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Y Kakehi

Publications and source records attributed to Y Kakehi.

At least 55 records · Page 3Linked to original sources
PubMed1999

[Molecular biological testing for diagnosis and treatment of urothelial cancer].

Detection of urinary telomerase activity is superior to the conventional urine cytological examination in terms of sensitivity for diagnosis of low grade urothelial cancers. Several causative factors including pyuria and hematuria which might have affected falsely positive and negative rates of urinary telomerase activity were investigated but their influence seemed negligible. As for progression from superficial to invasive urothelial cancers, destruction of the basement membrane underlying tumor is considered as an important event in the initial step of invasion. Our immunohistochemical analyses revealed that expression of type IV collagen in the basement membrane was reduced or disappeared in more than half of grade 2 to 3, pTa urothelial cancers. Overexpression of p53 tumor suppressor and/or mdm2 oncoprotein was strongly correlated with this basement membrane destruction. Urothelial cancers harboring p53 aberration may be resistant to cisplatin-based chemotherapy because of impairment of apoptosis induction. The relationship between chemosensitivity and p53 status in urothelial cancers was investigated, and a favorable response to neoadjuvant chemotherapy was found in tumors without p53 aberration.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract.

Recent molecular genetic studies have suggested that multifocal urothelial cancers are derived from an identical progenitor cell. However, the clonal origin of multifocal urothelial cancers of a low-grade superficial type has not been fully defined. Using microsatellite markers, we examined genetic alterations at 20 loci on eight chromosomal arms (2q, 4p, 4q, 8p, 9p, 9q, 11p, and 17p) in 87 metachronous and/or synchronous multifocal urothelial cancers, which included 84 low-grade superficial papillary tumors from 29 patients. Judging from the patterns of loss of heterozygosity, microsatellite shifts, and the subchromosomal partial deletion, multifocal tumors in at least 20 (80%) of the 25 evaluable patients were considered to be derived from a single progenitor cell, although the possibility remained that multifocal tumors in a small subset of patients might develop from distinct progenitor cells due to field cancerization. In 13 of the 20 patients, a chronological genetic analysis was available: genetic heterogeneity was detected in 3 (23%) patients, and an apparent accumulated pattern of genetic alterations was detected in only 1 (8%) patient. In the 20 patients with multifocal tumors of an identical clonal origin, discordant microsatellite alterations were observed, with significantly lower frequencies on chromosome 9 compared to those on the other chromosomes tested. The results indicate that most multifocal low-grade superficial urothelial cancers are genetically stable despite their incidence of frequent recurrence, and genetic divergence occurs in a subset of patients. This heterotopic spread and genetic divergence may occur long before the clinical manifestation of multiplicity from a single transformed cell. These data support the previous view that heterotopic spread of transformed progenitor cells and genetic divergence occur after chromosome 9 alterations in most of low-grade superficial urothelial cancers.

Chromosome Aberrations↗
PubMed1998

Prostate-specific amplification of expanded polyglutamine expression: a novel approach for cancer gene therapy.

For cancer gene therapy, it is of primary importance to develop a system to sufficiently and selectively express therapeutic genes in cancer cells. In this study, we showed that an approximately 5.3-kb promoter region of the prostate-specific antigen (PSA) gene can replicate the endogenous expression pattern, although its expression is very weak. We then developed a novel two-step transcriptional activation system in which the PSA promoter drives an artificial transcriptional activator, GAL4-VP16 fusion protein, and it in turn activates transgene expressions under the control of GAL4-responsive elements. By using this system, transgene expressions can be greatly augmented while maintaining prostate-specific expression. Finally, we applied this system to drive an expanded polyglutamine, a potent proapoptotic molecule, to induce apoptosis selectively in PSA-positive prostate cancer cells. This novel system would provide an ideal approach for cancer gene therapy applicable not only to prostate cancer but to other cancers as well.

Apoptosis↗
PubMed1998

Detection of tumor-derived DNA in exfoliated cells of urine sediments with a novel quantitative PCR method based on allele-specific PCR.

