Takashi Ohigashi

Prevention of Cancer Cachexia by a Novel Nuclear Factor κB Inhibitor in Prostate Cancer

Purpose: To investigate the association between serum interleukin-6 (IL-6) and cachexia in patients with prostate cancer and the inhibitory effect of a new nuclear factor κB (NF-κB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on IL-6 production and cachexia in an animal model of hormone-refractory prostate cancer. Experimental Design: The association between serum IL-6 levels and variables of cachexia was evaluated in 98 patients with prostate cancer. The inhibitory effects of DHMEQ on IL-6 secretion and cachexia were investigated in in vitro and in vivo studies using JCA-1 cells derived from human prostate cancer. Results: Serum IL-6 levels were significantly elevated and cachexia developed in JCA-1 tumor-bearing mice as well as in prostate cancer patients with progressive disease. IL-6 secretion was significantly inhibited in JCA-1 cells exposed to DHMEQ. Intraperitoneal administration of DHMEQ (8 mg/kg) to tumor-bearing mice produced a significant amelioration of the reduction in body weight, epididymal fat weight, gastrocnemius muscle weight, hematocrit, and serum levels of triglyceride and albumin when compared with administration of DMSO or no treatment. DHMEQ caused a significant decrease of serum IL-6 level in JCA-1 tumor-bearing mice (all P < 0.05). Conclusions: These results suggested an association between serum IL-6 and cachexia in patients with prostate cancer and in JCA-1 tumor-bearing mice and that a new NF-κB inhibitor, DHMEQ, could prevent the development of cachexia in JCA-1 tumor-bearing mice presumably through the inhibition of IL-6 secretion. DHMEQ seems to show promise as a novel and unique anticachectic agent in hormone-refractory prostate cancer.

Gemcitabine and paclitaxel chemotherapy for advanced urothelial carcinoma in patients who have received prior cisplatin-based chemotherapy

BackgroundThe objective of this study was to evaluate the efficacy and toxicity of combination chemotherapy with gemcitabine and paclitaxel as a second-line regimen in patients with advanced urothelial carcinoma.MethodsTwenty patients with advanced urothelial carcinoma who were resistant to an M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy regimen were administered chemotherapy consisting of intravenous gemcitabine 2500 mg/m2 and paclitaxel 150 mg/m2 (GP) every 2 or 3 weeks.ResultsThe patients received a median of 7.7 cycles of treatment (range, 2–20 cycles). Six of the 20 patients (30%; 95% confidence interval [CI], 10%–50%) had a major response to treatment (a complete response [CR] in 5% and a partial response [PR] in 25%). Seven patients (35%) had stable disease (SD). The median duration of response was 4.5 months (range, 1–9 months) and the disease control rate (CR + PR + SD) was 65%. The median survival was 11.5 months (range, 2–22 months) and the 1-year survival rate was 35%. The patients tolerated this regimen well, with only grade 3–4 neutropenia being observed in 6 patients (30%), anemia in 3 (15%), and thrombocytopenia in 1 (5%). The response rate to M-VAC in the first-line chemotherapy was significantly associated with the response to GP as the second-line chemotherapy.ConclusionThe combination of gemcitabine and paclitaxel is active and well tolerated as a second-line treatment in patients with advanced urothelial carcinoma.

Vitamin E succinate induced apoptosis and enhanced chemosensitivity to paclitaxel in human bladder cancer cells in vitro and in vivo

