[Prostate cancer gene therapy].
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Adenoviruses, Human↗
Biomedical subjects
Yasutomo Nasu
Publications and source records attributed to Yasutomo Nasu.
Dynamin-2 regulates oxidized low-density lipoprotein-induced apoptosis of vascular smooth muscle cell.
BACKGROUND: On exposure to oxidized low-density lipoprotein (oxLDL), vascular cells generally undergo apoptosis, which is one of the major pathogenic factors of atherosclerosis. In this study, we examined the role of dynamin (a crucial GTPase protein in endocytosis) in oxLDL-induced apoptosis of vascular smooth muscle cells (VSMC). METHODS AND RESULTS: After oxLDL stimulation, dynamin-2 colocalized with LOX-1 around the cell surface, as well as oxLDL in the cytoplasm, suggesting that dynamin-2 was involved in scavenger receptor-mediated oxLDL endocytosis. Downregulation of dynamin-2 induced by dynamin-2 dominant negative plasmid (K44A) resulted in a decrease of oxLDL uptake and thereby in a reduction of apoptosis. These data demonstrated that dynamin-2 was involved in oxLDL-induced apoptosis via the oxLDL endocytotic pathway. On the other hand, dynamin-2 wild-type plasmid transfection promoted oxLDL-induced apoptosis without increasing oxLDL uptake. Interestingly, the p53 inhibitor pifithrin-alpha (PFT) significantly reduced apoptosis promoted by wild-type dynamin-2 (78% reduction compared with the PFT[-] condition). These results indicated that dynamin-2 enhanced oxLDL-induced apoptosis of VSMC by participating in the p53 pathway, probably as a signal transducer. Moreover, we demonstrated that, in advanced plaques of apolipoprotein E-/- mice, dynamin-2 expression was often enhanced in apoptotic VSMC, suggesting that dynamin-2 might participate in apoptosis of VSMC even in vivo. CONCLUSIONS: Our data demonstrated that dynamin-2 at least partially regulated oxLDL-induced apoptosis of VSMC by participating in 2 independent pathways: the oxLDL endocytotic pathway and the p53 pathway. These findings suggest that dynamin-2 may serve as a new research or therapeutic target in vascular disease.
Animals↗
Comparative study of ureteral stripping versus open ureterectomy for nephroureterectomy in patients with transitional carcinoma of the renal pelvis.
OBJECTIVES: To evaluate the clinical outcome of nephroureterectomy with endoscopically assisted transurethral ureteral stripping for transitional cell carcinoma of the renal pelvis in a comparative study. METHODS: Sixty patients with localized renal pelvic cancer were enrolled in a prospective comparative nonrandomized study. Of these, 28 patients underwent nephroureterectomy with endoscopically assisted transurethral ureteral stripping and 32 underwent conventional nephroureterectomy with a bladder cuff. Both short-term and long-term results were analyzed in this series. RESULTS: The operating time for patients with ureteral stripping was significantly shorter than for those with a standard two-incision nephroureterectomy (median 183 versus 250 minutes, P = 0.0231), and the amount of blood loss was significantly less (median 150 versus 390 mL, P = 0.0002). Intravesical recurrence was detected in 10 (35.7%) of the 28 patients with ureteral stripping, and the 1-year and 3-year recurrence-free rate was 68.0% and 57.7%, respectively. Seven patients treated by the standard two-incision nephroureterectomy (21.9%) experienced intravesical recurrence, with a 1-year and 3-year recurrence-free rate of 96.8% and 75.0%, respectively. The recurrence rate was significantly greater in the group with ureteral stripping (P = 0.0287). CONCLUSIONS: Compared with conventional nephroureterectomy with a bladder cuff, nephroureterectomy with transurethral stripping is a minimally invasive procedure with a shorter operating time and less blood loss, but a statistically significantly greater intravesical recurrence rate. Greater consideration should be taken before selecting this procedure.
Aged↗
Kidney function after nephrectomy for renal cell carcinoma.
