Yasuhide Hori

Radiofrequency Ablation Combined with Renal Arterial Embolization for the Treatment of Unresectable Renal Cell Carcinoma Larger Than 3.5 cm: Initial Experience

The purpose of the study was to evaluate the feasibility, safety, and therapeutic effects of the combination of renal arterial embolization and radiofrequency (RF) ablation to reinforce the anticancer effect on renal cell carcinomas (RCCs) measuring 3.5 cm or larger. This study was undertaken to evaluate this combined therapy on large RCCs-based tumor geometry. Eleven patients with 12 RCCs 3.5 cm or larger in diameter (3.5–9.0 cm) underwent combined therapy. Two were exophytic tumors, and the remaining 10 tumors had components extending into the renal sinus fat. Tumor vessels were selectively embolized in nine patients and the renal artery was completely embolized in two patients with polyvinyl alcohol or ethanol mixed with iodized oil. RF ablation was percutaneously done under the computed tomographic (CT)–fluoroscopic guidance. Response to treatment was evaluated by dynamic contrast-enhanced CT and magnetic resonance (MR) imaging. Tumor enhancement was eliminated after a single RF session in nine tumors (75%), after two sessions in two tumors (17%), and after four sessions in one tumor (8%). Both exophytic tumors (100%) and 7 of 10 tumors having components in the renal sinus fat (70%) were completely ablated with a single RF session. All tumors remained controlled during a mean follow-up period of 13 months and showed significant reduction in tumor sizes (5.2 ± 1.7 cm to 3.6 ± 1.4 cm, p < 0.001). A delayed abscess developed in the ablated lesion in a patient, which was percutaneously drainaged. Combined therapy as described in this report is a feasible, relatively safe, and promising treatment method for large RCCs regardless of tumor geometry.

Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma

In prostate cancer, tumor–stroma interactions play a critical role in the promotion of tumorigenesis, and thus the prevention of those interactions is a promising target to suppress tumor growth. Several studies demonstrated that alpha1-adrenoceptor (α1-AR) antagonists, therapeutic drugs for benign prostatic hyperplasia, have growth inhibitory effects on human prostate cancer (PCa) cells through induction of apoptosis or G1 cell-cycle arrest. However, their direct actions on stromal cells surrounding cancer cells have not yet been elucidated. In this study, we investigated the effects of subtype-selective α1-AR antagonists (naftopidil, tamsulosin, and silodosin) on prostate tumor growth with a focus on the role of stroma, using commercially available fibroblast cells (PrSC). Tumorigenic studies in vivo showed significant reductions in tumor growth when E9 cells (an androgen low-sensitive LNCaP subline) grafted with PrSC were treated with naftopidil. In in vitro analyses, naftopidil and silodosin showed antiproliferative effects on PCa cells regardless of androgen sensitivity and α1-AR subtype expression. In PrSC, a strong growth inhibitory effect was observed with naftopidil but not silodosin. Flow cytometric analysis revealed that naftopidil, but not silodosin, induced G1 cell-cycle arrest in both PCa cells and PrSC. In naftopidil-treated PrSC, total interleukin-6 protein was significantly reduced with increased suppression of cell proliferation. Silodosin induced weak early apoptosis only in PCa cells. These findings demonstrated that naftopidil strongly suppressed cell proliferation of stromal cells, resulting in decreased tumorigenic soluble factor, suggesting that naftopidil might be effective in preventing stromal support of tumor cells. Cancer Prev Res; 4(1); 87–96. ©2011 AACR.

Heterogenous induction of carcinoma‐associated fibroblast‐like differentiation in normal human prostatic fibroblasts by co‐culturing with prostate cancer cells

In the tumor microenvironment, carcinoma‐associated fibroblasts (CAFs) are considered to play a critical role in the promotion of tumorigenesis. However, the mechanisms that generate CAFs are not well elucidated. To understand how CAFs are generated during primary cancer progression, we investigated the biochemical characteristics of normal human prostate stromal cells (PrSC) co‐cultured with human prostate cancer (PCa) cells in vitro. In primary cultures of human PCa‐derived stromal cells (PCaSC‐8 and PCaSC‐9), expression of TNC, ACTA2, EGF, FGF7, and IGF1 mRNA was generally higher than PrSC but gene expression patterns were not uniform between PCaSC‐8 and PCaSC‐9 cells. Transforming growth factor β (TGFβ) and vascular endothelial growth factor (VEGF) protein levels in both PCaSC‐8 and PCaSC‐9 cells were generally higher than PrSC but levels of both secreted proteins were not same. When PrSCs were co‐cultured with androgen‐sensitive LNCaP cells or its sublines, androgen‐low‐sensitive E9 cells and androgen‐insensitive AIDL cells, mRNA expression of IGF1 was significantly increased in all combinations. In contrast, expression of COL1A1, TNC, and ACTA2 mRNA was significantly increased only in LNCaP + PrSC and E9 + PrSC co‐cultures. Protein production of VEGF was significantly increased only in LNCaP + PrSC and E9 + PrSC co‐cultures. Increase of TGFβ protein was observed only in E9 + PrSC co‐cultures. These biochemical characteristics of PrSC were partially recapitulated in TGFβ‐treated PrSC. We have demonstrated that normal fibroblasts co‐cultured with cancer cells become activated and exhibit biochemical characteristics of CAFs in a heterogenous manner. Our results suggest that heterogenous induction of CAF‐like differentiation might be strongly dependent on biochemical characteristics of adjacent cancer cells. J. Cell. Biochem. 112: 3604–3611, 2011.