There have been several studies on the antitumor activities of vitamin E succinate (α‐TOS) as complementary and alternative medicine. In the present study, we investigated the cytotoxic effect of α‐TOS and the enhancement of chemosensitivity to paclitaxel by α‐TOS in bladder cancer. KU‐19‐19 and 5637 bladder cancer cell lines were cultured in α‐TOS and/or paclitaxel in vitro. Cell viability, flow cytometric analysis, and nuclear factor‐kappa B (NF‐κB) activity were analyzed. For in vivo therapeutic experiments, pre‐established KU‐19‐19 tumors were treated with α‐TOS and/or paclitaxel. In KU‐19‐19 and 5637 cells, the combination treatment resulted in a significantly higher level of growth inhibition, and apoptosis was significantly induced by the combination treatment. NF‐κB was activated by paclitaxel; however, the activation of NF‐κB was inhibited by α‐TOS. Also, the combination treatment significantly inhibited tumor growth in mice. In the immunostaining of the tumors, apoptosis was induced and proliferation was inhibited by the combination treatment. Combination treatment of α‐TOS and paclitaxel showed promising anticancer effects in terms of inhibiting bladder cancer cell growth and viability in vitro and in vivo. One of the potential mechanisms by which the combination therapy has synergistic cytotoxic effects against bladder cancer may be that α‐TOS inhibits NF‐κB induced by chemotherapeutic agents. (Cancer Sci 2009;)

Intravesical and intravenous therapy of human bladder cancer by the herpes vector G207.

G207, a conditionally replicating herpes vector, efficiently kills human bladder cancer cells in vitro. To evaluate the therapeutic potential of G207, we have established three in vivo models similar to the clinical situation. In vivo, G207 was intraneoplastically, intravesically, or intravenously inoculated in nude mice. Intraneoplastic inoculation into subcutaneous tumor caused significant tumor growth inhibition. Intravesical inoculation of G207 also caused decreased tumor growth in an orthotopic human bladder cancer model. Furthermore, multiple intravenous inoculation markedly inhibited subcutaneous tumor growth. These results suggest that intravesical therapy with G207 is effective for localized bladder tumor, especially for carcinoma in situ (CIS), and intravenous therapy with G207 is promising for invasive or metastasized bladder tumor.

Prediction of bone metastases by combination of tartrate‐resistant acid phosphatase, alkaline phosphatase and prostate specific antigen in patients with prostate cancer

Objective:  The clinical value of serum tartrate‐resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated.

Prognostic Implication of Microvascular Invasion in Biochemical Failure in Patients Treated with Radical Prostatectomy

Introduction: Micrometastasis before radical prostatectomy (RP) is considered to be related to the biochemical failure after surgery in patients with prostate cancer. To predict the biochemical failure, we evaluated microvascular (lymphatic/vascular) invasion and other pathological findings as prognostic factors for biochemical failure after RP. Materials and Methods: Eighty-two men who underwent RPs and received neither preoperative nor postoperative adjuvant therapy were analyzed. Pathological findings of each patient were carefully reviewed to determine pathological factors predicting biochemical failure. The influence of pathological findings on the biochemical failure was evaluated. Results: The overall biochemically assessed disease-free survival rate was 55.7% at 3 years. By univariate analysis, Gleason sum, capsular penetration, and microvascular invasion were significantly associated with the rate of biochemical failure. Microvascular invasion was strongly correlated with Gleason sum, capsular penetration, surgical margin, perineural invasion, and pathological stage. By multivariate analysis, Gleason sum, capsular penetration, and microvascular invasion were independent predictors of biochemical failure. Conclusion: This study suggests that in addition to Gleason grade and capsular penetration, microvascular invasion is one of independent prognostic factors in patients with prostate cancer treated with RPs.

Bladder Cancer Cells Express Functional Receptors for Granulocyte-Colony Stimulating Factor

The effects of human recombinant granulocyte-colony stimulating factor (G-CSF) on the growth of cultured human bladder cancer cells and G-CSF receptor on these cells were investigated. Human bladder cancer cell lines, KU-1 or NBT-2, were incubated with and without G-CSF. At 48 hours, 3H-thymidine uptake of both cells was significantly higher with G-CSF (one ng./ml., 10 ng./ml.) than that of control without G-CSF (p less than 0.05). The binding of 125I-labeled KW-2228, a muteins of G-CSF, to KU-1 and NBT-2 was inhibited by unlabeled KW-2228 in a dose-dependent manner. These results demonstrated that G-CSF stimulates the clonal growth of human bladder cancer cells by binding to its specific receptors.

