Tsunehito Kambara

Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer

BackgroundLymphovascular invasion (LVI) and lymph node metastasis are conventional pathological factors associated with an unfavorable prognosis of urothelial carcinoma of the upper urinary tract (UC-UUT), but little is known about the molecular mechanisms underlying LVI and nodal metastasis in this disease. Rac1 small GTPase (Rac1) is essential for tumor metastasis. Activated GTP-bound Rac1 (Rac1 activity) plays a key role in activating downstream effectors known as Pak (21-activated kinase), which are key regulators of cytoskeletal remolding, cell motility, and cell proliferation, and thus have a role in both carcinogenesis and tumor invasion.MethodsWe analyzed Rac1 activity and Pak1 protein expression in matched sets of tumor tissue, non-tumor tissue, and metastatic lymph node tissue obtained from the surgical specimens of 108 Japanese patients with UC-UUT.ResultsRac1 activity and Pak1 protein levels were higher in tumor tissue and metastatic lymph node tissue than in non-tumor tissue (both P < 0.0001). A high level of Rac1 activity and Pak1 protein expression in the primary tumor was related to poor differentiation (P < 0.05), muscle invasion (P < 0.01), LVI (P < 0.0001), and lymph node metastasis (P < 0.0001). Kaplan-Meier survival analysis showed that an increase of Rac1 activity and Pak1 protein was associated with a shorter disease-free survival time (P < 0.01) and shorter overall survival (P < 0.001). Cox proportional hazards analysis revealed that high Rac1 activity, Pak1 protein expression and LVI were independent prognostic factors for shorter overall and disease-free survival times (P < 0.01) on univariate analysis, although only Pak1 and LVI had an influence (P < 0.05) according to multivariate analysis.ConclusionsThese findings suggest that Rac1 activity and Pak1 are involved in LVI and lymph node metastasis of UC-UUT, and may be prognostic markers for this disease.

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.

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.

Prognostic significance of global grading system of Gleason score in patients with prostate cancer with bone metastasis

Study Type – Prognosis (case series)
Level of Evidence 4

Renal Metanephric Adenoma Mimicking Papillary Renal Cell Carcinoma on Computed Tomography: A Case Report

We present a case of renal metanephric adenoma (MA) mimicking papillary renal cell carcinoma (PRCC) on computed tomography (CT). In the present case, double-phase enhanced CT showed a hypovascular right renal tumor with gradual and prolonged enhancement. The renal tumor was surgically removed. Histological examination of the resected specimen showed renal MA. Although the radiological features of renal MA have been described by some authors, only a few reports have mentioned the pattern of enhancement on multiphase enhanced CT. The pattern of enhancement of a renal tumor is likely to be correlated with its pathological features. Since renal MA is thought to be genetically related to PRCC, these two tumors are likely to demonstrate similar radiological features, so that differentiating between them becomes difficult. In patients with a hypovascular renal mass that shows gradual and prolonged enhancement on multiphase enhanced CT, the diagnosis of renal MA should be considered.

Single minimum incision endoscopic radical nephrectomy for renal tumors with preoperative virtual navigation using 3D-CT volume-rendering

BackgroundSingle minimum incision endoscopic surgery (MIES) involves the use of a flexible high-definition laparoscope to facilitate open surgery. We reviewed our method of radical nephrectomy for renal tumors, which is single MIES combined with preoperative virtual surgery employing three-dimensional CT images reconstructed by the volume rendering method (3D-CT images) in order to safely and appropriately approach the renal hilar vessels. We also assessed the usefulness of 3D-CT images.MethodsRadical nephrectomy was done by single MIES via the translumbar approach in 80 consecutive patients. We performed the initial 20 MIES nephrectomies without preoperative 3D-CT images and the subsequent 60 MIES nephrectomies with preoperative 3D-CT images for evaluation of the renal hilar vessels and the relation of each tumor to the surrounding structures. On the basis of the 3D information, preoperative virtual surgery was performed with a computer.ResultsSingle MIES nephrectomy was successful in all patients. In the 60 patients who underwent 3D-CT, the number of renal arteries and veins corresponded exactly with the preoperative 3D-CT data (100% sensitivity and 100% specificity). These 60 nephrectomies were completed with a shorter operating time and smaller blood loss than the initial 20 nephrectomies.ConclusionsSingle MIES radical nephrectomy combined with 3D-CT and virtual surgery achieved a shorter operating time and less blood loss, possibly due to safer and easier handling of the renal hilar vessels.

