An unresectable advanced gastric cancer with Virchow's metastasis, carcinomatous ascites and rectal stenosis, effectively managed with combined chemotherapy of biweekly paclitaxel and TS-1

A 43-year-old woman who complained of abdominal fullness, appetite loss, and constipation was diagnosed as unresectable advanced schirrhous gastric cancer with left supra-clavicular lymph node metastases, massive ascites, rectal stenosis, and bilateral hydronephrosis due to peritoneal metastases. The biopsy specimen showed a poorly differentiated adenocarcinoma with signet-ring cells. After placement of the bilateral ureteral stents, she was treated with combined chemotherapy of biweekly paclitaxel (120 mg/m2, day 1, day 15) and TS-1 (80 mg/day, days 1-14 with 2-weeks rest). Subjective symptoms were relieved after one course of the chemotherapy. After 3 courses, computed tomography showed markedly reduced supra-clavicular lymph node metastases and no ascites. Radiographic and endoscopic examinations also demonstrated remarkable improvements in compliance of the gastric and rectal walls. These findings suggested that partial response on Response Evaluation Criteria in Solid Tumors (RECIST) was obtained. After the first course, the treatment was continued on an outpatient basis. There were no adverse effects over grade 2 throughout six courses of the chemotherapy. The biweekly paclitaxel and TS-1 chemotherapy may well be an effective treatment for advanced schirrhous gastric cancer with carcinomatous peritonitis.     

Clinical outcome of combined immunotherapy with low-dose interleukin-2 and interferon-α for Japanese patients with metastatic renal cell carcinoma who had undergone radical nephrectomy: a preliminary report

Background The objective of this study was to evaluate the clinical outcome of combined immunotherapy with interferon-α (IFN-α) and low-dose interleukin-2 (IL-2) for Japanese patients with metastatic renal cell carcinoma (RCC) who had undergone radical nephrectomy. Methods This study included 13 patients who were diagnosed as having metastatic RCC following radical nephrectomy. These patients received a subcutaneous injection of IFN-α (6 × 10⁶ IU per day) three times per week and an intravenous injection of IL-2 (1.4 × 10⁶ IU per day) twice per week. Tumor response was evaluated every 16 weeks, and as a rule, this weekly regimen was repeated 50 times in patients with evidence of objective response or stable disease. Results One of the 13 patients dropped out because of severe toxicity; hence, 12 patients were evaluable, with a median follow-up period of 18 months after the start of this combined therapy. Six patients (50.0%) achieved objective responses, with 1 complete response (CR), while only 2 (16.7%) demonstrated progressive disease. The median duration of response in the 6 responders was 13.5 months. Toxicity associated with this combined immunotherapy was limited to WHO grade 1 or 2 in these 12 patients. All patients were alive at last follow-up, and 2 remain disease-free after 1 additional patient showed a CR following surgical resection of the remaining metastatic disease. Conclusion Our preliminary experience suggests that long-term, repeated treatment with IFN-α and low-dose IL-2 is feasible in Japanese patients with metastatic RCC who have undergone radical nephrectomy. Although it will be necessary to accumulate data from a larger number of patients with a longer follow-up period, the combined immunotherapy tested in this study may become the preferred therapy for Japanese patients with metastatic RCC.     

Combination therapy with cerivastatin and nifedipine improves endothelial dysfunction after balloon injury in porcine coronary arteries

HMG-CoA reductase inhibitors and calcium channel blockers have antiatherogenic effects; however, their mechanisms remain to be elucidated. This study examined the effect of cerivastatin and/or nifedipine on the endothelial dysfunction in porcine balloon-injured coronary arteries. Normal male pigs were randomly divided into the following four groups: control, cerivastatin (1 mg/kg/d PO), nifedipine (4 mg/kg/d PO), and their combination (n = 10 each). We started the treatments 3 days before balloon injury in the proximal left coronary arteries and continued for 4 weeks after the procedure. Then, we examined endothelial vasodilator functions ex vivo in organ chambers and in vitro by Western blotting for eNOS expression. Endothelium-dependent relaxations to serotonin, but not those to bradykinin or the calcium ionophore A23187 or endothelium-independent relaxations to sodium nitroprusside, were significantly impaired by balloon injury. The monotherapy with cerivastatin or nifedipine partially improved, and their combination supernormalized the relaxations to serotonin without affecting those to bradykinin or A23187 or endothelium-independent relaxations to sodium nitroprusside. The expression of eNOS was significantly reduced by balloon injury and normalized by the combination therapy. These results indicate that the combination therapy improves endothelial dysfunction after balloon injury, in which the up-regulation of eNOS may be involved.     