We have established a novel quantitative method based on the allele-specific PCR, which uses the linearly amplified fragment of the PCR products as the internal control. The improved characteristics of the procedure are the high sensitivity for quantitation of the mutant alleles at ratios of up to 1:10000 and the reduced necessity of the optimization of the PCR conditions for each mutation. Using this modified allele-specific PCR, we could quantify the tumor alleles in the urine sediments of three patients with urothelial cancers that harbored different p53 gene mutations. This method can be applied to other genetic targets that have other types of alterations, such as deletions or insertions.

Alleles↗
PubMed1998

Low frequency of positive telomerase activity in a chromophobe subtype of renal cell carcinoma.

PURPOSE: In malignant tumors, telomerase reactivation plays an important role in the acquisition of cellular immortality. We evaluated the telomerase activity in renal cell carcinomas (RCCs) with special reference to their clinicopathologic features. MATERIALS AND METHODS: Telomerase activity was examined in 47 RCCs and 9 RCC cell lines by telomeric repeat amplification protocol assay (TRAP). The telomere lengths were assessed by Southern analysis of terminal restriction fragments (TRFs) generated by Hinfl-digested DNA. RESULTS: Thirty-six (77%) of the 47 RCCs and all 9 RCC cell lines showed telomerase activity, whereas no activity was detected in any of 30 normal kidneys. When the tumors were histopathologically classified, only one (17%) of the 6 chromophobe cell carcinomas was telomerase-positive. This frequency was significantly low (p < 0.001) when compared with those in clear cell RCCs (93%; 26/28). In 40 of the 47 patients, DNA from the tumor tissues and the paired normal kidneys was available for analysis of the TRF lengths. No tumor showed elongated TRF length compared to its paired normal kidney. Regarding the relationship between telomere length and telomerase activity, 23 (74%) of the 31 telomerase-positive RCC and 6 (67%) of the 9 telomerase-negative RCC exhibited reduced TRF. There was no significant correlation between the telomere reduction and telomerase activity. CONCLUSION: The mechanism for preventing telomere shortening may differ according to RCC subtype. Alternatively, telomerase-negative tumors may have yet to reach the immortal stage when they progress to clinical cancer. The telomerase activity status may contribute to the biological potential and the prognosis of RCCs.

Adenocarcinoma↗
PubMed1998

Absence of p53 overexpression and favorable response to cisplatin-based neoadjuvant chemotherapy in urothelial carcinomas.

It has been controversial whether cancer cells harboring loss or inactivation of the tumor suppressor p53 are resistant or sensitive to DNA-damaging agents including cisplatin and doxorubicin. Overexpression of mdm2 oncoprotein, a negative regulator of p53, is assumed to be an alternative to p53 dysfunction. Archival urothelial carcinoma specimens obtained from 60 patients prior to cisplatin-based chemotherapy were immunohistochemically studied for overexpression of p53 and mdm2. Thirty-two patients (group I) were treated with chemotherapy in the neoadjuvant setting, while 28 patients (group II) underwent chemotherapy for distant metastases or inoperable locoregional tumors. In group I, the responsiveness was correlated with staining status of p53 (P=0.0225) and the combination of p53 and mdm2 (P=0.0497). Negative staining of p53 and negative for both p53 and mdm2 could have predicted favorable response to chemotherapy in 16 of 18 (88.9%) and in 12 of 13 (92.3%) tumors, respectively. On the other hand, p53-positive and p53 and/or mdm2-positive staining could have predicted poor response only in 7 of 14 (50.0%) and 8 of 19 (42.1%) tumors, respectively. Disease-specific survival of the p53-negative group was significantly superior to that of the p53-positive group (P=0.0086). Difference in survival did not become more significant when overexpression of mdm2 was taken into consideration (P=0.0456). In contrast, in group II, there was no correlation of responsiveness to chemotherapy or survival with p53- or p53/mdm2-staining status. The patients with urothelial carcinomas negative for overexpression of p53 will benefit from neoadjuvant chemotherapy. From clinical viewpoint, however, p53 status alone or the combination of p53 and mdm2 status is not enough to identify those patients who will not benefit from the treatment.

Adult↗
PubMed1998

Decision analysis for treatment of early stage prostate cancer.

