Pharmacoeconomic analysis of hypertriglyceridemia treatment at medical institutions.

It has been demonstrated that HMG-CoA reductase inhibitors effectively decrease low density lipoprotein and total cholesterol levels, and presently, HMG-CoA reductase inhibitors are most widely used in hyperlipidemia treatment. On the other hand, it has been demonstrated that fibrate agents decrease triglyceride levels more effectively compared to HMG-CoA reductase inhibitors. A cost-effectiveness study comparing fenofibrate, a fibrate agent, and atorvastatin was therefore conducted in hypertriglyceridemia patients. Referring to an analytical method published in the UK, the percentage of patients received fenofibrate and atorvastatin treatments at each dose level was estimated from prescription records at the medical institutions investigated. Changes in the total cholesterol and triglyceride values after the drug administration were investigated examining published reports. Based on the said data, the treatment effectiveness was measured by the percentage of patients who achieved the target lipid levels. The treatment costs were estimated based on the number of patients investigated and reimbursement prices of the drugs. The incremental cost-effectiveness ratio of fenofibrate in decreasing triglyceride levels was dominant over atorvastatin. The incremental cost-effectiveness ratio of atorvastatin in decreasing low density lipoprotein cholesterol levels was JPY 69911. This provides a model for choosing drug treatments that reflects clinical practices at medical institutions by substituting figures for individual cases.

A randomized trial comparing radical prostatectomy plus endocrine therapy versus external beam radiotherapy plus endocrine therapy for locally advanced prostate cancer: results at median follow-up of 102 months.

BACKGROUND: To investigate the optimal treatment of locally advanced prostate cancer, a prospective randomized trial was conducted to compare radical prostatectomy plus endocrine therapy versus external beam radiotherapy plus endocrine therapy. METHODS: One hundred patients with T2b-3N0M0 prostate cancer were enrolled and 95 were evaluated. Of 95 cases, 46 underwent radical prostatectomy with pelvic lymph node dissection and 49 were treated with external beam radiation by linear accelerator with 40-50 Gy to the whole pelvis and 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiotherapy and continued thereafter. The long-term outcome and morbidity were examined. RESULTS: Median follow-up period was 102 months. At 10 years overall survival rates in the surgery group were better than the radiation group (76.2% versus 71.1% for biochemical progression-free rates; P=0.25, 83.5% versus 66.1% for clinical progression-free rates; P=0.14, 85.7% versus 77.1% for cause-specific survival rates; P=0.06, and 67.9% versus 60.9% for overall survival rates; P=0.30), although none of them reached statistical significance. Erectile dysfunction was recognized in almost all patients as a result of continuous endocrine therapy. Incontinence requiring more than one pad per day was observed more frequently in the surgery group than the radiation group (P<0.01). CONCLUSIONS: For the treatment of patients with locally advanced prostate cancer, when combined with endocrine therapy, either radical prostatectomy or external beam radiotherapy demonstrated favorable long-term outcomes. The radiation dose of 60-70 Gy might not be enough for the local treatment of locally advanced prostate cancer.

Long-term outcome from a study on the prevention of postoperative recurrence in patients with renal cell carcinoma: could PBL be a predictor of postoperative recurrence in patients postoperatively treated with IFN-gamma?

This study examined the outcome of postoperative recurrence therapy on renal cell carcinoma (RCC) prevention involving treatment with single doses of interferon-gamma (IFN-gamma). From 1990-2000, 37 patients with no distant metastasis at the time they underwent a nephrectomy were enrolled in this investigation. Subcutaneous IFN-gamma was administered once a week. Total and differential white blood cells were counted before the pre-administration of IFN-gamma and then monthly thereafter for all patients. Blood lymphocyte subsets were analyzed phenotypically by direct immunofluorescence. Disease-free survival rates (DFSR) at 5 and 10 years were 81.7% and 75.9%, respectively. To clarify the effects of preoperative peripheral blood lymphocyte (PBL) and NK activity on DFSR, we categorized the patients into two groups according to the median number of PBL before the administration of IFN-gamma. Except for CD11b, PBL level had no effect on DFSR. Multiple logistic regression analysis showed that CD11b levels greater than 16.5% were associated with 25.35 odds ratio increase in the risk of postoperative recurrence. A multivariate analysis found that CD11b may be an independent factor for postoperative recurrence. In terms of preventing postoperative recurrence, our results showed that an elevated CD11b level may indicate patients who can benefit from further combination therapy.

