Cost-effectiveness of Liple (LipoPGE1) for arteriosclerosis obliterans patients in Japan: an economic evaluation using the EQ-5D instrument.

AIM: This study was conducted to evaluate the health-related quality of life (HRQOL) and cost-effectiveness of LipoPGE(1) when added to the conventional treatment of arteriosclerosis obliterans (ASO) patients. The research design consisted of a before and after-treatment study without comparison groups. We collected data from May 1999 through July 2001 at 473 institutions located throughout Japan. The subjects were ASO patients who experienced pain at rest or had ulcers of the extremities. METHODS: The observation period was a 2-month period that commenced with the start of administration of LipoPGE1. The HRQOL score (utility value) was obtained from the EQ-5D instrument, and the incremental cost-effectiveness ratio was calculated on the basis of quality-adjusted life years (QALYs). RESULTS: The mean utility value for the 2 months after the start of the administration of LipoPGE(1) was 0.672, and it was a significantly higher (P<0.0001) than the 0.616 before administration of LipoPGE(1). The incremental cost-effectiveness ratio was 18,807 US dollar/QALY assuming that drug efficacy persisted for 1 year after the end of LipoPGE1 therapy, and 75,227 dollar/QALY assuming a duration of just 3 months. CONCLUSIONS: We concluded that when LipoPGE1 is added to the conventional treatment of ASO patients, the HRQOL of the patient improves, and it is highly cost-effective.

The effect of Liple on physical and emotional quality of life in the treatment of arteriosclerosis obliterans.

AIM: The purpose of this study was to determine the effect of treatment with prostaglandin E1, Liple, on both the physical and emotional health-related quality of life (QOL) of patients with arteriosclerosis obliterans (ASO). METHODS: Treatment with Liple was evaluated using the before and after treatment results obtained using the SF-36, a QOL questionnaire, and an assessment of symptoms by a physician. The study was designed as a non-randomized before and after treatment study without comparison groups, and the study was conducted from May 1999 to July 2001 at 473 facilities located within Japan targeting patients with ASO. No intervention other than the administration of Liple was performed, and no restrictions were placed on the dose amount or administration interval for Liple. RESULTS: The results suggest that there was a significant improvement in patients' symptoms after treatment with Liple. CONCLUSIONS: Both physical and emotional QOL also improved after administration of Liple compared to baseline, based on the results of the SF-36 and assessment of symptoms by a physician.

[Subjective criteria of chest CT findings for predicting pathological features and postoperative outcomes of small peripheral lung cancer (< or = 2 cm)].

One hundred fifty five patients with completely resected peripheral non-small cell lung cancer, clinically diagnosed 2 cm or less in diameter, are retrospectively reviewed on their preoperative chest CT films, clinico-pathological features, and postoperative outcomes. Pathologic type was classified according to Noguchi's classification. 7% and 8% of all the patients had pathologic N 1 and N 2 diseases, respectively. 19% of all the patients undergone limited resection (segmentectomy or partial resection). Maximum area of the tumor/soft tissue density area of the tumor (M/S ratio) was manually measured by chest CT film. According to the logistic regression analysis, M/S ratio was the only predicting factor of regional lymph node metastasis among factors including pleural indentation, spiculation, and maximum area of the tumor. Univariate analysis showed that maximum area of the tumor, pleural indentation, and M/S ratio were the significant factor for postoperative disease free survival. According to multivariate analysis of postoperative disease free survival with adjustment for operative modality, the result was same as that of univariate analysis. In conclusion, our determined criteria of the chest CT accurately predicted pathological status and postoperative outcome of patients with small peripheral lung cancer. These factors would be useful for stratification factor of prospective clinical study.

Surgically treated primary lung cancer associated with Brugada syndrome: report of a case.

A 71-year-old man with primary lung cancer associated with Brugada syndrome was safely operated on following the placement of an implantable cardioverter defibrillator (ICD). During examinations for Brugada syndrome, a tumor in the apicoposterior segment of the left lung was incidentally detected by chest computed tomography. Following the implantation of an ICD, surgical treatment of the left lung tumor was scheduled. A lung biopsy was thoracoscopically performed and adenocarcinoma was diagnosed based on a frozen section analysis. A left upper lobectomy with lymph node dissection was performed through a standard posterolateral thoracotomy. Ventricular fibrillation, which occurred during the night of the first day following surgery, was successfully managed by the ICD.

