Masahiro Yashi

Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma

BackgroundThe system L amino acid transporter (LAT) has an important role in the transport of various amino acids, and there have been reports about the relation of this system to cancer. Although LATs are highly expressed in the kidneys, little is known about their influence on human renal cancer.MethodsTo clarify the role of LATs in human clear cell renal cell carcinoma (RCC), we investigated the expression of mRNAs for LAT1, LAT2, LAT3, LAT4, and 4F2hc in clear cell RCC tissues. The mRNAs of these five genes were analyzed by the real-time reverse transcription polymerase chain reaction in matched sets of tumor and non-tumor tissues obtained at operation from 82 Japanese patients with clear cell RCC. We also measured phosphorylated S6 ribosomal protein (Ser-235/236) proteins levels in 18 paired tumor and non-tumor tissues of the patients by Western blotting.ResultsExpression of LAT1 mRNA was significantly increased in tumor tissue compared with non-tumor tissue, while expression of LAT2 and LAT3 mRNAs was reduced. There was no difference in the expression of LAT4 and 4F2hc mRNAs between tumor and non-tumor tissues. Increased expression of LAT1 mRNA was associated with less differentiated tumors, local invasion, microscopic vascular invasion, and metastasis. Kaplan-Meier survival analysis showed that a higher serum LAT1 mRNA level was associated with a shorter overall survival time. Phosphorylated S6 ribosomal protein levels were associated with metastatic potential. LAT1 mRNA levels positively correlated with phosphorylated S6 ribosomal protein proteins levels in primary tumors.ConclusionsThese findings suggest that LAT1 mRNA is related to the invasive and progressive potential of clear cell RCC.

Anteroposterior Dissection HoLEP: A Modification to Prevent Transient Stress Urinary Incontinence

OBJECTIVES The prevalence of transient stress urinary incontinence (SUI) after HoLEP has been reported to be as high as 44%. Anteroposterior dissection HoLEP was newly developed to protect the urethral sphincter and therefore lower the incidence rate of SUI. This study was conducted to determine the SUI incidence rate after anteroposterior dissection HoLEP. METHODS Sixty-eight consecutive patients with benign prostatic hyperplasia underwent HoLEP from January to December 2008. The first 31 cases (Surgery 1) underwent HoLEP according to Gillings method. The next 37 cases (Surgery 2) underwent anteroposterior dissection HoLEP, where adenoma was dissected antegradely. This antegrade movement of the cystoscope allows the apical gland to be removed from the sphincter without causing damage. Surgical quality indexes (hemoglobin change, operating time, resected prostate volume) between the 2 groups were compared. All patients were assessed at 2 weeks postoperatively for clinical SUI, international prostate symptom score (IPSS), quality of life (QoL), and peak flow rates (Q(max)). RESULTS Patient characteristics and surgical quality indexes did not differ between the 2 groups. Clinical SUI was found in 25.2% of cases in the Surgery 1 group, but only 2.7% in the Surgery 2 group. IPSS, QoL and Q(max.) were significantly improved postoperatively in both groups. At 2 weeks, the QoL of the Surgery 2 group was significantly improved compared with that observed for Surgery 1 (1.5 ± 1.1 vs 2.4 ± 1.0, P = .02). The Q(max.) of Surgery 2 was significantly higher compared with Surgery 1 (19.8 ± 8.4 vs 13.0 ± 4.7 ml/s, P = .02). CONCLUSIONS These results indicate that our anteroposterior dissection HoLEP is a promising procedure to avoid postoperative SUI and also to substantially improve QoL.

Clinically significant association between the maximum standardized uptake value on 18F-FDG PET and expression of phosphorylated Akt and S6 kinase for prediction of the biological characteristics of renal cell cancer