Adenocarcinoma with extensive neuroendocrine differentiation arising in an ileal diverticulum: report of a case.

A 62-year-old man presented with right-sided abdominal pain. Radiologic examinations disclosed a solid tumor in the ileocecal mesentery that obstructed the right ureter, thus resulting in urinary extravasation. An en bloc tumor resection with the ascending colon, the terminal ileum, and a portion of the right ureter was performed. Histopathologically, the tumor was adenocarcinoma with extensive neuroendocrine differentiation which had arisen in an ileal diverticulum. The patient developed metastases to the lymph nodes, liver, and brain, and died 18 months after surgery.

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.

Performance characteristics of prostate-specific antigen density and biopsy core details to predict oncological outcome in patients with intermediate to high-risk prostate cancer underwent robot-assisted radical prostatectomy

BackgroundMany urologic surgeons refer to biopsy core details for decision making in cases of localized prostate cancer (PCa) to determine whether an extended resection and/or lymph node dissection should be performed. Furthermore, recent reports emphasize the predictive value of prostate-specific antigen density (PSAD) for further risk stratification, not only for low-risk PCa, but also for intermediate- and high-risk PCa. This study focused on these parameters and compared respective predictive impact on oncologic outcomes in Japanese PCa patients.MethodsTwo-hundred and fifty patients with intermediate- and high-risk PCa according to the National Comprehensive Cancer Network (NCCN) classification, that underwent robot-assisted radical prostatectomy at a single institution, and with observation periods of longer than 6 months were enrolled. None of the patients received hormonal treatments including antiandrogens, luteinizing hormone-releasing hormone analogues, or 5-alpha reductase inhibitors preoperatively. PSAD and biopsy core details, including the percentage of positive cores and the maximum percentage of cancer extent in each positive core, were analyzed in association with unfavorable pathologic results of prostatectomy specimens, and further with biochemical recurrence. The cut-off values of potential predictive factors were set through receiver-operating characteristic curve analyses.ResultsIn the entire cohort, a higher PSAD, the percentage of positive cores, and maximum percentage of cancer extent in each positive core were independently associated with advanced tumor stage ≥ pT3 and an increased index tumor volume > 0.718 ml. NCCN classification showed an association with a tumor stage ≥ pT3 and a Gleason score ≥8, and the attribution of biochemical recurrence was also sustained. In each NCCN risk group, these preoperative factors showed various associations with unfavorable pathological results. In the intermediate-risk group, the percentage of positive cores showed an independent predictive value for biochemical recurrence. In the high-risk group, PSAD showed an independent predictive value.ConclusionsPSAD and biopsy core details have different performance characteristics for the prediction of oncologic outcomes in each NCCN risk group. Despite the need for further confirmation of the results with a larger cohort and longer observation, these factors are important as preoperative predictors in addition to the NCCN classification for a urologic surgeon to choose a surgical strategy.

Elevated serum levels of cardiovascular biomarkers are associated with progression of renal cancer

Objective Renal cell carcinoma (RCC) is a hypervascular tumour due to high constitutive production of vascular endothelial growth factor (VEGF), which is activated by hypoxia-inducible factor (HIF). Elevated levels of cardiovascular peptides, including brain natriuretic peptide (BNP), have been reported in patients with cancer, regardless of whether they have overt cardiovascular disease. Furthermore, it has been demonstrated that hypoxia stimulates BNP production by an HIF-dependent manner. However, the clinical implications of such cardiovascular peptides in patients with RCC have not been assessed. Methods In patients with clear cell RCC who underwent nephrectomy, we investigated the relationship between the serum level of BNP or N-terminal pro-BNP (NT-proBNP) and various clinicopathological characteristics, including serum VEGF and expression of BNP and HIF-2 alpha in the primary tumour. Results Elevated preoperative serum levels of BNP, NT-proBNP and VEGF, as well as increased tumour expression of HIF-2 alpha, were associated with a worse performance status, local invasion, distant metastasis and shorter overall survival. HIF-2 alpha expression showed a positive correlation with the preoperative serum VEGF level, while there was no relation between the serum levels of BNP/NT-proBNP and VEGF or tumour expression of HIF-2 alpha. BNP expression was very low in both tumour tissues and normal kidney tissues. Serum levels of BNP, NT-proBNP and VEGF all decreased significantly after nephrectomy. Conclusions Our findings suggested that the preoperative serum levels of BNP and NT-proBNP are markers of tumour progression, as well as indicators of subclinical functional and structural myocardial damage in patients with advanced RCC.