The influence of tumour resection on angiostatin levels and tumour growth--an experimental study in tumour-bearing mice.

The phenomenon of primary neoplasms inhibiting the growth of their metastatic lesions is thought to be related to endogenous angiogenesis inhibitors. The aim of this experiment was to investigate the influence of tumour resection on angiostatin levels and tumour growth using a tumour-bearing mouse model. A primary Lewis lung cancer tumour model was established in C57BL/6 mice and these mice were divided into two groups 10 days after the tumour cells were inoculated. In the surgical resection group (S group) the tumour was resected, but in the control group (C group) a sham operation was performed. The level of angiostatin in the sera was analysed 5 days after the operation by western blotting. To observe tumour growth, four Lewis lung cancer models were established in these mice from both the S and C groups. An immunohistochemical analysis of the tumour tissues was conducted to estimate the proliferation and apoptotic rates of the tumour cells, as well as the amount of neoangiogenesis in the tumours. Angiostatin was observed in the tumour-bearing mice, but disappeared within 5 days after the tumour had been resected. Increased tumour growth was observed in all of the tumour models in the S group compared with the C group and the differences were significant. A significantly higher intratumour vessel density and proliferation cell index, but a significantly lower apoptotic index were also found in the S group compared with the C group. These findings demonstrated that angiostatin was generated directly from the tumour tissue. Furthermore, tumour resection accelerates the growth of other tumours and this is probably related to multiple factors including increased neoangiogenesis, increased tumour cell proliferation, and decreased apoptosis.

Digitonin enhances the antitumor effect of cisplatin during isolated lung perfusion.

BACKGROUND: The antitumor effect of isolated lung perfusion with cisplatin was limited because the intracellular platinum concentration did not increase sufficiently. To solve this problem, digitonin, a detergent, was chosen to increase cell permeability and enhance intracellular uptake and antitumor effect. This study was designed to investigate toxicity, pharmacokinetics, and efficacy of isolated lung perfusion with the combined use of digitonin and cisplatin in Fischer 344 rats. METHODS: Systemic and local toxicities of isolated lung perfusion treatment were evaluated on the basis of body weight change, survival rate, and histologic findings. The maximal tolerated dose of digitonin was determined by assessing survival on day 21 after contralateral pneumonectomy, body weight change, and histologic findings. Pharmacokinetics were observed in a solitary lung tumor nodule model by measuring platinum concentration in tumor and normal lung tissue. The antitumor effect was evaluated by the number of tumor nodules in the left lung 21 days after isolated lung perfusion. Isolated lung perfusion was performed 7 days after 1.0 x 10(6) methylcholanthrene sarcoma cells were injected into the external jugular vein. RESULTS: The maximal tolerated dose of digitonin was 20 micromol/L. Platinum concentration of tumor nodules in the digitonin-cisplatin-treated rats was 20% higher than in the cisplatin-only group (5.48 +/- 0.64 microg/g tissue versus 4.50 +/- 1.09 microg/g tissue; p = 0.067). The number of pulmonary nodules decreased significantly by digitonin use (1.3 +/- 1.5 versus 9.7 +/- 2; p < 0.0001). CONCLUSIONS: Isolated lung perfusion with digitonin and cisplatin in combination was performed safely and enhanced the antitumor effect. These drugs in combination show promise for enhancing the effect of clinical isolated lung perfusion.

Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results.

A new therapy for severe ischemic heart disease has been developed; therapeutic angiogenesis induced by the local implantation of autologous bone marrow cells (BMC). After confirming that no detrimental changes were induced by this treatment in a canine heart model, a clinical trial was commenced in 1999. Thus far, 5 patients have been given this new treatment concomitant with coronary artery bypass grafting and all have been followed up for at least 1 year. Autologous BMC were implanted into the ungraftable area and postoperative cardiac scintigraphy showed specific improvement in coronary perfusion in 3 of the 5 patients. Postoperative chest radiography, electrocardiography, echocardiography and blood tests did not reveal any detrimental changes. In conclusion, this new therapy appears to be safe and could provide a treatment option for patients with otherwise untreatable ischemic heart disease.

[Delayed traumatic diaphragmatic hernia diagnosed by magnetic resonance imaging and direct coronal computed tomography: report of a case].