Strong significant correlation between MMP-9 and systemic symptoms in patients with localized renal cell carcinoma.

OBJECTIVES: To identify a relationship between clinical symptoms and matrix metalloproteinase (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, and membrane type MMP-1. METHODS: Tumor samples from 232 patients with renal cell carcinoma with no distant metastasis were immunohistochemically stained for MMP-2 and MMP-9, TIMP-1 and TIMP-2, and membrane type MMP-1. The immunoreactivity of these factors was analyzed by semiquantitative multivariate analysis for correlation with clinical symptoms. RESULTS: Patard's criteria were used to classify symptoms at initial tumor clinical presentation, with three groups defined: S1, S2, and S3. The cancer-specific 5-year survival rate was 88.7%, 74.7%, and 67.6% for S1 (145 patients), S2 (69 patients), and S3 (18 patients), respectively (P = 0.0015). Multiple logistic regression analysis of preference was used to determine whether differences in the contribution of the symptoms were statistically significant. A maximal tumor diameter of 40 mm or greater and positive venous invasion were associated with a 262% and 281% increase in the odds of local symptoms, respectively. MMP-9 positive cases were associated with a 2979% increase in the odds of systemic symptoms with significance. CONCLUSIONS: This study found a strong significant correlation between the histopathologic expression of MMP-9 and the systemic symptoms of renal cell carcinoma. We propose the histopathologic measurement of MMP-9 as a useful tool for assessing the prognosis of patients with renal cell carcinoma with systemic symptoms.

Fluorescence in situ hybridization analysis of c-myc amplification in stage TNM prostate cancer in Japanese patients.

OBJECTIVE: Genetic aberration such as the amplification of c-myc has been commonly found in advanced prostate cancer. The aim of this study was to elucidate chromosome 8 alteration, including a gain and amplification of 8q24 (c-myc gene), related to the progression and survival in advanced (Stage C) prostate cancer. MATERIALS AND METHODS: We used dual-probe fluorescence in situ hybridization with a centromere-specific probe for chromosome 8 (8cen), and with a region-specific probe for c-myc (8q24) to evaluate genetic changes in tumor samples from 50 patients who had undergone radical retropubic prostatectomy from 1986 to 2001. RESULTS: We classified the 8cen and c-myc copy numbers as normal, gain and amplification. The carcinoma foci with extra copies of c-myc, which was defined in 35 cases (70%), were divided into two groups: (a) a simple gain of the whole chromosome 8 (no increase in the c-myc copy number relative to the chromosome 8 centromere), which was identified in 15 cases (30%); and (b) a substantial amplification of c-myc (additional increases [AI] in the c-myc copy number relative to the chromosome 8 centromere), which was detected in 20 cases (40%). AI-c-myc was strongly associated with higher histopathological grades and Gleason's scores (P = 0.0330, 0.0190, respectively). Patients with the AI-c-myc had earlier disease progression (P = 0.0029) and earlier cancer death (P = 0.0087) than did patients with normal patterns. CONCLUSION: Identification of an AI-c-myc may serve as a potential marker of prostate cancer progression.

Prostate-specific antigen failure within 2 years of radical prostatectomy predicts overall survival.