We performed a decision analysis to evaluate the usefulness of pretreatment prediction of clinically significant or insignificant tumor in patients with prostate-specific antigen (PSA)-detected stage T1c prostate cancer nonpalpable on rectal examination. Analysis was done for otherwise healthy subjects with 20 years of life expectancy. The prevalence of insignificant tumor among those with T1c prostate cancer was initially assumed to be 0.2. Quality-adjusted life expectancy was calculated and compared between 2 strategies; one with prediction-based selection of either radical prostatectomy or watchful waiting and the other with unselective assignment of one of the treatments. The selection strategy was superior when the sensitivity and specificity for detecting clinically significant tumor were 0.92 and 0.73, respectively, as reported by Epstein et al. (1994) using criteria of PSA density and Gleason score in a needle biopsy specimen. Sensitivity analysis revealed that the prediction-based selection strategy is preferred, with sensitivity and specificity constant, when the prevalence of insignificant tumor exceeds 0.16. On the other hand, when the prevalence of insignificant tumor is kept constant at 0.2, sensitivity should be 0.85 or higher for the prediction strategy to be preferred. As the prevalence of insignificant tumor among those with T1c prostate cancer increased, the prediction-based selection strategy is preferred with lower values of sensitivity and specificity for detecting significant tumor. These results suggest that a selective treatment strategy of either radical or conservative treatment based on pretreatment prediction for significant tumor is a beneficial alternative to radical prostatectomy unselectively assigned to all patients at the T1c stage, if a reasonable accuracy in prediction is attained.

Decision Support Techniques↗
PubMed1998

[Combination therapy of daily intramuscular injection of interferon-alpha and oral administration of fluorouracil for advanced renal cell carcinoma].

BACKGROUND: To achieve optimum drug delivery of Interferon-alpha in treatment of renal cell carcinoma, a regimen consisting of its daily intramuscular administration, in combination with oral fluorouracil, was designed and carried out. Its efficacy is examined retrospectively. METHODS: In our department 7 patients with disseminated renal cell carcinoma were treated with daily intramuscular injection of interferon-alpha (3 x 10(6) IU) and daily oral administration of fluorouracil. All patient was nehprectomized before initiation of the regimen. RESULTS: Two patients achieved complete, and three patients achieved partial response radiographically (Overall response rate 71%). Metastatic sites of responders were lung (4) and pleura (2). The time required until response was 3.9 (median 5.4) months. In two responders, new lesions appeared in other organs despite durable response in initial pulmonary metastatic sites. There were two no-responders, one patient is alive with stable disease and the other patient died for progression of the disease. In all, two patients died of disease, one died for other cause, one surviving without evidence of disease, and three are surviving with disease. No significant side effect was noted in these seven patients. CONCLUSIONS: This regimen can be carried out on outpatient basis and considerable response can be expected for pulmonary and pleural lesions.

Administration, Oral↗
PubMed1998

[Intravesical bacillus Calmette-Guerin instillation for patients over 80 years old].

To study the efficacy and the safety of intravesical bacillus Calmette-Guerin (BCG) therapy for very elderly patients with superficial bladder cancer, we retrospectively compared patients over 80 years old who had received BCG therapy at our department between 1991 and 1996 (Group A; 10 patients 11 courses), with those below 80 years old (Group B, 17 patients 18 courses). In these patients, skin test reactivity to purified protein derivative showed a significant negative correlation with age (p = 0.016). No irreversible complications were observed in any patient. Persistence of acid-fast bacilli for more than one month after the termination of the course was observed in two patients in group A, and one in group B. A comparison of the cases undergoing eradicational BCG therapy in the two groups, grade 2 transitional cell carcinoma (TCC) was significantly more predominant than grade 3 TCC in group A (p = 0.004). (None of the tumors in group A were of grade 3) The disease-free rate was significantly lower in group A (p < 0.05), but 5 of the 10 patients in this group were finally disease-free. From these results, we conclude that intravesical BCG instillation therapy can be performed in patients over 80 years old, although a relatively lower disease-free rate is expected and special attention should be taken with regard to persistent BCG infection. The lower disease-free rate could be attributable to either diminished cellular immunity or a difference in tumor grade, although a definite conclusion could not be obtained here.

