Expression and localization of vascular endothelial growth factor in normal abdominal aorta and abdominal aortic aneurysm.

AIM: The genesis of abdominal aortic aneurysms is associated with remodeling of the vascular wall by angiogenesis as well as proteolysis. Vascular endothelial growth factor (VEGF) is known to be a regulator of angiogenesis and to simultaneously stimulate elastolytic proteinases. We analyzed the expression and localization of VEGF in human abdominal aortic aneurysms compared to normal human aorta METHODS: Eighteen infrarenal aortic aneurysm samples were collected at the time of abdominal aortic aneurysm surgery, while nine normal aortic samples were obtained from autopsy specimens. Immunohistochemical staining was performed to detect VEGF. Immunoenzyme or immunofluorescent double staining was also used to identify those cells presenting VEGF. RESULTS: VEGF was expressed in 18 (100%) of the 18 abdominal aortic aneurysm samples, while 0 (0%) in the 9 normal abdominal aorta samples. Of the 18 samples of aneurysms, all 18 displayed positive VEGF immunostaining in macrophages, 12 in smooth muscle cells (SMCs), and 9 in endothelial cells (ECs). CONCLUSION: Our study clearly demonstrated the expression of VEGF in ECs, and SMCs, and macrophages of abdominal aortic aneurysms as well as its absence in those cells of normal abdominal aorta, suggesting that VEGF may play an important role in aneurysm formation via its direct and/or indirect actions.

Hybrid surgical and endovascular therapy in multifocal peripheral TASC D lesions: up to three-year follow-up.

AIM: The authors described their three-year experience with hybrid surgical and endovascular therapy for multifocal peripheral TASC D lesions, involving both the aortoiliac and/or superficial femoral and common femoral arteries. METHODS: From February 2005 to March 2008, 21 lower limbs in 20 patients with multifocal peripheral artery disease, involving the aortoiliac and/or superficial femoral as well as common femoral arteries, were treated by hybrid surgical and endovascular therapy, such as aortoiliac and/or superficial femoral artery stenting as an adjunct to common femoral artery endarterectomy. Technical and hemodynamic success as well as primary and primary assisted patency and limb salvage rates were determined in concordance with the Society for Vascular Surgery guidelines. RESULTS: All lower limbs successfully underwent successful hybrid surgical and endovascular therapy. The average ABPI before and after hybrid therapy significantly increased from 0.50 +/- 0.32 to 0.79 +/- 0.24 (P = 0.0022). The mean duration of follow-up was 357 days (range, 4 to 1400 days). Over all, the primary patency rates were 94%, 70% and 70% at 6, 12, and 24 months, respectively, and the primary assisted patency rates were 94% at 24 months. The limb salvage rate was 100% at 24 months. The survival rates were 95%, 88%, and 88% at 6, 12, and 24 months, respectively. The primary patency rate for intermittent claudication was significantly higher that that for critical limb ischemia, while no significant difference was found in the assisted primary patency and survival rates between intermittent claudication and critical limb ischemia. CONCLUSION: Hybrid surgical and endovascular therapy, such as aortoiliac and/or superficial femoral artery stenting as an adjunct to common femoral artery endarterectomy, can provide a less invasive yet effective and durable option to patients with multifocal peripheral artery disease.

Fate of varicose veins after great saphenous vein stripping alone.

AIM: The aim of this study was to observe prospectively the clinical sequelae of varicose veins after great saphenous vein (GSV) stripping alone, and to examine whether spontaneous varicose vein regression or disappearance continued for a long period (>3 years). METHODS: Thirty-nine consecutive patients (20 males and 19 females; mean age 57.2), who underwent GSV stripping in Fujita Health University (55 limbs) between November 1, 2002 and December 31, 2003 were enrolled. RESULTS: At four to six weeks, varicose veins spontaneously resolved in 50 limbs (91%), in which subsequent sclerotherapy was not necessary. Five limbs subsequently underwent sclerotherapy for residual varicose veins (5%). At more than three years, 49 limbs (89%) completed the follow-up study. The recurrence after GSV stripping alone occurred in four of the 45 limbs (9%), while those of GSV stripping with sclerotherapy was one of the four limbs (25%). CONCLUSIONS: This study definitely demonstrated that spontaneous varicose vein resolution can continue for more than three years after GSV stripping alone, suggesting that varicectomy can be deferred or avoided in many patients.