OBJECTIVE: This study attempts to determine whether prostate-specific antigen (PSA) failure following radical retropubic prostatectomy (RRP) affects patients' long-term overall survival. METHODS: This study examined 155 men diagnosed as clinical stages T1b-T3a who received RRP as primary therapy. To evaluate whether PSA failure following RRP affects overall survival, the patients were grouped into those who experienced PSA failure within 2 years and those who did not. Clinical failure-free survival, prostate cancer-specific survival and overall survival were used as endpoints. Comparisons of survival curves were performed using the log-rank test. Logistic regression analysis was performed to determine the variable most predictive of PSA failure within 2 years of surgery. RESULTS: At 10 years, the PSA failure-free survival rate, clinical failure-free survival rate, prostate cancer specific survival rate and overall survival rate of the 155 patients were 40.1%, 83.1%, 94.9% and 84.2%, respectively. The overall survival curve for patients with PSA failure within 2 years of surgery was significantly lower than for patients with no PSA failure within 2 years of surgery (P = 0.042). The multivariate logistic regression analysis demonstrated that PSA greater than 20 ng/mL and poor differentiation of the tumor were significant independent predictors of PSA failure within 2 years of surgery. CONCLUSION: These results imply that prospective studies should be conducted to detect patients at high risk for PSA recurrence in whom metastasis may occur early and to investigate postoperative treatments for these high-risk patients to improve overall survival.

Usefulness of contrast-enhanced ultrasound for the diagnosis of recurrent renal cell carcinoma in contralateral kidney.

We studied contrast-enhanced ultrasound (CEU) for recurrence of renal cell carcinoma (RCC) at the contralateral kidney during postoperative follow up of localized renal cell carcinoma. CEU successfully detected all recurring cases, despite the fact that 5/6 cases were observed using conventional ultrasound; the remaining one case was not detected using conventional ultrasound. CEU using Levovisto successfully revealed renal tumors as RCC. Lesions were diagnosed as cystic renal tumors by Bosniac classification, and pathological findings demonstrated RCC, in accordance with the prior tumor.

Immunohistochemical and ultrastructural features of neuroendocrine differentiated carcinomas of the prostate: an immunoelectron microscopic study.

The purpose of this study was to further define the immunohistochemical and ultrastructural characteristics of neuroendocrine (NE) differentiated prostatic carcinomas. Seventy-seven specimens were obtained from prostatic carcinoma tumors during prostatectomy, transurethral resection of prostate or biopsy in 77 prostate cancer patients, and analyzed by immunohistochemical staining for chromogranin A (CgA). Nine of these tumors were also studied by elctron microscopy and 4 were examined by pre-embedding immunoelectron microscopy. CgA-stained cells were detected in 36 tumors (47%). Clinically advanced tumors or tumors with higher histological grades were associated with increased NE differentiation. Three of the tumors studied by electron microscopy contained cells showing unequivocal NE differentiation revealed by the presence of neurosecretory granules, while the poorly NE-differentiated malignant cells contained pleomorphic granules, which were lysosomal-like rather than NE-type granules. Immunoelectron microscopy demonstrated the presence of CgA immunoreactivity on the pleomorphic granules in the poorly differentiated malignant glands. This study suggests that NE-differentiated malignant cells in prostate cancer tissues may induce aggressive behavior in adjacent proliferating neoplastic cells via a paracrine mechanism.

Immunosuppressive acidic protein detects high nuclear grade localized renal cell carcinoma.

OBJECTIVES: To identify a potentially useful preoperative predictor of high nuclear grade renal cell carcinoma (RCC). METHODS: Our investigation consisted of 181 patients with histologically confirmed clear cell RCC. The positive predictive value, sensitivity, and specificity for detecting nuclear grade RCC were calculated individually for the largest tumor diameter. Hemoglobin, alkaline phosphatase, C-reactive protein, ferritin, and immunosuppressive acidic protein (IAP) levels were also determined in all patients preoperatively. RESULTS: The distribution of patients by nuclear grade was 74 patients (41%) with grade 1, 75 (41%) with grade 2, and 32 (18%) with grades 3 and 4. With respect to sensitivity, tumor diameter detected 28 (87.5%) of 32 high nuclear grade RCC specimens, and hemoglobin, C-reactive protein, alkaline phosphatase, ferritin, and IAP detected 10 (31.2%), 25 (78.1%), 8 (25.0%), 16 (50%), and 27 (84.3%) of 32, respectively. Multiple logistic regression analysis showed that a higher than normal C-reactive protein and IAP was associated with a 252% and 405% increase in the odds of a high nuclear grade, respectively. In the Stage T1 cases, elevated IAP was also associated with a 989% increase in the odds of a high nuclear grade. CONCLUSIONS: IAP level may be a useful predictor for detecting high nuclear grade localized RCC preoperatively.

