Masatoshi Moriyama

Plasma Free Amino Acid Profiling of Five Types of Cancer Patients and Its Application for Early Detection

Background Recently, rapid advances have been made in metabolomics-based, easy-to-use early cancer detection methods using blood samples. Among metabolites, profiling of plasma free amino acids (PFAAs) is a promising approach because PFAAs link all organ systems and have important roles in metabolism. Furthermore, PFAA profiles are known to be influenced by specific diseases, including cancers. Therefore, the purpose of the present study was to determine the characteristics of the PFAA profiles in cancer patients and the possibility of using this information for early detection. Methods and Findings Plasma samples were collected from approximately 200 patients from multiple institutes, each diagnosed with one of the following five types of cancer: lung, gastric, colorectal, breast, or prostate cancer. Patients were compared to gender- and age- matched controls also used in this study. The PFAA levels were measured using high-performance liquid chromatography (HPLC)–electrospray ionization (ESI)–mass spectrometry (MS). Univariate analysis revealed significant differences in the PFAA profiles between the controls and the patients with any of the five types of cancer listed above, even those with asymptomatic early-stage disease. Furthermore, multivariate analysis clearly discriminated the cancer patients from the controls in terms of the area under the receiver-operator characteristics curve (AUC of ROC >0.75 for each cancer), regardless of cancer stage. Because this study was designed as case-control study, further investigations, including model construction and validation using cohorts with larger sample sizes, are necessary to determine the usefulness of PFAA profiling. Conclusions These findings suggest that PFAA profiling has great potential for improving cancer screening and diagnosis and understanding disease pathogenesis. PFAA profiles can also be used to determine various disease diagnoses from a single blood sample, which involves a relatively simple plasma assay and imposes a lower physical burden on subjects when compared to existing screening methods.

Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: Relationship to clinicopathological parameters

To delineate more precisely the somatic von Hippel‐Lindau disease (VHL) gene alteration as well as to elucidate its etiologic role in renal tumorigenesis, we examined a total of 240 sporadic renal cell carcinomas (RCCs) for somatic VHL gene alterations by DNA‐SSCP followed by sequencing, methylation‐specific PCR assay, microsatellite LOH study, and Southern blot analysis. Intragenic mutation of the VHL gene was found exclusively in clear‐cell or variant‐type RCCs at a frequency of 51% (104/202). Hypermethylation of the VHL promoter region was detected in an additional 11 clear‐cell RCCs. Microsatellite analysis demonstrated that LOH of the VHL locus was found in 140/155 (90%) informative clear‐cell RCCs. The VHL gene therefore seems to be inactivated in a two‐hit manner by intragenic mutation or hypermethylation plus allelic loss in clear‐cell RCC. Genomic rearrangement of the VHL gene detected by Southern analysis was not found (0/216 cases); this is in contrast to germ lines in which Southern aberrations consisted of 7–19% of the mutations. Clinicopathologic data demonstrated that VHL mutation/LOH did not vary according to tumor progression in clear‐cell RCC, including tumor diameter, stage, grading, distant metastasis, and lymph node metastasis. Interestingly, VHL mutation was significantly less frequent in RCCs occurring in younger (≦ 55 years) than that in older (≧ 56 years) patients. These data suggested that the inactivation of the VHL tumor‐suppressor gene is a specific genetic change in clear‐cell RCC, and that it may occur at an early or first step in the clear‐cell tumorigenic pathway rather than as a late event.

c-erbb-2 gene amplification as a prognostic marker in human bladder cancer

OBJECTIVES To evaluate c-erbB-2 gene amplification and its prognostic significance in transitional cell carcinoma of the bladder. METHODS Alterations in the gene copy number of c-erbB-2 were detected in 57 bladder tumor samples using a method based on the polymerase chain reaction. RESULTS Eighteen tumors (32%) showed gene amplification of c-erbB-2, which correlated with tumor grade and stage. A strong association of c-erbB-2 amplification with patient survival was also found. The amplification resulted in a significantly poorer prognosis among the patients with high-grade and/or invasive tumors. Multivariate analysis revealed that c-erbB-2 amplification and tumor grade were independent prognostic factors. CONCLUSIONS Our data indicate a possible role of the c-erbB-2 gene in the development of aggressive behavior in bladder tumors. Moreover, the use of c-erbB-2 gene amplification, together with tumor grade and stage, could provide an accurate basis for determining the prognosis of bladder cancer.