Stent placement in the superficial femoral artery for patients on chronic hemodialysis with peripheral artery disease.

AIM: Chronic hemodialysis is associated with a high prevalence of peripheral artery disease (PAD), and patients on chronic hemodialysis with PAD have an increased risk of critical limb ischemia. The present study assessed the hemodynamic and clinical outcomes of stent placement in the superficial femoral artery (SFA) for patients on chronic hemodialysis. METHODS: Between February 2005 to August 2008, 43 consecutive lower limbs in 42 patients with SFA lesions that were successfully treated by primary stent placement were included in this study. Those were divided into a dialysis group (18 limbs) and a nondialysis group (25 limbs). Outcome measures included primary patency, assisted primary patency, limb salvage, and survival. RESULTS: Patients were significantly younger and presented with significantly more symptomatic limb ischemia in the dialysis group compared to the nondialysis group, despite comparable TransAtlantic Inter-Society Consensus (TASC) classification scores of SFA lesions between the two groups. The primary patency, primary assisted patency, limb salvage, and survival rates of the dialysis group were similar to those of the nondialysis group. CONCLUSIONS: Stent placement in the SFA is a feasible, safe, and effective procedure in patients on chronic hemodialysis with PAD, and may be offered as a first-choice therapeutic option for these patients.

Relationship between parameters of air plethysmography and types of superficial venous reflux in patients with primary varicose veins.

AIM: We investigated whether parameters of air plethysmography (APG) were correlated with types of superficial venous reflux as categorized by ascending venography in patients with primary varicose veins. METHODS: Two hundred and eight limbs with primary varicose veins in 135 patients were evaluated by both APG and ascending venography. Venous hemodynamics was assessed with APG. The location of incompetent vein segments was determined based on the results of ascending venography. RESULTS: Seventy-seven limbs had incompetence of the greater saphenous vein (GSV, G group), 36 had incompetence of the lesser saphenous vein (LSV, L group), and 77 had incompetence of the GSV and LSV (GL group). Twenty-five limbs did not have incompetence of the GSV or LSV (N group). The venous filling index (VFI) differed significantly between the N and the G and GL groups, the L group and the G and GL groups, and the G and GL groups. No significant difference was found between the N and L groups. The venous volume, ejection fraction, and residual volume fraction did not differ significantly among all four groups. CONCLUSION: The VFI as measured by APG discriminates well between limbs with incompetence of the GSV and those without incompetence of the GSV or LSV, and between limbs with incompetence of the GSV and those with the LSV in patients with primary varicose veins, suggesting that the hemodynamic severity of superficial venous reflux progresses with involvement from the LSV to the GSV to both saphenous veins.

Laser Doppler skin perfusion pressure in the diagnosis of limb ischemia in patients with diabetes mellitus and/or hemodialysis.

AIM: We investigated whether measurement of skin perfusion pressure (SPP), as measured by laser Doppler, can be used to evaluate the severity of limb ischemia in diabetes mellitus (DM) and/or hemodialysis (HD) patients. METHODS: From April 2004 to March 2005, the ankle brachial pressure index (ABPI) and SPP were evaluated in 44 consecutive lower limbs with peripheral artery disease (PAD) and in 24 patients (21 males and 3 females, aged from 45 to 84 years, with a mean age of 69.3 years) with DM and/or HD. Twelve limbs were categorized as Fontaine stage II, 19 as Fontaine stage III and 24 as Fontaine stage IV. RESULTS: The SPP did not differ significantly between limbs at Fontaine stage II and those at Fontaine stage III, but it was significantly lower in limbs at Fontaine stage IV than in those at Fontaine stage II or III. The ABPI did not differ significantly among limbs at Fontaine stages II, III and IV. CONCLUSION: The SPP, as measured by the laser Doppler technique, may be used as a standard for classifying the severity of PAD in patients with DM and/or HD.

Intermediate-term results of angioscopy-assisted anterior valve sinus plication for primary deep venous insufficiency.