Retroperitoneoscopic adrenalectomy for adrenal tumors via a single large port.

BACKGROUND AND PURPOSE: Laparoscopic adrenalectomy is generally performed with carbon dioxide insufflation of the cavity and requires multiple trocars. This study reports the outcomes of retroperitoneoscopic adrenalectomy (RA) for adrenal tumors via a single port using a large cylinder without carbon dioxide insufflation. PATIENTS AND METHODS: Fifty-four patients with adrenal tumors were treated using RA via a single large port. The average tumor size was 2.6 cm. For surgery, patients were placed in the lateral decubitus position with slight flexion, and a 4.5-cm skin incision was performed below the 12th rib in the midaxillary line. The retroperitoneal space was dissected using index fingers and a balloon dilator. A rectoscope tube with a 4-cm diameter was inserted, and the adrenal glands were removed endoscopically via the single large port without carbon dioxide insufflation. RESULTS: This procedure was completed in 53 patients (98.1%). The average duration of surgery was 203 minutes, and the mean estimated blood loss was 252 mL. Four patients (7.4%) required blood transfusion. Postoperative major complications, including fulminant hepatitis and pulmonary thrombosis, were observed in two patients (3.7%), and the patient with hepatic disease died on the 14th postoperative day. The mortality rate after surgery thus was 1.9%. However, no local tumor recurrence or hormonal relapse has occurred at a median follow-up of 34 months. CONCLUSIONS: This procedure appears to be effective and relatively minimally invasive. However, it is limited by the narrow working space and restriction of the manipulation of instruments.

Prospective study of estramustine phosphate for hormone refractory prostate cancer patients following androgen deprivation therapy.

INTRODUCTION: Estramustine phosphate (EMP) in combination with other cytotoxic agents has been widely used in clinical trials as an anti-tumor agent for the treatment of hormone-refractory prostate cancer (HRPC). However, few prospective studies have considered the efficacy of EMP monotherapy for HRPC patients following androgen-deprivation therapy (ADT), given the availability of methods to measure prostate-specific antigen (PSA) levels in the serum. We therefore initiated a prospective study to determine whether EMP is efficient for HRPC following ADT using changes in PSA levels as the major endpoint. METHODS: After a diagnosis of anti-androgen withdrawal syndrome had been excluded, 34 patients with HRPC who showed an elevated serum PSA level in 3 or more sequential tests following ADT were treated orally with 560 mg/day of EMP. The clinical stage and the median PSA value for inclusion in the study were D2 and 25.9 (range 6.5-540.8) ng/ml, respectively. Treatment was continued until evidence of disease progression reappeared or until severe adverse effects appeared. RESULTS: Of the 34 patients enrolled, 29 were evaluated, while the other 5 (15%) patients were discontinued due to severe gastrointestinal side effects. Seven of the 29 patients (24%) showed a decrease of 50% or greater in serum PSA levels from the initially elevated values, with the median duration of PSA response being 8.0 (range 2.2-18.8) months. Baseline PSA, hemoglobin, alkaline phosphatase, lactate dehydrogenase, performance status, and length of time of initial hormonal treatment did not correlate with the PSA response. With a median follow-up time of 20.0 (range 3.2-45.6) months, the cancer-specific survival rate at 2 years was 83% in the PSA responders and 44% in the non-responders. The PSA response was correlated with cancer-specific survival (p = 0.029). CONCLUSIONS: Following ADT one quarter of HRPC patients responded to EMP, with more than 50% of patients showing a decrease in PSA levels and an enhanced survival rate.

Long-term survival following radical prostatectomy in Japanese men with clinically localized prostate cancer: a single institutional study.