A 59-year-old woman was admitted to our hospital with abdominal symptoms. A diagnosis of delayed traumatic diaphragmatic hernia was made from the findings of a plain X-ray film, magnetic resonance imaging (MRI) and computed tomography (CT). We successfully performed repair of the diaphragm via abdominal approach. Thus, MRI and direct coronal CT can be very useful for establishing a diagnosis of traumatic diaphragmatic hernia.

The outcome of volume reduction surgery according to the underlying type of emphysema.

Lung volume reduction surgery (VRS) is widely performed to improve symptoms in patients with severe pulmonary emphysema; however, it remains unclear whether or not the underlying type of emphysema affects the surgical results. A total of 58 patients with advanced symptomatic emphysema underwent thoracoscopic VRS of emphysematous lung tissue. The resected lung tissue was examined microscopically, and the patients were classified into two groups according to the predominant pathological findings, as having either centrilobular-type or panacinar-type emphysema. A predominant pathological type was identified in only 34 patients (59%), 19 of whom had centrilobular-type emphysema and 15, panacinar-type emphysema. Patients with predominately panacinar emphysema had more compromised total lung capacity and residual volume than those with centrilobular emphysema. Significant improvements in forced expiratory volume in 1 s were evident 3 months after surgery in the group with centrilobular emphysema (+515 +/- 141ml) compared with that in the group with panacinar-type emphysema (+109 +/- 40ml, P = 0.03). The results of lung VRS were found to depend on the underlying type of emphysema, as the benefits of surgery for panacinar emphysema were less marked than those for centrilobular emphysema.

[A coronary artery bypass grafting using cardiopulmonary bypass with intraaortic balloon pumping in patient with low cardiac function combined with cerebral vascular disease].

We reported a 55-year-old man, who had coronary and cerebral vascular disease. Cerebral angiography showed occlusion at left internal carotid artery (ICA) and 50% stenosis at right ICA C4 portion. But acetazolamide reactivity was kept symmetrically. Coronary angiography showed severe three vessel disease, and left ventriculography showed diffuse severe hypokinesis/akinesis, and EF was below 30%. The patient underwent coronary artery bypass grafting using cardiopulmonary bypass with intraaortic balloon pumping to keep intraoperative blood pressure high. After the operation he recovered uneventfully without neurological complication.

[Recurrent angina due to high grade re-stenosis of the left subclavian artery after coronary artery bypass grafting in a patient on hemodialysis for chronic renal failure: report of a case].

A 49-year-old woman on hemodialysis for chronic renal failure was admitted to our hospital with chest pain. She had undergone quadruple coronary artery bypass grafting (CABG) including a left internal thoracic to left anterior descending coronary artery anastomosis 9 months earlier. The blood flow through the left internal thoracic artery had decreased due to high grade stenosis at the proximal portion of the left subclavian artery, and recurrent angina had developed. She was treated by the placement of Palmaz biliary stents in the left subclavian artery, but re-stenosis occurred after 9 months, causing recurrent angina again. There fore, an operation was proposed and bypass grafting from the descending aorta to the left subclavian artery was successfully performed, resulting in complete resolution of her recurrent angina. This case serves to reinforce that patients on dialysis must be carefully followed up after CABG.

The induction of angiogenesis by the implantation of autologous bone marrow cells: a novel and simple therapeutic method.

BACKGROUND: Bone marrow contains many kinds of primitive cells that could differentiate to endothelial cells and secrete several growth factors. In the current study, we attempted to induce therapeutic angiogenesis by implanting autologous bone marrow cells (BMCs) and using a rat ischemic hind limb model. METHODS: BMCs were prepared by removing red blood cells. A rat ischemic hind limb model was made by the ligation of the left femoral artery and its branches. BMCs were injected into 7 points of the ischemic muscles. To assess angiogenesis, a microangiogram, laser Doppler, and histologic evaluation were performed after the surgical procedure. RESULTS: A microangiogram and histologic evaluation showed that angiogenesis was significantly induced in the ischemic hind limb by the implantation of BMCs. Laser Doppler imaging analysis showed that blood flow was significantly increased after implantation of BMCs. Some implanted BMCs were stained positively with CD31 and vascular endothelial-cadherin (VE-cadherin), which might have been incorporated into the vasculature. The condition of ischemia caused an elevation in the level of basic fibroblast growth factor in the ischemic muscle and also in interleukin-1beta derived from the implanted BMCs, which might contribute to angiogenesis. CONCLUSION: These findings indicate that autologous bone marrow implantation may be a novel and simple method for inducing therapeutic angiogenesis.