BackgroundThe relationship between the clinicopathological features and molecular changes associated with standardized uptake value (SUV) determined by Positron emission tomography (PET) with [18F] fluorodeoxyglucose (18F-FDG PET) in human renal cell carcinoma (RCC) has not been elucidated. On the other hand, overactivation of the phosphatidylinositol 3’kinase (PI3K), serine/threonine kinase Akt, and mammalian target of rapamycin (mTOR) pathway has been detected in a variety of human cancers, including RCC. So far, little is known about the relationship between the SUV and these proteins in human RCC. Thus, it is important to study the relevance of SUV with clinicopathological features in human RCCs from a molecular point of view.MethodsSeventy-seven consecutive patients with RCC who underwent nephrectomy and pretreatment determination of the maximum SUV (SUVmax) by 18F-FDG PET were analyzed. We investigated the relationship between the SUVmax, phosphorylated-Akt (Ser-473) (pAkt(Ser-473)), phosphorylated-Akt (Thr-308) (pAkt(Thr-308), and phosphorylated-S6 ribosomal protein (Ser-235/236) (pS6) protein levels in the primary tumor and various clinicopathological features.ResultsThe average SUVmax of the primary tumor was 6.9 (1.5 to 40.3). A higher SUVmax was correlated with higher expression of pAkt(Ser-473), pAkt (Thr-308), and pS6 protein in the primary tumor. A higher SUVmax and increased expression of pAkt (Ser-473), pAkt (Thr-308), and pS6 of the primary tumor was associated with less tumor differentiation, a higher pT stage, regional lymph node involvement, microscopic vascular invasion, and distant metastasis, as well as with early relapse following radical nephrectomy in patients who had localized or locally advanced RCC without distant metastasis (cTanyNanyM0) and with shorter overall survival in all patients.ConclusionsA higher SUVmax on 18F-FDG PET is associated with elevated tumor levels of pAkt and pS6 protein and with aggressive behavior and metastatic potential of RCC, as well as with early relapse following radical nephrectomy and shorter overall survival. These findings suggest that SUVmax may be useful for predicting the biological characteristics of RCC.

The Rho-kinase inhibitor HA-1077 suppresses proliferation/migration and induces apoptosis of urothelial cancer cells

BackgroundActivation of Rho, one of the small GTPases, and its major downstream target Rho-kinase (ROCK) promotes the development and metastasis of cancer. We previously showed that elevation of Rho and ROCK expression was associated with tumor invasion, metastasis, and an unfavorable prognosis in patients with urothelial cancer of the bladder or upper urinary tract.MethodsWe investigated the effects of a ROCK inhibitor on the growth, migration, and apoptosis of bladder cancer cells. We also examined phosphorylation of RhoA (RhoA activity) by measuring its GTP-bound active form and assessed the expression of ROCK to explore the underlying molecular mechanisms.ResultsLysophosphatidic acid (LPA) and geranylgeraniol (GGOH) induced an increase of cell proliferation and migration in association with promotion of RhoA activity and upregulation of ROCK expression. The ROCK inhibitor fasudil (HA-1077) suppressed cell proliferation and migration, and also induced apoptosis in a dose-dependent manner. HA-1077 dramatically suppressed the expression of ROCK-I and ROCK-II, but did not affect RhoA activity.ConclusionsThese findings suggest that ROCK could be a potential molecular target for the treatment of urothelial cancer.

Leiomyoma of the Ureter

We report a case of leiomyoma of the ureter, and the patient underwent partial ureteral resection. This is the 8th case reported after 1955, and the clinical features of ureteral leiomyomas of these 8 cases are discussed.

Clinical significance of serum soluble T cell regulatory molecules in clear cell renal cell carcinoma.

To clarify the role of serum soluble T cell regulatory molecules in clear cell renal cell carcinoma (CCRCC), we measured the serum levels of soluble interleukin-2 receptor (sIL-2R), soluble B7-H3 (sB7-H3), and soluble cytotoxic T lymphocyte associated antigen-4 (sCTLA-4) in 70 CCRCC patients and 35 healthy controls. We investigated correlations between the serum levels of these soluble T cell regulatory molecules and the pathological grade, clinical stage, and prognosis of CCRCC. We also assessed the relations among each of these soluble molecules. As a result, the serum level of sIL-2R was significantly higher in CCRCC patients than in healthy controls (P < 0.05). In addition, elevation of serum sIL-2R was significantly correlated with the clinical stage (P < 0.001), and the survival of patients with high sIL-2R levels was shorter than that of patients with low sIL-2R levels (P < 0.05). Furthermore, the serum level of sB7-H3 was also significantly correlated with the clinical stage (P < 0.05), while the sIL-2R and sB7-H3 levels showed a positive correlation with each other (R = 0.550, P < 0.0001). These results indicate that the serum level of sIL-2R reflects tumor progression in CCRCC patients. In addition, the possibility was suggested that the IL-2/IL-2R and B7-H3 pathways may be involved in the progression of CCRCC.

Lower ureteral replacement using a tubularized gastric segment

OBJECTIVES To review our early experience with the use of a gastric segment for lower ureteral replacement in patients with bilateral ureteral stenosis after pelvic radiotherapy. METHODS Four adult patients (three women and one man) underwent bilateral ureteral substitution using stomach. All patients received whole pelvic irradiation for malignant disease and had undergone bilateral nephrostomy because of severe bilateral ureteral stenosis. The postoperative follow-up period was 11 to 50 months. RESULTS No major complication was recognized, and the bilateral nephrostomy tubes were removed in all patients. Three female patients could void urethrally without incontinence, and the male patient needed regular self-catheterization. The three women were alive with normal renal function at a follow-up of 11 to 50 months. The man had a vesicorectal fistula 8 months postoperatively, and colostomy was performed. He died of a cause unrelated to the operation 11 months after surgery. CONCLUSIONS Stomach has not been used commonly for ureteral replacement. In patients with bilateral severe ureteral stenosis after pelvic radiotherapy, ureteral substitution with a gastric segment can be safely performed and will increase the patients quality of life.