AIM: The intermediate-term efficacy of angioscopy-assisted anterior valve sinus plication for primary deep venous insufficiency was evaluated. METHODS: Twelve limbs in 11 patients had class 4 or higher disease on the SVS/ISCVS classification. Descending venography revealed grade-3 or 4-reflux in all limbs. The limbs were treated with angioscopy-assisted anterior valve sinus plication of the highest valve of the superficial femoral vein. Clinical evaluation and air plethysmography were performed at the final follow-up. RESULTS: The mean follow-up was 38.4 months with a range of 24 to 48 months. Postoperative descending venography revealed significant improvement of the reflux of the superficial femoral vein. At the final follow-up, all patients reported relief of subjective symptoms. The ulcers healed and did not recur in the single limb with class-6 disease, the ulcers did not recur in four class-5 limbs, and there was a distinct clinical improvement with resolution of skin changes in the seven class-4 limbs. The venous filling index measured by air plethysmography was in a normal range in 8 of the 12 limbs. CONCLUSIONS: Angioscopy-assisted anterior valve sinus plication may be a surgical technique that results in intermediate-term clinical and hemodynamic improvement in patients with primary deep venous insufficiency.

Relationship between air-plethysmographic venous function and clinical severity in primary varicose veins.

AIM: The role of air plethysmography (APG) in the diagnosis of chronic venous insufficiency has not been well established. The purpose of this study was to elucidate the relationship between APG parameters and clinical severity in patients with chronic venous insufficiency. METHODS: Two hundred and ninety-four limbs in 154 patients with primary varicose veins were evaluated by APG. Limbs were categorized according to the clinical classification of chronic venous disease suggested by the Ad Hoc Committee on Reporting Standards in Venous Disease of the North American Chapter of the Society for Vascular Surgery and International Society for Cardiovascular Surgery (SVS/ ISCVS). RESULTS: The venous filling index (VFI) was significantly higher in classes 2, 3, 4, and 5+6 than in class 0 or 1, and did not differ among classes 2, 3, 4, 5+6. The ejection fraction did not differ significantly among the 6 classes, and the residual volume fraction was significantly higher in classes 2, 3, 5+6 than in class 0. CONCLUSIONS: APG is a reasonable method for distinguishing the presence or absence of chronic venous insufficiency, but it cannot discriminate the clinical severity. Among APG parameters, the VFI is the most useful diagnostic parameter in the evaluation of chronic venous insufficiency.

Long-term results of treatments for varicose veins due to greater saphenous vein insufficiency.

AIM: The purpose of this study was to determine the long-term recurrence rates of greater saphenous vein (GSV) insufficiency after treatments for primary varicose veins, and to elucidate risk factors for recurrence. METHODS: This was a multicenter retrospective analysis of 376 limbs of 296 patients treated for primary varicose veins due to GSV insufficiency from January 1996 to December 1997. The recurrence-free rates after stripping surgery, saphenofemoral ligation, and sclerotherapy were estimated. The risk factors for the recurrence of primary varicose veins were estimated by multiple regression analysis. RESULTS: The follow-up period was 3.1+/-1.3 (mean+/-SD) years. The recurrence-free rates at 4 years after stripping, saphenofemoral ligation and sclerotherapy were 80.7%, 64.5%, and 51.3%, respectively. The saphenofemoral ligation group and sclerotherapy group had significantly higher recurrence rates than the stripping group (P=0.002, P<0.001, respectively). There was no difference in recurrence rates between the saphenofemoral ligation group and sclerotherapy group (P=0.074). Logistic regression analysis revealed that being female (P<0.029) and treatment without stripping (P<0.001) increased the recurrence rate. CONCLUSIONS: Stripping surgery may be the treatment of first choice for patients with varicose veins due to GSV insufficiency. Patients who have not received stripping surgery and female patients require closer follow-up.

Autologous transplantation of peripheral blood endothelial progenitor cells (CD34+) for therapeutic angiogenesis in patients with critical limb ischemia.

AIM: Intramuscular injection of endothelial progenitor cells (EPCs) may constitute an alternative treatment strategy for patients with critical limb ischemia (CLI). We performed transplantations of EPCs (CD34(+)) extracted from peripheral blood in patients with CLI. The objective of this report is to present the method and early results of intramuscular autologous peripheral blood CD34(+) cell transplantation in the ischemic limb. METHODS: CD34(+) cell transplantation was performed in 2 limbs of 2 patients with CLI, in cases in which it was not possible to perform surgical or percutaneous revascularization. The patients received a granulocyte colony-stimulating factor (G-CSF) prior to the treatment. CD34(+) cells were retrieved from peripheral blood and injected directly into the muscle of the ischemic limb. RESULTS: CD34(+) cells retrieved in patient 1 were 1 x 10(5)/ml and in patient 2 were 1.6 x 10(5)/ml. Transcutaneous oxygen pressure in the foot increased and clinical symptoms improved. Newly visible collateral blood vessels were directly documented by angiography. CONCLUSION: Satisfactory clinical improvement was achieved by using peripheral blood EPCs (CD34(+)) in the patients with CLI. No complications arose following the intramuscular administration of peripheral blood CD34(+) cells.