BACKGROUND: We evaluated the outcome of radical prostatectomy to provide information about long-term survival following this procedure. METHODS: One hundred and twenty-three otherwise healthy Japanese patients with clinically localized tumors underwent radical prostatectomy. Treatment outcomes were measured in terms of clinical progression-free survival, prostate cancer-specific survival and overall survival. Overall survival was compared with expected survival of age-matched Japanese men. RESULTS: For these 123 patients, clinical progression-free survival and prostate cancer-specific survival at 10 years were 72.5% and 86.4%, respectively. Results of Cox multivariate analysis showed that only pathological stage (P = 0.047) and tumor grade (P = 0.009) were independent predictors of clinical progression. Only tumor grade was a statistically significant independent predictor (P = 0.048) in terms of prostate cancer death. Both the 10 and 15-year overall survival rates for these 123 patients were 58.6%, whereas the expected survival of age-matched Japanese men was 65.0% at the 10-year follow up, and 43.8% at the 15-year follow up. CONCLUSIONS: The long-term overall survival in this surgically treated group is comparable to the expected survival rate of age-matched Japanese men. These results might be useful in counselling patients with clinically localized prostate cancer.

The impact of angiogenesis on the prognosis of advanced renal cell carcinomas.

We studied the relationship between angiogenic factors and clinical responses in advanced renal cell carcinomas (RCCs) and evaluated the angiogenic factors to clarify the potential impact of these factors on the cancer-specific survival. From January 1990 to December 2000, 148 patients underwent a nephrectomy for RCCs at our institution. Of the 32 patients who had distant metastasis, 17 met the histopathologic analysis requirements for an immuno-histochemical investigation. Fifteen of them were administered interferon-gamma and the remaining two patients were added to interferon-alpha and eight of seventeen patients also underwent radiation therapy. Both thymidine phosphorylase (TP) and Factor VIII immunostaining were performed. The overall survival rates at 1, 5 and 10 years were 82.4%, 30% and 30%, respectively. Three of these patients were diagnosed with lung metastasis and a complete response was seen in two, while a partial response was observed in one. In addition another patient who was diagnosed with bone metastasis also showed a partial response (group A). The remaining 13 patients showed progressive disease (group B). Group A had a higher TP-positive ratio (TP-PR) than that of group B. A multivariate analysis of the clinicopathologic data showed that a positive mean vascular area (PMVA) could be an independent factor regarding the potential impact of these factors on a long survival in advanced RCCS. PMVA was thus found to be an independent factor regarding the prognosis with advanced RCCs.

Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy.

OBJECTIVE: To evaluate the relationship between neuroendocrine differentiation (NED) status and hormone refractory prostate cancer (HRPC) following hormone therapy based on immunohistochemical study. METHODS: Seventy-two prostate cancer specimens obtained at radical prostatectomy and 21 prostate cancer autopsy specimens from patients who died from HRPC after androgen deprivation therapy were examined for NED status using an antibody against chromogranin A. These specimens were classified into 3 arms: 38 radical prostatectomy specimens from patients with no neoadjuvant hormone therapy (Group 1); 34 from patients with neoadjuvant hormone therapy for 3 to 6 months (Group 2); and 21 autopsy specimens from patients with HRPC following androgen deprivation therapy for more than 1 year (Group 3). Staining of prostatic carcinoma was scored as: 0 = no staining; 1 = staining cells <10%; 2 = staining cells 10-20%; and 3 = staining cells >20%. Differences in scores among the groups were compared using the Kruskal-Wallis rank test. Multivariate analysis using a logistic regression model was performed to examine whether NED status was associated with pathological stage (pT), grade and group. RESULTS: Forty-nine (53%) tumors had CgA stained cells. NED status increased with longer duration of hormone therapy (p<0.0001). The mean staining score (and standard deviation) was 0.4+/-0.7 in Group 1, 0.7+/-0.7 in Group 2, and 1.4+/-1.1 in Group 3, respectively. By multivariate analysis Group 3 had a relative risk of 5.46 (95%CI 1.28-23.29) for NED compared to the other groups. But other variables were not related to NED. HRPC following Long-term hormonal therapy was the only independent predictor of NED. CONCLUSIONS: The results of this study demonstrated that NED status was significantly increased in patients with HRPC following long-term androgen deprivation therapy, but it could not be discriminate whether the increase of NED is attributable to condition of hormone refractoriness or long-term hormonal therapy.

[Enucleation of renal cell carcinoma in von Hippel-Lindau disease using a microwave tissue coagulator].