Chromophobe renal cell carcinoma with sarcomatoid change. A case report

Chromophobe renal cell carcinoma (RCC) is a newly established entity of renal neoplasm with histological and molecular biological features different from those of common RCCs. Chromophobe RCC shows characteristically cloudy and reticular cytoplasm and cellular features resembling distal nephron. Its prognosis has been reported to be more favorable than that of common RCCs. Recently, however, several cases have been reported which showed sarcomatoid change to present poor prognosis. Here we present a case of chromophobe RCC with sarcomatoid change which was once resected surgically. The surgically resected tumor was histologically composed of chromophobe epithelial cell sheets and sarcomatoid elements. The former showed positivity for colloid iron staining, and was immunohistochemically positive for E-cadherin and epithelial membrane antigen (EMA), whereas the latter was positive for vimentin instead of colloid iron and E-cadherin. EMA was focally positive in the sarcomatoid element. The patient died with systemic metastases 14 months after the operation. Histologically, the metastatic tumors were composed only of sarcomatoid element lacking epithelial element. Based on these findings and previous reports, this case supports the existence of a tumor progression pathway from chromophobe to sarcomatoid RCC. It is necessary to perform careful postoperative investigation of chromophobe RCC due to its possible histological progression to the sarcomatoid subtype.

A case of rhabdomyosarcoma of the bladder with a (2;5) chromosomal translocation in peripheral lymphocytes

Chromosome analysis was performed on peripheral blood lymphocytes of a patient with rhabdomyosarcoma of the urinary bladder. It showed a reciprocal t(2;5) translocation with the breakpoints at 2q37.3 and 5q31.3. This is the first report of such an anomaly in the peripheral lymphocytes of a patient with rhabdomyosarcoma of the urinary bladder.

Inhibition of PSA flare in prostate cancer patients by administration of flutamide for 2 weeks before initiation of treatment with slow-releasing LH-RH agonist

AbstractBackground. A prospective randomized study was designed to determine whether flutamide (FLU) administered before treatment with a luteinizing hormone-releasing hormone agonist (LH-RHa) prevented prostate-specific antigen (PSA) flare in prostate cancer patients. Methods. Prostate cancer patients were randomized into two groups and received either FLU (n = 11) or no pretreatment (n = 13) for 2 weeks before the initial injection of LH-RHa. LH-RHa (every 4 weeks) and FLU (every day) were administered throughout the period of this study. Blood samples, for the determination of PSA, testosterone (T), and luteinizing hormone levels, were collected before FLU administration, and before and 2, 7, 14, 28, 56, and 84 days after the first administration of LH-RHa. Results. Treatment with FLU prior to LH-RHa induced an early decline in PSA level. The mean PSA level showed no significant secondary rise after LH-RHa administration in those patients with FLU pretreatment. Patients in both groups showed T flare after the first LH-RHa administration. However, the number of patients with PSA flare was significantly lower in patients with prior FLU administration than in those with LH-RHa alone. Conclusion. These results clearly demonstrate that, in patients with prostatic cancer, the administration of FLU for 2 weeks prior to the first LH-RHa administration is effective in preventing PSA flare, as well as in inducing an early decline in PSA levels.