Administration, Intravesical↗
PubMed1998

[Epidemiology and clinical features of prostate cancer in Japan].

The incidence rate of clinically manifest prostate cancer in 1992 was estimated 15.7 per 100,000 men, although it is increasing exponentially. Accordingly, 5399 deaths from prostate cancer in 1995 will be increased to 13,494 deaths in 2015. Change in dietary habit (more Western-style diet) is considered to be a major cause of the increase. Escalating number of elderly people in the Japanese population is another major reason of elevated incidence. On the other, public awareness of prostate cancer and introduction of serum PSA measurement to health check-up undoubtedly have raised the detection rate of early stage disease. The way of androgen ablation do not seem to have influenced on survival of the advanced disease so far. It remains to be clarified whether the combined androgen blockade using pure anti-androgens with castration provide better patients' survival than castration alone.

Adult↗
PubMed1998

[Expression of major histocompatibility complex antigens and adhesion molecules on renal cell carcinoma cells, and effect of interferon-alpha and/or cimetidine on the expression].

Recently the combined therapy with interferon-alpha (IFN-alpha) and cimetidine has been reported to be effective against advanced renal cell carcinoma (RCC). IFN-alpha and cimetidine have an antitumor effect partly due to enhancement of cytotoxic activity of lymphocytes against cancer cells. We examined the expression of major histocompatibility complex (MHC) antigens and adhesion molecules on 4 fresh RCC cells and 5 RCC cultured cell lines, which have an important role in recognition and killing of cytotoxic lymphocytes against cancer cells. The effect of treatment with IFN-alpha and/or cimetidine on the expression of MHC antigens and adhesion molecules on RCC cells was also investigated. MHC class I and leukocyte function-associated antigen-3 (LFA-3) were expressed on all RCC cells, but not MHC class II. Intercellular adhesion molecule-1 (ICAM-1) and B7 were expressed on 6 and 5 of 8 RCC cells, respectively. IFN-alpha significantly augmented the expression of MHC class I in 6 of 9 RCC cells, ICAM-1 in 1 and LFA-3 in 2 of 8 RCC cells. However, IFN-alpha did not affect the expression of MHC class II and B7. On the other hand, cimetidine enhanced the expression of LFA-3 in 2 of 8 RCC cells, but not MHC antigens, ICAM-1 or B7. The combination of IFN-alpha and cimetidine did not show a synergistic enhancing effect on the expression of MHC antigens, ICAM-1, LFA-3 or B7. These results suggest that IFN-alpha augments the sensitivity of RCC cells to lysis by cytotoxic lymphocytes partly due to the enhancement of expression of MHC class I, ICAM-1 and LFA-3 on RCC cells, and that cimetidine also augments the susceptibility of RCC cells to lymphocytes by the enhanced expression of LFA-3 on RCC cells.

Adjuvants, Immunologic↗
PubMed1998

[Three cases of the nephrogenic adenoma of the bladder].

Nephrogenic adenoma is a rare, benign tumor of the urinary tract. The origin of this tumor is supposed to be a metaplastic transformation of urothelium in response to stimulation such as recurrent urinary tract infections or surgical trauma. We experienced three cases of nephrogenic adenoma originating in the bladder. The first patient was a 29-year-old man with right vesicoureteral reflux (VUR). When Teflon injection for VUR was performed, a papillary tumor was found on the right wall of the bladder. Transurethral resection of the bladder tumor (TUR-Bt) was performed. The second patient was a 72-year-old woman who was suffering from chronic cystitis. Although she was treated with antibiotics for one year, the symptoms were not improved. Cystoscopy showed multiple papillary tumors at the retrotrigonum of the bladder and TUR-Bt was performed. The third patient was a 75-year-old man who had a history of the left pelvic and bilateral ureteral tumors. Left radical nephroureterectomy and right radical ureterectomy with an ileal graft replacement was performed. Three years later, cystoscopy demonstrated a papillary tumor at the retrotrigonum, which was resected transurethrally. Our cases are the 20th to 22nd cases of the nephrogenic adenoma of the bladder reported in the Japanese literature.