The patient was a 37-year-old man who had undergone left nephrectomy under the diagnosis of left renal cell carcinoma associated with von Hippel-Lindau (VHL) disease 4 years ago. Computed tomography (CT) revealed 3 individual tumors 20 mm, 13 mm and 9 mm in maximum diameter in the right kidney. All three renal tumors were enucleated with a microwave tissue coagulator (MTC) without renal pedicle clamping. There were no major complications related to nephron-sparing surgery such as postoperative bleeding, persistent urine leakage and deterioration of renal function. Our findings suggest that renal tumors with VHL disease can be enucleated using a MTC safely and successfully without damaging renal function.

Expression and regulation of tumor suppressor gene maspin in human bladder cancer.

Maspin is a member of serine protease inhibitor family with tumor suppressing activity for breast and prostate cancers, acting at the level of tumor invasion and metastasis. However, there have been no published data regarding the role of maspin in human bladder cancer. We evaluated maspin expression in 65 series of bladder cancer samples (22 transurethral resection (TUR) and 43 radical cystectomy) and studied the regulatory mechanism of maspin gene activation in bladder cancer cells. Maspin expression was immunohistochemically detected in four (18.2%) patients with TUR and 22 (51.2%) patients with radical cystectomy whereas no expression was observed in normal transitional cells located at tumor-free area in bladder. The maspin expression was significantly correlated with the development of muscle invasive bladder cancer (P=0.00008). Using a luciferase reporter system, maspin promoter activity was induced in the maspin-positive bladder cancer cell lines as well as maspin-negative RT4 cells. Furthermore, treatment with the DNA methyltransferase inhibitor, 5-aza-2' deoxycytidine, and histone deacetylase inhibitor, trichostatin A, led to re-expression of maspin in RT4 cells. Our results indicate that maspin may contribute to bladder cancer development and that DNA methylation and histone deacetylation may be important for regulating maspin gene activation in bladder cancer cells.

Multicentric liposarcoma.

Abstract A 72-year-old man complaining of upper abdominal discomfort was diagnosed as having retroperitoneal liposarcoma by means of diagnostic imaging. He then underwent an operation. One mass existed on the curvatura ventriculi major, extending to the hilum splenicum and pressing back the pancreal head and body. There was another mass to the left of the first, situated on the ventral side of the left kidney. Also, another mass was intramurally found adjacent to the curvatura ventriculi major. Histologically, the mass on the curvatura ventriculi major ranged from the peritoneal cavity to the retroperitoneum Its intraperitoneal portion was classified as a differentiated lipoma-like type and the retroperitoneal mass was of mucous type. The mass on the left kidney was of a differentiated fibrosing type. The intramural mass in the gastric curvature was found to be a differentiated lipoma-like type. The patient has been under observation for 12 months and has shown no recurrence.

Histopathological analysis of angiogenic factors in renal cell carcinoma.

AIM: The present study was carried out to clarify whether a histopathological analysis of vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1) and matrix metalloproteinase 2 (MMP-2) can help predict the outcome of renal cell carcinoma (RCC). We examined the expression of VEGF, TGF-beta1 and MMP-2 in a large series of RCC with a long follow-up, based on histopathological factors and survival. METHODS: Immunostaining for VEGF, TGF-beta1 and MMP-2 was performed on formalin-fixed, paraffin-embedded tissue sections from 84 patients with RCC who underwent nephrectomy at our institution between 1985 to 2000. The microvessel density (MVD) of tumor tissue was measured after it immunohistochemically stained with CD105 (Endoglin) monoclonal antibody. RESULTS: A significant association was observed in the expression of VEGF and TGF-beta1 regarding the stage (P < 0.01, P < 0.01), nuclear grade (P < 0.01, P < 0.01) and MVD (P < 0.001, P < 0.001), respectively. However, no correlation was found among the results of MMP-2, nuclear grade and MVD. A multivariate analysis demonstrated both the nuclear grade and MVD to be independent prognostic factors. CONCLUSION: Our results suggested that the expression of both VEGF and/or TGF-beta1 can be useful predictive prognostic factors RCC. In addition, a multivariate analysis demonstrated MVD to be an independent prognostic factor of RCC.