[Show abstract][Hide abstract] ABSTRACT: The 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.
Seventy-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.
The 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.
A 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.
BMC Cancer 12/2015; 15(1):1097. DOI:10.1186/s12885-015-1097-0 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
Castration-resistant prostate cancer (CRPC) 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 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 due to deteriorated performance status (PS). All patients had already shown resistance to continuous dexamethasone therapy. Demographic and clinical data were collected prospectively.
A total of 16 patients (66.7%) experienced a reduction in prostate-specific antigen (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%) that had exceeded the response ≥ 8 months achieved long overall survival of 28 months in median. None of the patients discontinued therapy due to the presence of toxicities.
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 by favorable PSA decrease; thus, we must identify the predictive factors of response other than known clinical factors.
Clinical Genitourinary Cancer 10/2014; 12(5). DOI:10.1016/j.clgc.2014.02.007 · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
BioMed Research International 06/2014; 2014:396064. DOI:10.1155/2014/396064 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Gleason pattern 3 less often has molecular abnormalities and often behaves indolent. It is controversial whether low grade small foci of prostate cancer (PCa) on biopsy could avoid immediate treatment or not, because substantial cases harbor unfavorable pathologic results on prostatectomy specimens. This study was designed to identify clinical predictors for classical and redefined insignificant cancer on prostatectomy specimens in Japanese men with favorable pathologic features on biopsy.
Retrospective review of 1040 PCa Japanese patients underwent radical prostatectomy between 2006 and 2013. Of those, 170 patients (16.3%) met the inclusion criteria of clinical stage ≤ cT2a, Gleason score (GS) ≤ 6, up to two positive biopsies, and no more than 50% of cancer involvement in any core. The associations between preoperative data and unfavorable pathologic results of prostatectomy specimens, and oncological outcome were analyzed. The definition of insignificant cancer consisted of pathologic stage ≤ pT2, GS ≤ 6, and an index tumor volume < 0.5 mL (classical) or 1.3 mL (redefined).
Pathologic stage ≥ pT3, upgraded GS, index tumor volume ≥ 0.5 mL, and ≥ 1.3 mL were detected in 25 (14.7%), 77 (45.3%), 83 (48.8%), and 53 patients (31.2%), respectively. Less than half of cases had classical (41.2%) and redefined (47.6%) insignificant cancer. The 5-year recurrence-free survival was 86.8%, and the insignificant cancers essentially did not relapse regardless of the surgical margin status. MRI-estimated prostate volume, tumor length on biopsy, prostate-specific antigen density (PSAD), and findings of magnetic resonance imaging were associated with the presence of classical and redefined insignificant cancer. Large prostate volume and short tumor length on biopsy remained as independent predictors in multivariate analysis.
Favorable features of biopsy often are followed by adverse pathologic findings on prostatectomy specimens despite fulfilling the established criteria. The finding that prostate volume is important does not simply mirror many other studies showing PSAD is important, and the clinical criteria for risk assessment before definitive therapy or active surveillance should incorporate these significant factors other than clinical T-staging or PSAD to minimize under-estimation of cancer in Japanese patients with low-risk PCa.
[Show abstract][Hide abstract] ABSTRACT: 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.
Urologia Internationalis 10/2012; 90(3). DOI:10.1159/000341940 · 1.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interferon (IFN) alpha is one of the central agents in immunotherapy for renal cell carcinoma (RCC). It acts by binding to the IFN-alpha receptor (IFNAR). We previously reported that increased tumor expression of IFNAR2 mRNA was associated with the metastatic potential and progression of RCC, as well as with a poor response of metastatic RCC to IFN-alpha therapy. This study investigated the influence of serum IFNAR2 in RCC patients.
We measured serum IFNAR2 mRNA levels and quantified IFNAR mRNA expression in paired tumor and non-tumor tissues from the surgical specimens of 66 consecutive RCC patients by the real-time reverse transcription polymerase chain reaction (RT-PCR). We also measured phosphorylated Akt (Ser-473) and phosphorylated-S6 ribosomal protein (Ser-235/236) proteins levels in paired tumor and non-tumor tissues of patients with metastatic RCC by Western blotting.
The serum level of IFNAR2 mRNA was not associated with its tumor tissue level. Serum IFNAR2 mRNA was positively correlated with tumor size (P < 0.05), but not with tumor grade, pT stage, metastasis, microscopic vascular invasion, or serum C-reactive protein. Serum levels of IFNAR2 mRNA were significantly higher in patients with a good response to IFN-alpha ± sorafenib than in those with a poor response (P < 0.0001). Tumor tissue IFNAR2 mRNA levels and phosphorylated-S6 ribosomal protein (Ser-235/236) levels were associated with metastatic potential (P < 0.001 and P < 0.01, respectively), and patients with a low IFNAR2 mRNA level and low phosphorylated Akt (Ser-473) protein level in the primary tumor showed a good response to IFN-α ± sorafenib (IFN-α ± Sor: CR-PR) (P < 0.01 and P < 0.05, respectively). Kaplan-Meier survival analysis showed that a higher serum IFNAR2 mRNA level was associated with longer overall survival of treated patients (P < 0.05), while a higher tumor tissue IFNAR2 mRNA level was related to shorter overall survival (P < 0.01).