Adenoma↗
PubMed1998

[Synchronous multifocal development of invasive transitional cell carcinoma of the urinary tract in a patient with renal failure receiving long-term hemodialysis: a case report].

We report a case of transitional cell carcinoma in a patient with chronic renal failure receiving hemodialysis for 22 years. A 55-year-old man was admitted to our hospital. Under diagnosis of invasive bladder cancer and left renal pelvic tumor, removal of the whole urinary tract, e.g., bilateral nephroureterectomy and total cystourethrectomy was performed. Transitional cell carcinoma was found in bilateral renal pelvis, left ureter, bladder and prostate in the resected specimen. Thirteen months after the operation, multiple lung metastases and pathologic bone fracture of the 4th lumber vertebra were found. Chemotherapy (3 courses of modified CISCA, consisting of cisplatin, adriamycin and cyclophosphamide) was performed, but the died of systemic metastases of cancer and bleeding due to perforation of multiple gastric ulcers.

Carcinoma, Transitional Cell↗
PubMed1997

Detection of telomerase activity in exfoliated cells in urine from patients with bladder cancer.

BACKGROUND: Telomeres are specific structures located at the ends of chromosomes that help maintain chromosome stability. In most tissues, telomeres become shorter as cells divide, a phenomenon thought to be associated with limitations on normal cell proliferation. Almost all types of cancer cells, including bladder cancer cells, express the enzyme telomerase, which can maintain or extend telomere length. PURPOSE: We examined telomerase activity in tumor specimens from a cohort of patients with bladder cancer and determined whether telomerase could be detected in exfoliated cancer cells present in urine from these patients. METHODS: Spontaneously voided urine specimens and bladder-washing fluids (obtained by propelling normal saline into the bladder through a catheter and then withdrawing the liquid contents) were taken from 45 patients before they underwent surgery. Telomerase activity was examined by means of the TRAP (telomeric repeat amplification protocol) assay on extracts of tumor samples from 42 patients and extracts of exfoliated cells in urine and bladder-washing fluid from 42 and 43 patients, respectively. Standard cytologic examination (Pap staining) of urine specimens was also used to detect exfoliated cancer cells. RESULTS: Telomerase activity was found in 41 (98%; 95% confidence interval [CI] = 87%-100%) of the 42 tumor samples examined. In contrast, it was not detected in normal bladder tissue from two autopsied individuals who were free of bladder cancer and five of six individuals who had bladder cancer. Telomerase was detected in exfoliated cells in 23 (55%; 95% CI = 39%-70%) of the 42 spontaneously voided urine specimens and in 36 (84%; 95% CI = 69%-93%) of the 43 bladder-washing fluids examined. Considering voided urine specimens and bladder-washing fluids together, telomerase was detected in exfoliated cells from 40 (89%; 95% CI = 76%-96%) of the 45 patients. Telomerase activity was not detected in bladder-washing fluids from 12 cancer-free individuals. Cancer cells were detected by means of standard cytologic examination in the urine of 19 (42%; 95% CI = 28%-58%) of the 45 patients. Urine cytologic examination detected cancer cells in one (8%; 95% CI = 0%-38%) of 12 patients with grade 1 tumors and in 13 (46%; 95% CI = 28%-66%) of 28 patients with grade 2 tumors. In contrast, telomerase activity was detected in exfoliated cells (in voided urine or bladder-washing fluids) from nine (75%; 95% CI = 43%-95%) of 12 patients with grade 1 tumors and from 27 (96%; 95% CI = 82%-100%) of 28 patients with grade 2 tumors. CONCLUSION AND IMPLICATION: Telomerase activity can be detected in exfoliated cells in urine from patients with bladder cancer, and measurement of this activity appears to be more sensitive in detecting the presence of cancer than standard urine cytologic examination. These findings suggest that measuring telomerase activity in exfoliated cells would be useful in the diagnosis and follow-up of patients with bladder cancer, a possibility that warrants further study.

Aged↗
PubMed1997

HLA-DRB1*0101 and *0405 as protective alleles in Japanese patients with renal cell carcinoma.