OBJECTIVES: To evaluate the function of the remaining kidney after nephrectomy for renal cell cancer by technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) renal scintigraphy. METHODS: We evaluated 30 consecutive patients who were undergoing unilateral radical nephrectomy by 99mTc-MAG3 scintigraphy. All patients underwent three consecutive 99mTc-MAG3 scintigraphy studies. The first study was performed before nephrectomy, the second 1 month after surgery, and the third 1 year after surgery. At these times, the serum creatinine levels were also evaluated. RESULTS: The mean preoperative MAG3 clearance of the remaining kidney of the 30 patients was 155.4 mL/min/1.73 m2. The mean MAG3 clearance of the remaining kidney had increased to 209.2 mL/min/1.73 m2 by 1 month after nephrectomy, and the average percentage increase was 39.5%. After 1 year, it had increased to 211.3 mL/min/1.73 m2, with a 40.5% average percentage increase. The preoperative MAG3 clearance of the remaining kidney was inversely correlated with the percentage of increase in MAG3 clearance of the remaining kidney. Abnormal serum creatinine levels (greater than 1.3 mg/dL) were more common after nephrectomy, occurring in 6 patients at 1 month and in 5 patients at 1 year postoperatively. In all 6 patients with elevated creatinine levels, the preoperative MAG3 clearance of the remaining kidney was less than 150 mL/min/1.73 m2. CONCLUSIONS: Adaptive hyperfunction occurs soon after nephrectomy that is not associated with age or sex and continues for at least 1 year. A greater compensatory response is produced in patients with more severe renal deterioration. Using 99mTc-MAG3 scintigraphy, we may be able to predict postoperative renal function.
Adaptation, Physiological↗
Effects of gonadotropin-releasing hormone agonists on bone metabolism markers and bone mineral density in patients with prostate cancer.
OBJECTIVES: To better understand bone metabolism and predict bone loss in treatment using gonadotropin-releasing hormone agonist for patients with prostate cancer. METHODS: The changes in bone mineral density and blood levels of bone metabolism markers and the level of pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen, a specific marker of bone resorption, and carboxy-terminal pro-peptide of human type I procollagen, a specific marker of bone formation, were examined in 27 consecutive patients with prostate cancer without bone metastasis. RESULTS: After 2 years of gonadotropin-releasing hormone treatment, the bone mineral density was significantly lower (median 0.937 g/cm2) than before treatment. Pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen began to increase significantly 6 months after the start of treatment (3.0 to 8.3 ng/mL, median 4.6, at baseline versus 3.4 to 8.2 ng/mL, median 5.2, after 6 months). Carboxy-terminal pro-peptide of human type I procollagen began to show a significant rise 1 year after the start of treatment (from 72.8 to 221.5 ng/mL, median 102.0, at baseline to 82.7 to 293.4 ng/mL, median 132.0, at 1 year). CONCLUSIONS: Functional coupling between bone resorption and formation was noted, and a decrease in bone mass, even in men, owing to androgen deficiency, was biochemically demonstrated. Fluctuations in these two bone metabolism markers preceded the decrease of bone mineral density. Therefore, these markers might be a predictor of bone loss.
Adenocarcinoma↗
Positive correlation between allelic loss at chromosome 14q24-31 and poor prognosis of patients with renal cell carcinoma.
OBJECTIVES: To report our development of a new application of the inter-Alu long polymerase chain reaction (PCR) for genomic scanning to screen for tumor-specific alterations in tumor DNA. Using this method, we detected a rearranged chromosomal region in renal cell carcinomas (RCCs). We then examined tumor-specific allelic loss in this region using microsatellite markers and determined whether a relationship was present between this allelic loss and the clinicopathologic features of the patients. METHODS: The inter-Alu long PCR genomic scan method was performed using RCC DNA samples and primers specific for a minor subset of the human repeat sequence Alu. We analyzed DNA samples from 42 pairs of matched normal and nonpapillary RCC tissues with seven microsatellite markers. RESULTS: The inter-Alu long PCR genomic scan method revealed an altered DNA region on chromosome 14q24-31, which is the location of several putative tumor suppressor genes. At least one of seven microsatellite markers on chromosome 14q24-31 showed loss of heterozygosity in 23 (54.8%) of 42 informative cases of RCC. The prevalent loss region was confined to a 2-Mb region around D14S67. We found a positive correlation between the presence of the loss of heterozygosity on 14q24-31 and tumor stage (P <0.05). We also found that cases with allelic loss at 14q24-31 had a poor prognosis (P = 0.045). CONCLUSIONS: Our inter-Alu long PCR genomic scan method is a powerful method for the screening of DNA alterations, and our data suggest that the chromosome 14q24-31 region contains likely tumor suppressor genes associated with the progression of RCC.
Adult↗
Decreased expression of REIC/Dkk-3 in human renal clear cell carcinoma.