A Case of Vesical Varices as a Complication of Portal Hypertension and Manifested Gross Hematuria

We report a unique case of vesical varices in a patient who presented with an episode of serious gross hematuria. He also had cirrhosis of the liver and portal hypertension, and had undergone transection of the esophagus 10 years ago. A hemangiomatous mass was discovered on cystoscopic examination, and sonographic examination, computerized tomography and abdominal angiography revealed vesical varices. The genesis of vesical varices and possible treatment in this case are discussed.

Expression of androgen receptor in non-muscle-invasive bladder cancer predicts the preventive effect of androgen deprivation therapy on tumor recurrence

Our recent retrospective study revealed a significantly reduced risk of bladder cancer (BC) recurrence in men who received androgen deprivation therapy (ADT) for their prostate cancer. However, whether androgen receptor (AR) signals contributed to the preventive effect of ADT remained unclear because ADT could reduce serum estrogens as well. The purpose of this study is to investigate the associations between the expression of AR/estrogen receptors (ERs) and BC recurrence in patients treated with ADT. We immunohistochemically stained 72 BCs and 42 corresponding normal urothelial tissues. AR/ERα/ERβ were positive in 44(61%)/22(31%)/39(54%) tumors and 35(83%)/24(57%)/34(81%) corresponding normal urothelial tissues, respectively. There were no statistically significant correlations between AR/ERα/ERβ expression and clinicopathological features of BC. With a median follow-up of 31.3 months, 12 (43%) of 28 patients with AR-negative tumor versus 11 (23%) of 44 patients with AR-positive tumor experienced BC recurrence. Thus, patients with AR-positive tumor had a significantly lower risk of BC recurrence (P=0.031), compared with those with AR-negative tumor. Meanwhile, the expression of ERα/ERβ in tumors and that of AR/ERα/ERβ in normal urothelial tissues were not significantly correlated with BC recurrence. A multivariate analysis revealed AR positivity in tumors as an independent prognosticator (hazard ratio: 0.27; 95% confidence interval: 0.11-0.67) for BC recurrence. These results indicate that ADT prevents BC recurrence via the AR pathway, but not via the ERα/ERβ pathways.

A phase II study of prophylactic intravesical chemotherapy with 4′-epirubicin in recurrent superficial bladder cancer: comparison of 4′-epirubicin and Adriamycin

Since intravesical recurrence of superficial bladder cancer (Ta, T1) after transurethral resection (TUR) is frequent, adjuvant therapy to reduce the recurrence rate has been extensively investigated. Although intravesical chemotherapy has been employed for 30 years or more, neither the exact effect on the bladder epithelium nor the optimal dose and administration schedule has yet been clarified. In recent years, several derivatives of Adriamycin (ADR) have been developed, and 4′-epirubicin (FARM) is one of them. This drug has been shown to have antitumor effects almost equal to those of ADR and to produce less toxicity when given systemically as chemotherapy. In an attempt to clarify the effect of intravesical FARM in the prevention of recurrence of superficial bladder cancer, we conducted a prospective randomized trial to compare the effects of equal doses of FARM and ADR given by intravesical instillation after TUR in cases of highly recurrent superficial bladder cancer. A total of 73 patients with recurrent superficial bladder cancer were randomized to receive TUR and either 30 mg FARM or 30 mg ADR by intravesical instillation every 2–4 weeks for 1 year. The prophylactic effect on recurrence and the toxic effects of these drugs were investigated. The current results show that FARM provides efficacy almost equal to that of ADR in the prevention of recurrence in these patients. However, FARM also caused almost the same local toxic effects (bladder irritation, among others) as ADR. On the basis of these preliminary results, FARM is surmised to be one of the agents as beneficial as ADR in the prevention of recurrence of superficial bladder cancer.

Bellini Duct Carcinoma of the Kidney

We report a very rare case of Bellini duct carcinoma originating from the collecting tubules of the kidney. A left renal tumor was detected during a health examination and radical nephrectomy was performed. Histological examination showed papillary adenocarcinoma. By means of immunohistochemical methods, we felt that the tumor was a renal carcinoma of Bellini duct origin.