Increasing drug concentration in a rat lung tumor model by combining isolated lung perfusion with hypertensive chemotherapy.

Isolated left lung perfusion (ILP) with cisplatin was performed in Fisher 344 rats. Before perfusion, bolus injection with endothelin was given via the pulmonary artery. The vasoconstrictive potency was estimated by monitoring the perfusion pressure. The toxicity was estimated by tracking body weight change, survival rate after right pneumonectomy, arterial blood gas analysis and histological findings. To observe the pharmacokinetic changes, a solitary Methylcholanthrene-induced sarcoma model was established in a rat lung and the total platinum concentration in perfused lung and tumor tissues was measured. Perfusion pressure was increased significantly in a dose-dependent manner. Pulmonary toxicity from ILP with cisplatin was limited by the use of endothelin. Significantly higher levels of total platinum were obtained in tumors but not in normal lung tissues by endothelin injection before ILP than by ILP alone. The combination of ILP and hypertensive chemotherapy should be one of the available treatments for unresectable pulmonary carcinoma.

Stress caused by minimally invasive cardiac surgery versus conventional cardiac surgery: incidence of systemic inflammatory response syndrome.

The present study was conducted to evaluate the degree of stress in patients induced by minimally invasive cardiac surgery (MICS) in comparison with that caused by conventional cardiac surgery. We did this by assessing the incidence of systemic inflammatory response syndrome (SIRS). A total of 48 adult patients who underwent surgery for single valve disease were included in this study, 27 of whom underwent conventional surgery and 21 MICS. We evaluated the stress inflicted on the patients in these two groups by analyzing the duration and degree of SIRS and the level of C-reactive protein (CRP). SIRS was assessed by measuring body temperature, heart rate, respiratory rate, and white blood cell counts. There were no significant differences in the operating times, perfusion times, or aorta clamp times between the two groups; and the mean volume of blood transfusion did not differ significantly either. There was no significant difference in the incidence of SIRS or the mean duration of SIRS between the two groups. The CRP levels did not differ significantly between the two groups. Thus although MICS is superior to conventional cardiac surgery in that only a small skin incision is required, the stress experienced by the patient may be the same as that experienced by the patient undergoing conventional cardiac surgery.

Enhanced expression of matrix metalloproteinase-9 in abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAAs) are characterized by structural alterations of the aortic wall resulting from degradation of collagen and elastin. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, show strong elastinolytic activity. We examined the levels of mRNA for MMP-2, MMP-9, membrane type (MT)-MMP-1, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in AAAs (n = 8), atherosclerotic occlusive diseases (AOD) (n = 8), and normal subjects (n = 8) using the reverse transcription-polymerase chain reaction (RT-PCR). We also analyzed the gelatinolytic activity of these metalloproteinases using gelatin zymography. The levels of MMP-2 and MMP-9 mRNA were increased in the AAA group compared with those in the AOD group and normal subjects. The levels for TIMP-1 and TIMP-2 mRNA in the AAA group were also higher than those in the AOD and normal groups. Only in the case of MT-MMP-1 was the difference between AAA and AOD not statistically significant. By gelatin zymography with the same samples used for RT-PCR, gelatinolytic activity of MMP-9 was elevated in all AAA tissues. The 62-kDa form of MMP-2 was elevated in both the AAA and AOD groups and did not differ significantly between them. Linear regression analysis demonstrated a significant positive correlation between mRNA levels of MMPs and those of TIMPs. These observations suggest that aneurysm formation in patients with atherosclerosis is related to the degree of MMP-9 expression.

[Assessment of stage IIB lung cancer from the pathological factors].

In our experience, the prognosis of patients with pathological T3N0M0 lung cancer is generally poor, the 5-year survival rate being almost the same as that of patients with stage IIIA disease. Thus, we assessed patients with stage IIB disease by examining the pathological factors, lymphatic invasion, vessel invasion, histological type, differentiation, tumor size, and node dissection. Lymphatic invasion was found to be positive in 20 of 21 cases, patients with T3N0M0 lung cancer, and all of those with positive vessel invasion had a significantly poor prognosis. This indicates that positive lymphatic and vessel invasion could be a prognostic factor predicting a poor outcome. Patients with T3N0M0 lung cancer that are found to have this poor prognostic factor may not be diagnosed as having stage IIB disease.

DNA amplification and chromosomal translocations are accompanied by chromosomal instability: analysis of seven human colon cancer cell lines by comparative genomic hybridization and spectral karyotyping.