PURPOSE: We examined the expression of REIC/Dkk-3, a possible candidate for a tumor suppressor gene, in human renal clear cell carcinoma (RCCC) cell lines and sporadic RCCC surgical specimens. MATERIALS AND METHODS: Human RCCC cell lines (Caki-1, Caki-2, ACHN and KPK-1) and several control cell lines were used to examine the expression of REIC/Dkk-3 mRNA and characterize a newly raised antibody specific for REIC/Dkk-3 protein. Pairs of cancerous and adjacent noncancerous tissues were obtained from 20 patients with RCCC. Of them 17 and 7 cases were analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction, and by Western blot analysis and/or immunohistochemical analysis, respectively. RESULTS: The decreased expression of REIC/Dkk-3 mRNA and protein in human RCCC cell lines, and the specificity of the new antibody were confirmed. In a real-time quantitative reverse transcriptase-polymerase chain reaction study using 17 pairs of RCCC and adjacent normal tissues REIC/Dkk-3 mRNA levels were significantly decreased in carcinoma tissues (by 25% to approximately 95% in 15 pairs). Western blot analysis and immunohistochemistry revealed a significant decrease in REIC/Dkk-3 protein levels in 6 of the 7 and 13 of the 14 RCCC cases analyzed, respectively. CONCLUSIONS: The decrease in REIC/Dkk-3 mRNA and protein levels was observed irrespective of tumor grade and stage, indicating the involvement of REIC/Dkk-3 in an initial step of malignant conversion. Consequently REIC/Dkk-3 could be a new molecular target for therapeutic measures against RCCC.
Adaptor Proteins, Signal Transducing↗
Long-term consequence of renal function following nephrectomy for renal cell cancer.
AIM: A retrospective analysis was performed involving patients who had undergone radical nephrectomy for renal cell cancer to determine the long-term outcome of this surgery on renal status. MATERIALS AND METHODS: Between 1977 and 2001, 172 patients having undergone radical nephrectomy for renal cell cancer were followed for a period of more than one year at the Department of Urology Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. The preoperative and postoperative serum creatinine values of these individuals were reviewed. Long-term effects of radical nephrectomy on renal function and factors influencing postoperative renal dysfunction were analyzed. RESULTS: Six (3.5%) of the 172 individuals progressed to hemodialysis. Eleven (6.4%) patients displayed serum creatinine values of > or =1.6 mg/dL. The remaining 155 patients (90.1%) demonstrated postoperative serum creatinine values of <1.6 mg/dL. The present study suggests that aging, a high degree of proteinuria, hypertension and diabetes mellitus were the predominant risk factors for renal deterioration following nephrectomy. CONCLUSIONS: We have primarily selected radical nephrectomy for cases exhibiting smaller renal tumors with a normal contralateral kidney. We encourage nephron-sparing surgery where possible in patients displaying risk factors, including a high degree of proteinuria, hypertension, or diabetes mellitus.
Adult↗
Ureteroscopy using a detachable access sheath.
Ureteroscopy has evolved in many aspects, particularly in the flexibility and size of ureteroscopes. We have developed a new detachable access sheath to make ureteroscopic procedures more straight-forward and to reduce possible damage to delicate instruments used in the procedure.
Equipment Design↗
[Adenovirus-mediated interleukin-12 gene therapy for prostate cancer].
As a human prostate cancer gene therapy trial, we have performed Herpes Simplex Virus-thymidine kinase gene transduction and ganciclovir therapy in locally advanced prostate cancer after radiation therapy(USA) or endocrine therapy(Japan). Safety and clinical efficacy were confirmed. In our current studies, we demonstrated the efficacy and safety of gene therapy approaches using recombinant adenoviral vector that transduce interleukin-12 in an orthotopic mouse model of prostate cancer. These preclinical studies will soon be resulted in the initiation of clinical trials using this approach(USA: FDA approved, Japan: Under IRB review) in advanced prostate cancer patients with or without metastasis after endocrine therapy. In this chapter, preclinical data and clinical protocol are introduced.
Adenoviridae↗
Eradication of HPV post-surgical treatments, its correlation with specific types, types of surgery and the physical status.