A variety of malignancies have been linked to major histocompatibility complex genes, including the DRB1 alleles. The association of certain DRB1 antigens with renal cell carcinoma (RCC) has been both claimed and disclaimed. To determine whether HLA-DRB1 genotypes are associated with RCC, we used the modified PCR-RFLP method for the high-resolution HLA-DRB1 genotyping of 96 Japanese RCC patients. There were no significantly frequent HLA-DRB1 alleles, whereas the DRB1*0101 and *0405 alleles had significantly lower frequencies [P = 0.004, relative risk (RR) = 0.2 and P = 0.002, RR = 0.4) in the RCC patients than in the healthy Japanese controls (n = 1216). Moreover, patients with the HLA-DRB1 *0101 or *0405 allele tended to be in earlier stages and to have less aggressive tumors than patients with neither of these alleles. The corresponding serotyping subclassification, however, showed a significantly lower frequency only for DRB1-DR1 (P = 0.01, RR = 0.3). High-resolution genotyping is essential because the polymorphism of the peptide-binding domain of major histocompatibility complex class II molecules is more precisely determined by genotypes than serotypes. In addition, inherent technical difficulties and potential typing errors render serotyping inefficient. Our data suggest that HLA-DRB1*0101 and *0405 are protective alleles for both RCC development and tumor progression.

Adult↗
PubMed1997

Association of in vitro growth potential of urinary exfoliated cells with tumor localization and intraluminal recurrence rates of urothelial cancers.

PURPOSE: One problem in the treatment of urothelial cancers, in particular of upper urinary tract cancers, is multifocal synchronous and/or metachronous tumor development in the heterotopic urothelium. We investigated the abilities of exfoliated cells in the urine of patients with urothelial cancers to colonize and proliferate in vitro. MATERIALS AND METHODS: Short-term cultures of 129 urine samples obtained from patients with urothelial cancers and 53 samples from healthy volunteers were compared as to the growth potential of urinary-exfoliated cells and clinico-pathological features, in particular tumor localization and evidence of intraluminal tumor recurrence. RESULTS: Primary cell outgrowth occurred in 112 (86.8%) of the 129 cell cultures from the patients and in 29 (54.7%) of the 53 from the healthy volunteers (p < 0.0001). "Sufficient cell growth" (more than 10(5) cells per flask) was obtained for 77 (59.7%) of the 129 cultures from patients and 7 (13.2%) of the 53 from the healthy volunteers (p < 0.0001). In terms of tumor localization, the rate of sufficient cell growth was significantly higher for patients with upper urinary tract tumor (21/25, 84.0%) than for those with bladder tumor (56/104, 53.8%) (p = 0.0062). Proportional hazard regression analysis showed that only the growth potential of the urinary-exfoliated cells was significantly predictive of intravesical tumor recurrence in patients with superficial bladder tumors (p = 0.011). CONCLUSIONS: The potentials for the colonization and proliferation of urinary-exfoliated cells are associated with intraluminal multifocal tumor recurrence of urothelial cancers.

Adult↗
PubMed1997

High-resolution HLA-DRB1 and DQB1 genotyping in Japanese patients with testicular germ cell carcinoma.

We report for the first time the frequency distributions of HLA-DRB1 and -DQB1 genes in 55 patients with testicular germ cell carcinoma (TGC) using the modified PCR-RFLP method and compare the results with those for 1216 healthy Japanese control subjects. The modified PCR-RFLP method produced accurate, reproducible cleavage patterns that are easily discriminated. HLA-DRB1*0410 was the susceptibility allele (RR = 3.26, P = 0.006) and DQB1*0602 appears to be a candidate protective allele (RR = 0.26, P = 0.02) for TGC in the Japanese. None of the HLA-DRB1 and -DQB1 alleles showed a specific tendency for histological type or clinical stage of the tumours. Previous studies based on serotyping methods failed to show these allelic associations. High-resolution genotyping is essential because the peptide-binding domain of MHC class II molecules is determined more precisely by their genotypes than by their serotypes. In addition, inherent technical difficulties and typing errors of up to 25% make serotyping inefficient. Our results suggest that high-resolution genotyping is a useful genetic marker to determine risk for TGC.

Female↗