Genetic instability in human cancers is classified as chromosomal instability (CIN) or microsatellite instability (MIN). DNA amplification and translocations are observed frequently in various cancers. We used comparative genomic hybridization (CGH) and spectral karyotyping (SKY) to study seven human colon cancer cell lines and investigate the relations among genetic instability, DNA amplification, and chromosomal translocations. DNA amplification was found in five cell lines (COLO320DM, COLO201, WiDr, CoCM-1, and CACO-2), and all were aneuploid. In these five cell lines, segments of chromosomes were translocated to other chromosomes. In contrast, cell lines with MIN, DLD-1, and LoVo did not show DNA amplification. The LoVo cells with MIN were considered near diploid and contained translocations. These findings suggest that DNA amplification and chromosomal translocations are accompanied by CIN.

Congenital cystic adenomatoid malformation of the lung with an esophageal cyst: report of a case.

The authors report the case of a 7-month-old girl found to have both congenital cystic adenomatoid malformation of the lung (CCAM) and esophageal cyst. She suffered repeated episodes of pneumonia and exhibited signs of respiratory distress on admission to our hospital. Chest radiography and magnetic resonance imaging (MRI) showed 2 different kinds of cystic lesions. Resection of the lower lobe of the right lung and excision of the posterior mediastinal cyst were performed. Histologic examination showed Stocker type I CCAM and esophageal cyst. Coexistence of both CCAM and esophageal cyst is extremely rare. The authors speculate that the pathologies of this case originated from a regional disturbance of common embryologic origin during 2 different phases of lung-bud foregut malformations.

Fatal diffuse atheromatous embolization following endovascular grafting for an abdominal aortic aneurysm: report of a case.

A 78-year-old woman with an abdominal aortic aneurysm, 57 mm in diameter, was admitted to our hospital for endovascular grafting. Preoperative computed tomography and angiography showed friable mural thrombus in the suprarenal and infrarenal aorta, and a diagnosis of shaggy aorta was made. Postoperatively, the patient suffered cerebral infarction, and disseminated intravascular coagulopathy with multiple organ failure developed, resulting in early death on the third day after surgery. An autopsy revealed diffuse atheromatous embolization into the celiac, superior mesenteric, bilateral renal, bilateral hypogastric (trash buttock), and peripheral arteries. This case report serves to demonstrate that an abdominal aortic aneurysm with a shaggy aorta in the proximal neck is a contraindication to endovascular grafting, and that predicting the possibility of diffuse atheromatous embolization by detecting a shaggy aorta is the best way to prevent this catastrophic complication.

Effects of cardioplegic arrest and reperfusion on rabbit cardiac ryanodine receptors.

Calcium overload is considered to be a primary contributor to ischemia-reperfusion injury. Cardiac sarcoplasmic reticulum (SR), the main regulator of intracellular Ca2+ concentration under normal conditions, is a target for ischemic myocardial injury. The ryanodine receptor (RyR) is the SR Ca2+ release channel. Previous reports have shown that a reduction in RyR activity during global myocardial ischemia correlates with concomitant myocardial dysfunction. Crystalloid cardioplegia, a technique for myocardial protection during heart operations, reduces Ca2+ accumulation during global ischemia. Hence, the effects of cardioplegia on RyR in isolated rabbit hearts was investigated. The study also compared [3H] ryanodine binding before ischemia (control group), after 30 min of ischemia (either global ischemia (GI group) or cardioplegic arrest (CA group)), and after 20 min of reperfusion. The GI group, but not the CA group, showed a significant reduction in the maximum number of binding sites (Bmax) for RyR compared with the control group (Control vs GI group: after ischemia, 1.33+/-0.27 vs 0.83+/-0.12 pmol/mg protein, p<0.05; after reperfusion, 1.33+/-0.27 vs 0.80+/-0.08 pmol/mg protein; p<0.05). CA group: after ischemia, 1.22+/-0.20 pmol/mg protein; after reperfusion, 1.15+/-0.28 pmol/mg protein). The affinity (Kd) values for [3H] ryanodine binding were not different among the 3 groups at any point. The preservation of RyR numbers during cardioplegia correlated with the concomitant preservation of cardiac functions. The results indicate that number of functional RyR was much better preserved during cardioplegia than during global ischemia. It is postulated that cardioplegia-induced protection of cardiac RyR may result in the protection of SR function during ischemia-reperfusion.