Low-risk human papillomaviruses (HPVs) will be completely eradicated as long as most visible lesions are treated. However, it is uncertain whether this is also the case for high-risk HPVs that are capable of causing cervical cancer. Many recent studies have demonstrated a high incidence of HPV persistence during post-conization or loop electrosurgical excision (LEEP) due to high-grade cervical intraepithelial neoplasia (CIN). In this report, we correlated the post-operative HPV status with pre-operative HPV type, types of surgery and HPV's physical status. Post-operative HPV E6 amplification by nested PCR was carried out for 157 female patients with positive pre-operative HPV. They underwent LEEPs, therapeutic laser conizations, and simple or radical hysterectomies. We found that high-risk types of HPVs were eradicated in 26.4% (42/159) of patients after extirpation of the lesions. The clearance rate of HPVs increased to 39.2% (40/102), excluding patients with other high-risk (OHR) kinds of type 31, 52b and 58, since OHR persisted after almost all surgeries. Eradication of HPV after radical hysterectomies are highly expected for patients with invasive cancer (70.0%, when excluding OHR), while more than half of them with CIN continue to carry pre-operative types of HPV or some different types from before treatment. Type 33 is most frequently persistent among types 16, 18 and 33. Persistent high-risk HPVs increase the risk for recurrence of post-surgical treatments of CIN, but the incidence is not high as long as the lesion is completely removed.
Carcinoma in Situ↗
NY-ESO-1 mRNA expression and immunogenicity in advanced prostate cancer.
NY-ESO-1 mRNA expression was investigated in advanced prostate cancer by conventional and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). NY-ESO-1 mRNA was detected in 20 of 53 (38%) tumor specimens. Four of 15 (27%) stage C, 1 of 3 stage D1 (33%) and 15 of 35 (43%) stage D2 prostate cancers were positive. The presence of NY-ESO-1 antibodies was evaluated in sera from a panel of 218 patients with prostate cancer, including the 53 patients whose tumors were examined for NY-ESO-1 mRNA expression. NY-ESO-1 antibodies were detected in 1 of 30 (3.3%) stage D1 and 9 of 110 (8.2%) stage D2 patients, whereas none of the 78 patients with localized prostate cancer (stages A, B and C) had detectable NY-ESO-1 antibodies. Of the 53 patients whose tumors were examined for NY-ESO-1 mRNA expression, 2 of 20 patients with NY-ESO-1 mRNA-positive tumors had NY-ESO-1 antibodies. No antibody was found in the sera of 32 patients with NY-ESO-1 mRNA-negative tumors, with the exception of one patient with regional lymph node metastasis (stage D1). CD8 T cell responses specific to NY-ESO-1 were detected in two of three patients with NY-ESO-1 antibodies.
Aged↗
Laparoscopic removal of Müllerian structures and orchiopexy for persistent Müllerian duct syndrome.
A 1-year-old boy presented for evaluation of bilateral undescended testes. Diagnostic laparoscopy was conducted, and uterine tissue with bilateral gonads was detected in the rectovesical fossa. Chromosomal analysis revealed a 46,XY karyotype. Persistent müllerian duct syndrome was diagnosed, and laparoscopic surgery was performed to treat this condition. The uterus was incised at a distal site and withdrawn through the port. The bilateral testes were fixed in the scrotum. The patient was discharged 3 days later. We believe that the laparoscopic approach is a valid, alternative choice to traditional surgery for resolution of this condition, permitting minimally invasive surgery.
Cryptorchidism↗
Anterior urethral recurrence of superficial bladder cancer: its clinical significance.
The aim of this study was to reveal the clinical features of anterior urethral recurrence in patients with superficial bladder cancer, and to determine the appropriate treatment. Three hundred and three patients with superficial bladder cancer, who were newly diagnosed and initially treated conservatively in our hospital between 1965 and 1990, were followed for at least 5 years and their clinical outcomes were analyzed. Clinical factors, including anterior urethral recurrence, were evaluated statistically regarding tumor progression. Eight patients (2.6%) had anterior urethral recurrence following superficial bladder cancer. Twenty-four patients (7.9%) had tumor progression and 149 (49.2%) had tumor recurrence. In a multivariate analysis using a logistic model, anterior urethral recurrence was the most important factor, followed by histological grade. Four of 5 patients who were treated for anterior urethral recurrent tumors by transurethral resection showed progression and died of the cancer within one year. Two of the remaining three patients who underwent radical cysto-urethrectomy at the time of anterior urethral recurrence survived. Anterior urethral recurrence following superficial bladder cancer is a predictor for rapid subsequent malignant progression. Once there is anterior urethral recurrence, radical intensive therapy, including radical cysto-urethrectomy, should be carried out immediately.
Carcinoma, Transitional Cell↗
[Suicide gene therapy for prostate cancer--update of current development].