Plasma sFas and sFas ligand levels in patients with thrombotic thrombocytopenic purpura and in those with disseminated intravascular coagulation

Fas, a member of the tumor necrosis receptor superfamily, is 36 kD surface protein containing a single transmembrane region and induces apoptosis by Fas–Fas ligand binding. Soluble Fas (sFas) is produced as the form lacking 21 amino acid residues containing the transmembrane domain by alternative splicing. We found that the plasma sFas levels of 33 patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), 19 patients with disseminated intravascular coagulation (DIC), and 10 non‐DIC patients with multiple organ failure (MOF) were significantly higher than those of 21 non‐DIC patients without organ failure and those of 25 healthy volunteers. The plasma sFas ligand levels of the TTP/HUS patients, the DIC patients, and the non‐DIC patients with MOF were significantly higher than those of the non‐DIC patients without organ failure and those of the healthy volunteers. The plasma sFas levels were significantly correlated with the plasma sFas ligand levels in all subjects. The plasma thrombomodulin (TM) levels were increased significantly in the TTP/HUS patients, the DIC patients, and the non‐DIC patients with MOF compared with the levels of the non‐DIC patients without organ failure and the healthy volunteers. The plasma sFas antigen levels were correlated significantly with the plasma TM levels in all subjects. These findings suggest that the increases of sFas and sFas ligand that cause apoptosis might be related to the vascular endothelial cell injuries in TTP and DIC with organ failure. Am. J. Hematol. 61:21–25, 1999.

Photoselective vaporization of the prostate using high power (80 W) KTP laser: One year follow up of the first 101 patients in Japan

Objectives:  We present one year observations on Photoselective Vaporization of the Prostate (PVP) of 101 men with benign prostatic hyperplasia (BPH) to investigate its safety and efficacy.

Effect of transforming growth factor α overexpression on urogenital organ development in mouse.

Transforming growth factor-α (TGFα) promotes cell proliferation by binding to the epidermal growth factor receptor (EGFR). TGFα and EGFR overexpression have been reported in various human cancers. However, whether TGFα induces cancer by itself is unknown in urogenital organs. To investigate whether TGFα overexpression induces carcinogenesis in urogenital organs, we analyzed the phenotypes of urogenital organs in male TGFα transgenic (TG) mice of the CD1 strain. Urogenital organs including the kidney, bladder, prostate, seminal vesicles, testes, and epididymis were isolated from 4- to 48-week-old TGFα TG and wild-type (WT) CD1 mice. Prostates were separated into anterior prostate (AP), dorsolateral prostate (DLP), and ventral prostate (VP). Neither tumor formation nor epithelial hyperplasia was observed in the TGFα TG mouse urogenital organs that we have investigated. Histopathologically, in prostate, we found an increased number of p63-positive basal epithelial cells in the TGFα TG mice AP and DLP. There was no morphological change in the stromal component, such as hypercellular stroma or fibrosis. However, bladder weight was greater in TGFα TG mice than that in WT mice, and distended bladders were observed macroscopically in 19 of 20 TGFα TG mice over 20 weeks of age. Ki67 labeling index was increased significantly in the TGFα TG mouse urethral epithelium, whereas neither epithelial hyperplasia nor hypertrophy was observed. In conclusion, our results suggest that TGFα overexpression in mouse urogenital organs alone may not be responsible for tumor formation and epithelial hyperplasia, but is involved in bladder outlet obstruction.

Manserin as a novel histochemical neuroendocrine marker in prostate cancer.

OBJECTIVES To investigate the presence of manserin in human prostate cancers and to correlate manserin expression with pathologic outcomes and progression-free survival. METHODS Eighty-seven patients with recent prostate cancer were classified into 4 groups based on Gleason score, and manserin immunohistochemistry was correlated with Gleason sum grade. To investigate the validity of manserin as a prognostic factor, the Cox proportional hazards regression model was performed on 48 patients in our cohort with T3 or T4 prostate cancer who were initially treated with androgen deprivation therapy. RESULTS The manserin-positive rates of patients with Gleason sums of 6, 7, 8, and ≥9 were 0%, 20.0%, 35.0%, and 48.1%, respectively. Manserin-positive rates were positively correlated with Gleason sums (P = 0.0001). Median times to cancer progression in groups with (n = 8) and without (n = 40) manserin expression were 8 months and 28 months, respectively (P = 0.01). Univariate Cox analysis revealed that manserin expression, clinical stage T4, and high Gleason sum were significantly associated with progression. Multivariate analysis revealed that only 2 factors, manserin expression (hazard ratio (HR) 4.99, P = 0.01) and clinical stage T4 (HR 4.77, P = 0.03), were independent risk factors for progression. CONCLUSIONS This is the first report of manserin expression in human prostate cancers. Manserin may serve as a marker of prostate cancer progression.

