Minoru Horinaga

Enhanced Antitumor Effect of Coincident Intravesical Gemcitabine Plus BCG Therapy in an Orthotopic Bladder Cancer Model

OBJECTIVES To evaluate the antitumor effect of the coincident administration of intravesical gemcitabine (Gem) plus bacillus Calmette-Guérin (BCG) in an orthotopic bladder cancer model. METHODS We evaluated the cytotoxic effect of gemcitabine against MBT-2 cells in vitro. Orthotopic tumors were established by implanting MBT-2 cells into the bladder of syngeneic female C3H mice. Intravesical Gem administration was evaluated at various doses: 0 mg (control); 1, 2, 4, and 8 mg (n = 8 for each group). Next, a comparative evaluation of tumor growth among the control, Gem-alone, BCG-alone, and combined Gem + BCG groups was performed (n = 16 for each group). Therapy was administered at 3-day intervals starting on day 5 and repeated 6 times. To evaluate the proliferative activity among the groups, Ki-67 immunostaining of the tumor was performed. RESULTS Gemcitabine exhibited a dose-dependent antitumor effect. Of the 8 mice in each group treated with a dose of 0, 1, 2, 4, or 8 mg of Gem, 1, 4, 4, 4, 5, and 4 mice failed to develop tumors and survived, respectively. The combination of Gem + BCG (54.1 ± 9.4 days) provided a significant survival advantage compared with BCG-alone (39.0 ± 16.4 days) (P = .02). Ki-67 expression, representing tumor proliferation, was significantly lower in the combined Gem + BCG group than in the BCG-alone group (P < .01). CONCLUSIONS Our results suggest that intravesical Gem + BCG treatment induces an enhanced antitumor effect against bladder tumors.

Clinical Value of Prostate Specific Antigen Based Parameters for the Detection of Prostate Cancer on Repeat Biopsy: The Usefulness of Complexed Prostate Specific Antigen Adjusted for Transition Zone Volume

PURPOSE To our knowledge the indications for repeat prostate needle biopsy in men whose previous transrectal ultrasound guided biopsy results revealed no evidence of cancer have not yet been defined. We identified the most effective method for detecting prostate cancer on repeat biopsy. MATERIALS AND METHODS One or more systematic repeat prostate biopsies were performed in 144 consecutive patients, including 86 with prostate specific antigen (PSA) levels between 4 and 10 ng./ml. at repeat biopsy. Men in whom cancer was detected on repeat biopsies were compared with their counterparts in terms of digital rectal examination findings, PSA based parameters and an atypical prostate on initial prostate biopsy. RESULTS Prostate cancer was detected on repeat biopsy in 39 of the 144 patients and in 19 on subset analysis of 86. Serum PSA levels at repeat biopsy did not differ significantly in patients with and without prostate cancer. According to receiver operating characteristics analysis the alpha1-antichymotrypsin-PSA complex adjusted for transition zone volume had the greatest area under the curve values, that is 0.756 for all 144 patients and 0.768 for the subset analysis of 86. Multiple logistic regression analysis of the subset of 86 patients showed that alpha1-antichymotrypsin-PSA complex adjusted for transition zone volume was the only significant independent predictor of cancer. CONCLUSIONS alpha1-Antichymotrypsin-PSA complex adjusted for transition zone volume was the most powerful predictor of cancer in men who had undergone previous negative prostate biopsies. This parameter may be used to avoid more unnecessary repeat biopsies with an acceptable decrease in sensitivity.

Prostate Cancer Screening with Prostate-Specific Antigen in Hemodialysis Patients

Background/Aims: The diagnostic validity of prostate-specific antigen (PSA) among men receiving hemodialysis (HD) has not been well defined. The aim of this study was to evaluate PSA levels in HD men and to compare them with those of non-uremic controls. Methods: PSA levels were measured in 620 HD men (40–89 years old, mean age 62.4 years). In patients with PSA >4.1 ng/ml, prostate biopsies were performed. Cancer-free men were defined as having PSA ranging between 0 and 4.0 ng/ml, or PSA >4.1 ng/ml but with a pathologically negative biopsy. The resulting data was compared with that for 3,636 non-uremic controls (55–59- (n = 468), 60–69- (n = 2,220), and 70–79-year-old men (n = 948)). Results: Of 45 HD men with PSA >4.1 ng/ml, 22 consented to undergo a biopsy. Ten were positive and 12 were negative. The mean PSA of cancer-free HD men of 50–59 (n = 159), 60–69 (n = 214), 70–79 (n = 116), and 80–89 (n = 30) were 1.0, 1.0, 1.3, and 2.1 ng/ml, respectively. Cancer-free HD men demonstrated significantly lower PSA compared to controls. Conclusions: HD men had lower PSA levels than those of controls.

Mucosa-associated lymphoid tissue lymphoma arising from the kidney

Primary renal lymphoma is rare, and most are intermediate- and high-grade lymphomas of B-cell lineage, such as diffuse large B-cell or Burkitt lymphoma. We report a case of low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) arising from the kidney. Only a few cases of primary renal MALT lymphoma have been published.