Our findings suggest that a high serum level of IFNAR2 mRNA may be a useful marker for predicting the response of metastatic RCC to IFN-alpha ± sorafenib therapy.
Cancer Immunology and Immunotherapy 02/2011; 60(6):793-808. DOI:10.1007/s00262-011-0989-3 · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lymphovascular 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.
We 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.
Rac1 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.
These 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.
BMC Cancer 04/2010; 10:164. DOI:10.1186/1471-2407-10-164 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Single 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.
Radical 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.
Single 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.
Single 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.
[Show abstract][Hide abstract] ABSTRACT: To investigate the influence of the revised Gleason grading system (GGS, revised at a consensus conference organized by the International Society of Urological Pathology in 2005) on prediction of prognosis for patients with prostate cancer with bone metastasis.
Prostatic needle biopsy specimens from 113 patients with prostate cancer with bone metastasis were scored using the conventional GGS (CGGS), modified global GGS (MGGGS), and modified highest GGS (MHGGS). The patients were divided into two groups (Gleason score < or = 7 and > or = 8) using each grading system. Prostate-specific antigen failure-free survival after hormone therapy (HT) was estimated retrospectively. The Cox proportional hazard method was used for univariate and multivariate analysis.
Patients with a Gleason score of < or = 7 had a significantly longer remission than patients with a score of > or = 8 according to each GGS. However, the better prognosis patients were detected more precisely by the CGGS and MGGGS than the MHGGS. Multivariate analysis showed that the CGGS and MGGGS were significant prognostic indicators for the outcome of HT after adjustment for other prognostic factors.
These results suggest that the CGGS and MGGGS are more useful than the MHGGS as prognostic indicators for HT. Further evaluation in larger series is needed to define its clinical usefulness.
BJU International 11/2009; 105(11):1519-25. DOI:10.1111/j.1464-410X.2009.09048.x · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 32-year-old man underwent orchiectomy for his right testicular tumor (pure seminoma, pT1, stage A(I)). Pelvic and para-aortic lymph nodes were irradiated with 18 Gy as adjuvant therapy. Two years later, he developed low back pain. Computed tomography, magnetic resonance imaging and bone scans showed an enhanced mass at the 10th left costa. Aspiration cytology showed seminoma. After administration of chemotherapy with bleomycin, etoposide and cisplatinum, following high dose chemotherapy with peripheral blood stem cell transplantation, the costal lesion was diminished and symptoms relieved. Then radical costectomy was performed. A histopathological study showed non-viable cells of seminoma. Post-operative progress was uneventful. Testicular pure seminoma with bone metastasis is rare, and to our knowledge, only 9 cases have been reported.
[Show abstract][Hide abstract] ABSTRACT: A 67-year-old male presented for examination of a retroperitoneal tumor, incidentally found by abdominal computed tomography (CT). CT and magnetic resonance imaging (MRI) revealed a round heterogeneous tumor, 10 cm in diameter, at the left renal hilus and involving the left renal vein. The tumor was low-intensity on T1-weighted MRI imaging, and high-intensity on T2-weight MRI imaging. The tumor was easily resected via a transabdominal approach. The pathological diagnosis was ganglioneuroma.
[Show abstract][Hide abstract] ABSTRACT: 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.
Surgery Today 02/2002; 32(5):439-42. DOI:10.1007/s005950200071 · 1.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine whether the K-ras oncogene is associated with parathyroid hormone-related protein (PTHrP) production in renal cell carcinoma (RCC) and whether the serum value of PTHrP is related to the patients' survival.
The serum levels of PTHrP and corrected serum calcium levels were analysed in 51 consecutive patients (29 men and 22 women, mean age 63.7 years, range 33-82) with newly diagnosed RCC. Matched pairs were analysed of the mRNA levels of K-ras and PTHrP in tumour and in corresponding non-tumour tissue originating from the same patient, using the polymerase chain reaction after reverse transcription.
Seven patients had elevated serum PTHrP values at the diagnosis of RCC. The mRNA expression of K-ras and PTHrP were detected in both tumour and non-tumour tissues, with K-ras mRNA levels being higher in the former than the latter (P < 0.05), and correlated with tumour stage (P < 0.05). There were no differences in PTHrP mRNA levels between the tissues. Furthermore, the mRNA levels of K-ras and PTHrP in seven tumours from patients with high serum values of PTHrP were higher than in tumours from those with normal values (both P < 0.01). The expression of mRNAs of K-ras and PTHrP was positively correlated (r = 0.771, P < 0.001). In seven patients with high serum PTHrP values the mRNA levels of PTHrP correlated with serum values of PTHrP and calcium (r = 0.875, P < 0.01 and r = 0.762, P < 0.05, respectively). Kaplan-Meier plots of survival rate in patients with elevated or normal serum PTHrP showed that high serum PTHrP was associated with a shorter overall survival (P < 0.05). The Cox proportional hazards model showed that serum PTHrP was an independent predictor of overall survival (P < 0.05).
These findings suggest that K-ras may be associated with PTHrP-induced hypercalcaemia and that PTHrP levels may reflect the aggressiveness of tumour cells through the K-ras oncogene in RCC.
BJU International 12/2001; 88(9):960-6. DOI:10.1046/j.1464-4096.2001.01294.x · 3.13 Impact Factor