The Predictors of Local Recurrence after Radical Cystectomy in Patients with Invasive Bladder Cancer

OBJECTIVES To examine the association between local recurrence and distant metastasis or disease-specific survival and identify independent factor predictors for local recurrence. METHODS We identified a study population of 146 consecutive patients treated surgically for invasive bladder cancer at our institution between 1987 and 2003. We clarified the relationship among local recurrence, distant metastasis and disease-specific survival and identified significant predictors for local recurrence. RESULTS Local recurrence developed in 26 (17.8%) of the 146 patients at a median of 10 months (range, 1-73 months) after cystectomy. It was independently associated with distant metastasis in addition to the number of retrieved lymph nodes. The 2- and 5-year metastasis-free rates were 86.7 and 76.5% in patients without local recurrence and 26.5 and 0% in those with local recurrence (P < 0.001), respectively. The presence or absence of local recurrence and tumor grade were independent predictors of disease-specific survival. The 2- and 5-year disease-specific survival rates were 93.5 and 88.3% in patients without local recurrence and 55.1 and 35.4% in those with local recurrence (P < 0.001). The presence of concomitant adenocarcinoma component, pathological nodal involvement and the number of retrieved lymph nodes were independent predictors of local recurrence. CONCLUSIONS Local recurrence was independently associated with distant metastasis and disease-specific survival. Patients who have the predictive factors described above may benefit from integrated surgical therapies with post-operative adjuvant chemotherapy.

Preoperative Prognostic Nomogram (Probability Table) for Renal Cell Carcinoma Based on TNM Classification

PURPOSE Recently several prognostic nomograms have been developed to predict the prognosis of malignant diseases, including renal cell carcinoma. However, to our knowledge a preoperative prognostic nomogram that predicts survival in patients with renal cell carcinoma is not available. We developed a preoperative nomogram based on the TNM classification that predicts cause specific survival in patients with renal cell carcinoma. MATERIALS AND METHODS A total of 545 patients with renal cell carcinoma, including metastatic disease, who underwent radical nephrectomy or nephron sparing surgery at our institution were included in the study. Cases were staged according to the 2002 UICC TNM system, 6th edition. T, N and M factors were used as prognostic factors and a Cox proportional hazards regression model was developed to predict cause specific survival. A nomogram to predict cause specific survival was developed by repeating the analysis on 200 bootstrap samples. To validate the nomogram a concordance index was estimated and calibration was also examined by plotting the predictions made by the nomogram. RESULTS Overall 1, 3 and 5-year patient survival was 95.2%, 92.0% and 89.9%, respectively. T, N and M factors were significant prognostic factors in the Cox proportional hazards regression model. Using the combined TNM factors we developed a nomogram predicting 1, 3 and 5-year cause specific survival rates. The nomogram had excellent ability to discriminate, as evidenced by a concordance index of 0.81, and it was generally well calibrated. CONCLUSIONS The preoperative information shown by this nomogram may be important for obtaining informed consent from patients with renal cell carcinoma who have indications for surgery.

Urinary steroid profile in adrenocortical tumors

Determination of the urinary steroid profile has been proposed as a sensitive tool for diagnosing adrenocortical tumors. The urinary steroid profiles were determined for patients with adrenocortical tumors. Urinary steroids were extracted, derivatized to form methyloxime-trimethylsilyl ether and analyzed by gas chromatography/mass spectrometry. Patients with adrenal adenomas from primary hyperaldosteronism had increased metabolites of 18-hydroxycorticosterone and aldosterone, and those with Cushings syndrome had elevated excretion of 11 -deoxycortisol, cortisol, 18-hydroxycortisol, and cortisone metabolites. In patients with adrenocortical carcinomas, increased levels of metabolites of 11-deoxycortisol or 33-hydroxy-5-ene steroids were observed. The urinary steroid profiles of adrenal adenomas and adrenocortical carcinomas were quite different, suggesting the diagnostic validity for discriminating malignant from benign diseases.