Axitinib for preoperative downstaging of renal cell carcinoma with sarcomatoid differentiation and direct invasion of the duodenum and inferior vena cava: a case report.

Background Renal cell carcinoma (RCC) with sarcomatoid differentiation is invasive, refractory to treatment, and has a higher mortality. Therefore, systemic therapy is still challenging, and the curative resection of localized or locally advanced RCC with sarcomatoid differentiation is very important. Axitinib is a potent and selective second-generation vascular endothelial growth factor receptor tyrosine kinase inhibitor with improved safety and tolerability. Axitinib is generally recommended as second-line therapy for advanced RCC because the phase III axitinib versus sorafenib in advanced RCC (AXIS) trial demonstrated that it achieved longer progression-free survival than sorafenib in patients with metastatic RCC after failure of an approved first-line regimen. Methods We present a 73-year-old man who had a large (13 cm in diameter) right RCC with sarcomatoid differentiation that directly invaded the duodenum and inferior vena cava. The patient presented with gastrointestinal bleeding, was unable to eat solid food, and had become emaciated. Thus, his classification was poor risk with anemia, hypercalcemia, and poor performance status, according to the Memorial Sloan-Kettering Cancer Center criteria. He seemed unlikely to survive if radical nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed. To reduce the tumor burden and potential operative complications, we administered axitinib as first-line neoadjuvant therapy. Results Six weeks of treatment reduced the tumor burden without causing severe toxicities. Subsequently, radical right nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed successfully. The pathological treatment effect of axitinib was grade 2 (two-thirds necrosis). The resected tumor showed a heterogeneous reaction for phosphorylated Akt (Ser-473) by Western blotting and immunohistochemistry, indicating that parts of the tumor were sensitive to axitinib and other parts were not. Conclusion Axitinib might be promising as preoperative or neoadjuvant therapy for locally advanced RCC (>cT3b or >cTanyN1).

Metronomic oral cyclophosphamide chemotherapy possibly contributes to stabilization of disease in patients with metastatic castration-resistant prostate cancer: a prospective analysis of consecutive cases.

INTRODUCTION/BACKGROUND Castration-resistant prostate cancer remains a therapeutic challenge, even after establishing the survival benefits of docetaxel chemotherapy. Metronomic chemotherapy stabilizes various cancers through antiangiogenic and immunomodulatory effects. We evaluate the activity of metronomic oral cyclophosphamide chemotherapy in metastatic CRPC patients, and assess predictive factors for clinical outcomes. PATIENTS AND METHODS Twenty-four patients with metastatic CRPC received an oral cyclophosphamide and dexamethasone regimen. Of those, 11 patients (45.8%) had been exposed and resistant to previous docetaxel chemotherapy. Six patients had refused to receive docetaxel chemotherapy, and 7 patients could not receive the therapy because of deteriorated performance status. All patients had already shown resistance to continuous dexamethasone therapy. Demographic and clinical data were collected prospectively. RESULTS A total of 16 patients (66.7%) experienced a reduction in PSA levels, and PSA decrease ≥ 50% was observed in 8 patients (33.3%). The median PSA progression-free and overall survival were 5.0 months and 19.0 months, respectively. The favorable PSA decrease had no associations with the progression-free and overall survival, but 7 patients (29.2%) in whom response had exceeded 8 months achieved long overall survival of 28 months in median. None of the patients discontinued therapy because of the presence of toxicities. CONCLUSION Metronomic cyclophosphamide is an active and well tolerated chemotherapy and can be an option for metastatic CRPC patients. The benefit of this regimen could not always be evaluated according to a favorable PSA decrease; thus, we must identify the predictive factors of response other than known clinical factors.

Ring-Enhanced Malignant Meningioma Mimicking a Brain Metastasis from a Renal Cell Carcinoma

We report a case of ring-enhanced malignant meningioma mimicking a solitary brain metastasis in a patient with renal cell carcinoma. This misleading situation is rarely encountered and has not been documented previously. Considering the low incidence of brain metastases from a renal cell carcinoma staged T1–2 without systemic metastases, a clinical diagnosis requires circumspection, and both primary and metastatic tumors should be considered when a solitary brain lesion is encountered.