Lymphoepithelioma-like carcinoma of rectum: possible relation with EBV.

Lymphoepithelioma-like carcinoma (LEC) of the colon is very rare. Here we report a case of LEC originating in the rectum that was closely associated with Epstein-Barr virus (EBV) infection. The histologic and immunohistologic features, namely, poorly differentiated adenocarcinoma with lymphoid stroma, showed this tumor to be an LEC. The EBV genome was detected by PCR using DNA obtained from tumor tissue sections. Immunohistochemically, EBV-determined nuclear antigen 2 was detected in the tumor cells, and in situ hybridization using EBV-encoded small RNAs probe showed positive labeling in some tumor cells together with a few stromal lymphoid cells. There are some reports of LEC cases that originated in the colon; however, a relation with EBV was not demonstrated. We report here a case of LEC of the rectum demonstrating a possible relation with EBV.

Perforated leiomyosarcoma of Meckel's diverticulum: report of a case.

We report herein a case of leiomyosarcoma of Meckel's diverticulum which presented as a rare manifestation of perforation. A previously healthy 63-year-old man was referred to the Tetsujinkai Eniwa hospital following the sudden development of acute abdominal pain. Abdominal computed tomography revealed a solid mass in the pelvic cavity, and an emergency operation was performed under a provisional diagnosis of peritonitis associated with a pelvic tumor. A perforated tumoral mass was found in Meckel's diverticulum. Segmental resection of the ileum, including the tumor-bearing diverticulum, was performed along with regional lymph node dissection. Histologic examination revealed the lesion to be leiomyosarcoma.

[A case of advanced breast cancer receiving combination therapy with 5'-DFUR and MPA with remarkable results].

A 75-year-old woman was admitted to our hospital with advanced breast cancer (T4bN3M0, Stage IIIb). She received chemoendocrine therapy of 5'-DFUR 800 mg/day and MPA 800 mg/ day for 2 months. The main tumor and metastatic lymph nodes were remarkably reduced and became resectable. Histological examination revealed necrotic change of the tumor tissues. This combination therapy proved very useful for advanced breast cancer.

A new synthetic lipid A analog, ONO-4007, stimulates the production of tumor necrosis factor-alpha in tumor tissues, resulting in the rejection of transplanted rat hepatoma cells.

ONO-4007 is a new synthetic lipid A derivative with low endotoxic activities. We have examined the therapeutic effects of ONO-4007 on rat hepatocellular carcinoma KDH-8 cells, rat fibrosarcoma KMT-17 cells and rat mammary adenocarcinoma SST-2 cells in vivo. Multiple systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after tumor implantation of KDH-8 and SST-2 cells, and on days 5, 10 and 15 after tumor implantation of KMT-17 cells. ONO-4007 showed significant therapeutic effects on KDH-8 cells; by the administration of ONO-4007 (2.5 mg/kg) 70% of rats were cured and by the administration of ONO-4007 (5 mg/kg) 50% of rats were cured. Furthermore, the ONO-4007 treatment prolonged the mean survival time of KDH-8-bearing rats. However, ONO-4007 had no effect on KMT-17 and SST-2 cells, and it had no direct effect on the growth of KDH-8 cells in vivo. Albeit the stimulation with ONO-4007 induced mRNA expressions of interleukin (IL)-1alpha, IL-6 and tumor necrosis factor (TNF)-a, those of IL-2, IL-4, IL-10 and interferon (IFN)-gamma were not induced. Using a bioassay, we found that the production of TNF-alpha in the tumor tissues was induced by ONO-4007 in a dose-dependent manner. KDH-8 cells were sensitive to human natural TNF-alpha in vitro. However, KMT-17 and SST-2 cells were resistant against TNF-alpha in vitro. These results suggest that ONO-4007 is therapeutically useful for the treatment of TNF-alpha-sensitive tumors.

