted to our hospital for treatment of a right common iliac artery aneurysm. Aortography revealed aneurysms in both the right common iliac artery and the left internal iliac artery. Notably, the right common iliac artery aneurysm had a "string-of-beads" appearance. At surgery, the aneurysms were resected, and replaced with Y-shaped vascular prostheses. The histopathological diagnosis was fibromuscular dysplasia (FMD). We report this case of common iliac artery aneurysm caused by FMD due to its rarity.

Novel anastomotic method enables aortofemoral bypass for patients with porcelain aorta.

PURPOSE: Porcelain aorta is an indication for axillofemoral bypass. However, the procedure has definitive flaws. We present a new method for achievement of aortofemoral bypass. METHODS: The portion of the distal aorta for anastomosis is wrapped with a double polytetrafluoroethylene mesh and fixed to the adventitia with continuous sutures. The adventitia of the anastomotic site is cut over the mesh until the calcified surface is disclosed. Margins of the mesh and the peeled adventitia are fixed along the anastomotic margin with continuous sutures. After the aorta and distal arteries are occluded with balloon catheters, an opening on the bared calcification is made with an airdrill and enlarged with a laminectomy rongeur. The anastomosis is performed between a graft and the mesh-reinforced adventitia with continuous sutures. Over 6 years, this method has been applied to nine patients with porcelain aorta who are diabetic or undergoing dialysis. The indications were disabling claudication in three patients and limb salvage in six patients. RESULTS: No anastomotic complications or operative deaths were seen, and satisfactory mid-term results were obtained, with follow-up ranging from 3 to 62 months after surgery. One patient died of coronary heart disease 3 years after surgery, but the grafts retained a good function. CONCLUSION: This method is safe and effective, and more liberal application of this method may help improve outcome and quality of life.

[Phyllodes tumor of the prostate: a case report].

Prostatic phyllodes tumor is an unusual lesion for which there are only occasional reports in the literature. We encountered a phyllodes tumor of the prostate in a 36-year-old man who had complained of urinary frequency and dysuria for one month. In October 1998, he visited our hospital and had a transurethral resection of the prostate (TUR-P) for obstructive symptoms. He experienced recurrent same symptoms in September 1999 and underwent another TUR-P. The pathologic examination at this time revealed phyllodes tumor. In the tumor, despite its regular alternating growth of ducts and stroma, the stromal element appeared histologically malignant, showing marked atypia and rhabdomyosarcoma-like components. Consequently, in December 1999, the patient underwent radical prostatectomy with lymph node dissection. The resection margins and pelvic lymph nodes were free of tumor. The patient remains alive and well after 14 months.