Ductal adenocarcinoma of the prostate forming a mass in the retrovesical space

Ductal adenocarcinoma of the prostate is a rare histologic variant of prostate cancer that often presents with normal prostate-specific antigen levels and is inherently aggressive enough to spread beyond the prostate gland. Here, we describe a case of prostatic ductal adenocarcinoma that formed a mass in the retrovesical space and presented with a high prostate-specific antigen level.

1757 CYTOKERATIN 18 AND EAU SCORE PREDICT TUMOR RECURRENCE IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER FOLLOWING SINGLE POSTOPERATIVE IMMEDIATE INTRAVESICAL CHEMOTHERAPY INSTILLATION

269 Background: We examined the prognostic factors for recurrence after TURBT using molecular markers as well as the scoring system of the EAU. METHODS Eighty-eight patients with primary or recurrent bladder tumors who underwent TURBT followed by the single postoperative immediate instillation of pirarubicin and no further instillations were enrolled between 2003 and 2006; the median follow-up period was 46 months. The time to first recurrence was the primary end point of this study. Patients were divided into EAU recurrence risk groups as follows: low-risk group (total score, 0), intermediate-risk group (total score, 1-9) and high-risk group (total score, 9-17). The intermediate-risk group patients were subdivided into a total score of 1-4 and a total score of 5-9. Immunostaining using Ki-67, pHH3, CK18 and Survivin were performed on the TURBT specimens. RESULTS According to the risk stratification, 5, 82, and 1 were assigned to the low-, intermediate-, and high-risk recurrence groups, respectively. During the follow-up, recurrences were observed in 0% of the low-risk group, 45% (37 out of 82) in the intermediate-risk group and 100% in the high-risk group. We evaluated various predictors of a recurrence-free outcome among the 82 intermediate-risk patients. In univariate analyses, EAU score (1-4, 32.1% vs 5-9, 62.1%; p = 0.0011), high CK18 expression (negative, 31.4% vs positive 88.8%; p < 0.0001), high Ki-67 index (< 5%, 35.4% vs > 5%, 52.5%; p = 0.017) and high Survivin nuclear staining (< 5%, 35.9% vs > 5%, 62.5%; p = 0.004) were associated with recurrence. In a multivariate analysis, EAU score (HR 2.95, p = 0.003) and a high CK18 immunostaining (HR 6.70, p < 0.0001) were independent predictors of disease recurrence. CONCLUSIONS A single immediate chemotherapy instillation is, by itself, insufficient for the treatment of patients in the intermediate- or high-risk recurrence groups defined by the EAU guidelines. Strong immunohistochemical expression of CK18 and the EAU scoring system appeared to be independent predictors of clinical outcome among patients with urothelial carcinoma of the bladder. No significant financial relationships to disclose.

ENHANCED ANTITUMOR EFFECT OF INTRAVESICAL GEMICITABINE THERAPY PLUS BCG IN AN ORTHOTOPIC MURINE BLADDER CANCER MODEL

INTRODUCTION AND OBJECTIVES: Intravesical immunotherapy with bacillus Calmette-Guerin (BCG) is the most successful adjuvant agent for superficial bladder tumors. However, tumors recur in 60 to 70% of the cases, and 30 % of these recurrent tumors present with a higher grade with invasive properties.Gemicitabine is a strong and specific deoxycytidine analog with activity in bladder tumors. To treat superficial bladder tumors that are resistant, we evaluated the combination treatment strategies with intravesical BCG plus Gemicitabine for bladder tumors in a model of orthotopic murine bladder cancer(MBT-2). METHODS: Superficial murine bladder cancer was established by simple instillation of 1 x 106 MBT-2 cells into the lumen of the bladder of female C3H mouse. To assess the antitumoral effect of gemicitabine, intravesical gemicitabine therapy was administered at various doseescalating concentrations; 0(control), 1mg, 2mg, 4 mg and 8mg (n = 8 for each group). Intravesical therapy was administered at 3-days intervals starting on day 5 and repeated 6 times. Next, comparative evaluation of tumor growth among the control group, Gemicitabine-alone group, Gemicabine plus BCG group and BCG-alone group were performed (n= 16 for each group). On day 60 after the initial implantation of the MBT-2 cells, all the surviving mice were sacrificed and necropsied. To evaluate the proliferative activity among the group, Ki67 staining of the tumor cells was performed following corresponding single intavesical administration in an orthotopic bladder tumor model. RESULTS: In the Gemicitabine-only groups of 8 mice each at the dose of 0(control), 1mg, 2mg, 4 mg and 8mg, one, four, four, four, five and four of the mice, respectively, survived. In the 8mg group, three of the eight mice were died due to adverse events. There was no significant difference in the tumor growth rate between any doses of Gemicitabine groups. There was a significant survival advantage in the Gemecitabine plus BCG group (54.1 ± 9.4 days) as compared with that in the BCG-alone group (39.0 ± 16.4 days) (p = 0.02). The Ki67 expression level as the proliferation index was significantly decreased in the Gemecitabine plus BCG group as compared with that in the BCG-alone group (p <0.05). CONCLUSIONS: Our results suggest that intravesical BCG plus Gemicitabine exhibited augmented antitumor effect against bladder tumors. Combined BCG plus Gemicitabine therapy was associated with a reduced proliferation rate as compared to BCG-alone therapy in the orthotopic bladder tumor model.