A pharmacological pilot study: application of an intermittent schedule of oral uracil and ftorafur (UFT) for hepatocellular carcinoma patients.

Patients with hepatocellular carcinoma (HCC) are highly compromised by failing liver function. To retain good compliance in the administration of uracil and ftorafur (UFT) in such patients, an intermittent schedule for oral administration of UFT was expected to have the same effect as daily continuous use without affecting liver function. A pharmacological pilot study was carried out to confirm the efficacy of this schedule. Sixteen patients with HCC who underwent hepatectomy were given UFT 200 mg b.i.d. for five consecutive days. Blood samples were drawn before the last administration of UFT and at the operation (2 days after the last administration of UFT), and the tumor and adjacent liver tissue were collected. The concentration of ftorafur (FT), 5-fluorouracil (FUra) and uracil (Ura) in serum and liver tissue were measured. Oral administration of UFT 200 mg b.i.d. resulted in a trough level of FT, FUra and Ura in serum of 9.4 micrograms/ml, 13.3 ng/ml and 64.2 ng/ml, respectively. At the operation, FT and FUra in serum had decreased significantly. However, FUra in tissue was still higher than that in serum, in contrast to the results for FT and Ura. There was no difference in the concentration of FUra between the tumors and adjacent liver tissues. No side effect was noted in any of the patients. These results indicated that an intermittent schedule for the administration of oral UFT is not only tolerable but also effective because a sufficient concentration of FUra in the liver tissue is reached and maintained.

Transforming growth factor beta 1 (TGF-beta 1) produced in tumour tissue after chemotherapy acts as a lymphokine-activated killer attractant.

Using an under agarose migration (UAM) assay, we studied lymphokine-activated killer (LAK)-attractant activity in cultured conditioned medium of tumour tissues after chemotherapy as a possible mechanism of enhanced LAK cell accumulation into tumour tissues after chemotherapy. BMT-11 is a fibrosarcoma developed in C57BL/6 mice. The conditioned medium of BMT-11 tumour tissues obtained from mice treated with various anti-cancer drugs had chemotactic activity for LAK cells (LAK-attractant activity). mRNA expression of interleukin (IL)-1 alpha, IL-6, IL-8, interferon (IFN)-gamma, and tumour necrosis factor (TNF)-alpha was observed in untreated tumour tissues, which were not enhanced by cyclophosphamide treatment. mRNA expression of TGF-beta 1 was not detected in untreated tumour tissues by reverse transcription-polymerase chain reaction (RT-PCR), but was detected in tumour tissues treated with cyclophosphamide. Recombinant human TGF-beta 1 showed LAK-attractant activity at a concentration of 0.1 ng ml-1 and 1 ng ml-1, whereas fresh splenocytes were not attracted by TGF-beta 1. Anti-TGF-beta 1 antibody inhibited LAK-attractant activity in the conditioned medium of tumour tissues treated with cyclophosphamide to approximately 35% that of control at 100 micrograms ml-1. These findings indicate that TGF-beta 1 produced in the tumour tissues of mice treated with anti-cancer drugs could be a LAK attractant. By a 4 h 51Cr release assay of natural killer cell-resistant BMT-11 tumour cells, we observed that TGF-beta 1 at a concentration from 0.01 ng ml-1 to 10 ng ml-1 did not inhibit LAK activity in an effector phase. Taken together, we suggest that TGF-beta 1 produced in tumour tissues after chemotherapy participates in gathering transferred LAK cells and contributes to the therapeutic effects of transferred LAK cells.

HLA class I antigens are possible prognostic factors in hepatocellular carcinoma.

Thirty patients who underwent hepatectomy for the treatment of hepatocellular carcinoma (HCC) were examined for expression of HLA class I antigens on HCC cells by flow cytometry. The expression was found significantly lower in cases of stage IV compared with those of stage I or stage II (p<0.05), and in cases of intrahepatic metastases compared with those without metastases (p<0.001). In cases of non-curative hepatectomy, the expression of HLA class I antigens was lower compared with those treated by curative resection. Postoperative cumulative disease-free survival rates were well correlated with the expression rate of HLA class I antigens (p<0.05). Expression of HLA class I antigens on HCC may indicate low malignancy and better prognosis.