Ureteral stents for malignant extrinsic ureteral obstruction: outcomes and factors predicting stent failure

BackgroundThis study investigated the clinical outcomes of stent placement for malignant extrinsic ureteral obstruction (MUO) and predictive factors for stent failure.MethodsWe retrospectively analyzed clinical data for 91 patients with radiologically significant hydronephrosis due to MUO who underwent successful stent placement. In total, 132 ureters were stented for the decompression. Factors related to stent failure were analyzed with a Cox proportional hazards model.ResultsStent failure occurred in 25 ureters in 20 patients. The median interval to failure was 63 days. The multivariate analysis showed that the significant predictors of stent failure were bladder invasion and severe hydronephrosis before the stent insertion. The patients were divided into three groups based on these two factors: low-risk (neither factor; 85 patients), intermediate-risk (one factor; 37), and high-risk (both factors; 10). The median stent failure-free survival rate at 3 months was 94.8% in the low-risk, 71.8% in the intermediate-risk and 55.6% in the high-risk group, respectively. Of the ureters with stent failure, there was successful re-replacement of internal stents in 3 low-risk, 6 intermediate-risk and no high-risk ureters. Replacement by nephrostomy was done in 2 low-risk, 5 intermediate-risk and 7 high-risk ureters.ConclusionThe patients considered at low-risk could be managed without stent failure by internal stenting. However, the patients at high-risk may require the consideration of nephrostomy or other alternatives as the initial treatment. Our stratification model may allow better risk stratification for patients with regard to ureteral stenting, helping to identify patients for whom ureteral stenting is indicated.

The long-term results with delayed-combined androgen blockade therapy in local or locally advanced prostate cancer.

OBJECTIVE To evaluate long-term clinical outcomes in cT1c-T3a prostate cancer patients following delayed-combined androgen blockade therapy. METHODS From January 2001 to December 2004, 92 cT1c-T3a prostate cancer cases were enrolled. Medical castration and anti-androgen treatment were used sequentially as delayed-combined androgen blockade therapy. Time to prostate-specific antigen biochemical failure was estimated, and risk factors for prostate-specific antigen biochemical failure were evaluated. RESULTS The average patient age was 76.4 years (range, 59-91 years), the median observation period was 52.8 months (range, 26-106.6 months) and the median pre-treatment prostate-specific antigen level was 14 ng/ml (range, 3.68-492 ng/ml). The TNM classification distribution was as follows: T1c, n= 27; T2a, n = 39; T2b, n = 20; and T3a, n = 6. In the multivariate analysis, Gleasons score ≥8 (P < 0.05; hazard ratio, 3.02), prostate-specific antigen nadir >1.4 ng/ml (P = 0.001; hazard ratio, 8.76) and a half-life of the prostate-specific antigen level >1.2 months (P < 0.005; hazard ratio, 6.3) during the initial 6 months of luteinizing hormone-releasing hormone agonist monotherapy were significant independent risk factors for prostate-specific antigen biochemical failure with luteinizing hormone-releasing hormone agonist monotherapy. The high-risk group, which had at least one of these three risk factors, had a shorter time to prostate-specific antigen biochemical failure than the low-risk group, during luteinizing hormone-releasing hormone agonist monotherapy (P < 0.0001). For the total delayed-combined androgen blockade therapy observation period, the free-prostate-specific antigen biochemical failure rate was 88.3% at 5 years. Only a maintenance period following luteinizing hormone-releasing hormone agonist monotherapy (P < 0.005; hazard ratio, 16.8) was revealed to be a significant independent risk factor for prostate-specific antigen biochemical failure with total delayed-combined androgen blockade. CONCLUSIONS The free-prostate-specific antigen biochemical failure rate of delayed-combined androgen blockade therapy in our study was as valuable as those in other androgen deprivation therapy of previous reports.

Ureteral obstruction associated with pelvic inflammatory disease in a long-term intrauterine contraceptive device user

Abstract  We report herein a case of ureteral obstruction associated with pelvic inflammatory disease in a long‐term intrauterine contraceptive device (IUD) user. A 62‐year‐old woman presented with a 2‐week history of left flank pain and high fever, but no abdominal pain. She had forgotten the use of an IUD. Retrograde pyelography showed a stricture in the lower third of the left ureter. Magnetic resonance showed swelling of the uterus wall and left parametria, but did not reveal the presence of an IUD. Subtotal hysterectomy, bilateral salpingo‐oophorectomy and left nephronureterectomy was performed. The IUD was then found in the uterine cavity. The results of pathological and bacteriological findings for Actinomyces infection were negative. Therefore we diagnosed this case as ureteral obstruction associated with pelvic inflammatory disease. Ureteral obstruction associated with pelvic inflammatory disease in a long‐term IUD user is extremely rare.