Prostate cancer is the leading internal malignancy in men with an age over 50. Therapeutic options for patients with recurrence after hormonal therapy are limited. New therapeutic options are needed. In our previous studies, we demonstrated the efficacy and safety of 'suicide gene therapy' using herpes simplex virus-thymidine kinase gene transduction and ganciclovir therapy in an orthotopic mouse model. These preclinical studies resulted in the initiation of clinical trials using this approach in USA and Japan. Safety and positive clinical response were shown in these clinical studies. In this review article, current status of prostate cancer 'suicide' gene therapy is updated and future direction of its development is also discussed.
Adenoviridae↗
Prostate specific antigen complexed to alpha-1-antichymotrypsin in patients with intermediate prostate specific antigen levels.
BACKGROUND: The authors attempted to evaluate prospectively the usefulness of serum prostate specific antigen (PSA) complexed to alpha-1-antichymotrypsin (PSA-ACT) in the early detection of prostate carcinoma and its ability to discriminate between prostate carcinoma and benign prostatic hyperplasia (BPH), especially among patients with intermediate PSA levels. METHODS: Between December 1999 and August 2000, systematic sextant biopsies were performed on 281 prospective patients with prostate carcinoma who had serum PSA levels between 4.1 ng/mL and 20.0 ng/mL. The serum samples were assayed by using kits that were designed specifically for measuring serum PSA, PSA-ACT, and free PSA levels. The clinical values of PSA, PSA-ACT, the free PSA to total PSA ratio (F/T ratio), the free PSA to PSA-ACT ratio, PSA density (PSAD), and PSA-ACT density (ACTD) were compared by using receiver operating characteristic (ROC) curve analysis. RESULTS: Biopsy yielded no evidence of malignancy in 198 patients, and prostate carcinoma was confirmed in 83 patients. ROC analysis demonstrated that the area under the curve (AUC) for PSA-ACT was greater than that for total PSA and was equivalent to that for the F/T ratio in both groups of patients (PSA ranges of 4.1-20.0 ng/mL and 4.1-10.0 ng/mL, respectively). The AUC for the ACTD was greater than the AUC for the PSAD and had the highest value of all parameters. CONCLUSIONS: The measurement of PSA-ACT represents an alternative to the use of total and free PSA. The ACTD value is the most useful for discriminating between BPH and prostate carcinoma.
Adult↗
Clinical study of G3 superficial bladder cancer without concomitant CIS treated with conservative therapy.
OBJECTIVE: The treatment for superficial G3 transitional cell carcinoma (TCC) of the urinary bladder remains controversial. It is important to reveal the clinical features of superficial G3 bladder cancer that can be treated conservatively. PATIENTS AND METHODS: A total of 39 patients with primary superficial bladder cancer (Ta, T1) with G3 components but without concomitant carcinoma in situ (CIS), who had been treated initially with transurethral resection (TUR), were retrospectively analyzed for factors related to tumor recurrence, progression and survival. The patients were 34 males and five females whose age ranged from 49 to 85 years (average, 68 years). Initial tumor stages were Ta in one patient and T1 in 38. Initial treatments were TUR alone in 18 patients and TUR with adjuvant therapy (intravesical chemotherapy or BCG therapy) in 21. Factors examined included age, gender, morphology, size and number of tumors and adjuvant therapies. RESULTS: Follow-up periods were 3-138 months (median, 37 months). Tumor recurrence, progression and cancer death were observed in 23, seven and four cases, respectively. The 5-year progression-free rate (75%) and survival rate (83%) in 39 patients with G3 did not show a statistically significant difference from those of the 109 patients with G1 or the 187 patients with G2 superficial bladder cancer who were treated with TUR initially. Only the rate of recurrence of patients with G3 was significantly higher than that of patients with G2 or G1. Adjuvant therapies reduced the recurrence rate of the patients with G3. Only tumor morphology, papillary or non-papillary, affected both the progression-free rate and the survival rate of patients with G3. There were no statistically significant differences associated with other factors. CONCLUSION: The results suggest that superficial G3 bladder cancer could be treated with TUR initially, especially for papillary tumors.
Aged↗
Laparoscopic radical prostatectomy: initial cases at Okayama University Hospital.
We performed laparoscopic prostatectomy in seven cases with organ-confined prostate cancer. In 6 cases, the surgery was completed successfully and the mean operative time was 424 min. Volume of blood loss was 200 to 3,200 ml and catheterization lasted 6 to 37 days. No major complications were observed in 6 of the cases. In one case, open surgical conversion was necessary mainly due to a bladder injury. Although these were the first cases of laparoscopic prostatectomy in our institution, the technical difficulty and complexity of the surgery were moderate. We believe that laparoscopic radical prostatectomy will become a standard option for the treatment of organ-confined prostate cancer.
Aged↗