Effects of 4-tert-pentylphenol on the gene expression of P450 11beta-hydroxylase in the gonad of medaka (Oryzias latipes)

Alkylphenols including 4-tert-pentylphenol (4-PP) have been shown to alter sexual differentiation in fish due to their estrogenic properties. Medaka (Oryzias latipes) is so sensitive to these substances because morphological sex reversal and testis-ova induction are well developed in the exposed males. However, little work has been done to characterize the molecular effects of estrogenic substances on the morphological and gonadal feminization in male fish. Cytochrome P450 11beta-hydroxylase (P450(11beta)) is a key steroidogenic enzyme in production of 11-ketotestosterone which is the predominant androgen in male fish. In this study, we cloned a cDNA encoding medaka testicular P450(11beta), and then investigated the gene expression of P450(11beta) in the testes of genetically male medaka exposed to 4-PP. The cDNA contains 1740 nucleotides that encode a protein of 543 amino acids, which shares 68.9% and 73.4% homology with testicular P450(11beta)s from Japanese eel (Anguilla japonica) and rainbow trout (Oncorhynchus mykiss), respectively. HeLa cells transfected with an expression vector containing the open reading frame of medaka P450(11beta) cDNA showed 11beta-hydroxylating activity in the presence of exogenous testosterone. Analysis of tissue distribution by RT-PCR showed great abundance of P450(11beta) mRNA in testis. In the partial life-cycle exposure with 4-PP, morphologically sex-reversal was observed in XY medaka exposed to 4-PP concentrations of > or =238 microg/L. Furthermore, exposure to 4-PP completely inhibited P450(11beta) mRNA expression in the gonads of sex-reversed XY fish at 60-day posthatch. These results suggest that xeno-estrogen 4-PP may have inhibitory effects on the synthesis of testicular 11-oxygenated androgens through downregulation of P450(11beta) expression in the genetically male fish.     

Limited value of perineural invasion in radical prostatectomy specimens as a predictor of biochemical recurrence in Japanese men with clinically localized prostate cancer

The objective of this study was to determine whether the presence of perineural invasion (PNI) in radical prostatectomy specimens could be a useful prognostic parameter in Japanese men with prostate cancer. Between January 1995 and September 2003, 202 Japanese men underwent radical retropubic prostatectomy for prostate cancer without any neoadjuvant therapies prior to surgery. We retrospectively analyzed the relationship between PNI in radical prostatectomy specimens and other prognostic factors, and also assessed the significance of PNI in biochemical recurrence after radical prostatectomy. The presence of PNI was significantly related to clinical stage, pathological stage, Gleason score, seminal vesicle invasion, lymph node metastasis and tumor volume, but not pretreatment serum prostate specific antigen value. During the observation period, biochemical recurrence occurred in 20 patients (3 in patients without PNI and 17 in those with PNI), and the biochemical recurrence-free survival rate in patients with PNI was significantly lower than that in patients without PNI. In addition to-PNI, pathological stage, seminal vesicle invasion, lymph node metastasis and tumor volume were significantly associated with the biochemical recurrence-free survival rate; however, among these five factors, only seminal vesicle invasion was an independent predictor of biochemical recurrence on multivariate analysis. Despite a significant association between several prognostic parameters, PNI was not an independent predictor of biochemical recurrence; therefore, it may not provide an additive effect to consider the presence of PNI in predicting the prognosis of Japanese men who underwent radical prostatectomy if there are other conventional parameters available.     

Significance of the Percentage of Prostate Needle Biopsy Cores with Cancer as a Predictor of Disease Extension in Radical Prostatectomy Specimens in Japanese Men

Objectives: To evaluate the significance of the percent of positive biopsy cores (PPBC) with cancer, which has been shown to be one of the most useful predictors of prostate cancer extension in patients undergoing radical prostatectomy. Materials and methods: This study included 120 patients who underwent radical prostatectomy for prostate cancer without any neoadjuvant therapies. All of these patients were diagnosed by random prostate biopsy targeting 8 cores; that is, standard sextant cores and 2 additional cores from the bilateral anterior lateral horns. We evaluated the appropriate cut-off points of PPBC for predicting disease extension according to the number of biopsy cores. Based on these criteria, multivariate analysis was then performed to determine whether PPBC could be an independent factor differentiating organ-confined disease from extraprostatic disease. Results: The most suitable PPBC cut-off value using findings targeting 8 cores for predicting disease extension was 37.5%. If PPBC was calculated based on the outcome of standard sextant cores alone, it is most appropriate to use 33.3% as the cut-off point. Multivariate analysis showed that PPBC calculated based on the standard sextant cores and percent of cancer in the biopsy set could be used as independent factors predicting disease extension irrespective of other biopsy-associated factors. Conclusions: For predicting disease extension, it may be useful to calculate PPBC based on the outcomes of standard sextant biopsy cores alone even if additional cores were taken, and that PPBC calculated in such a way may be the strongest preoperative predictor of prostate cancer extension in Japanese men scheduled for radical prostatectomy.     

Long-term outcome of hand-assisted laparoscopic radical nephrectomy for localized stage T1/T2 renal-cell carcinoma

PURPOSE: To evaluate the efficacy of hand-assisted laparoscopic radical nephrectomy (HALRN) in patients with localized stage T(1)/T(2) renal-cell carcinoma, we analyzed the clinical results of our patients treated in this way. PATIENTS AND METHODS: From March 1999 to March 2003, a total of 96 patients aged 28 to 86 years (mean 61 years) with clinical stage T(1)/T(2)N(0)M(0), pathologically confirmed renal-cell carcinoma underwent HALRN. The outcomes were compared with those of open radical nephrectomy, which was performed in 86 patients from November 1991 to February 1999 in our institution. Kaplan-Meier analysis was used to analyze survival. RESULTS: Ten patients (10.4%) had perioperative complications. During a mean follow-up of 25 months (range 6-54 months), no patients died of the cancer, although three patients had metastatic disease. The 4-year disease- free and overall survival rates were 88% and 100%, respectively. Seventy-eight patients who underwent open radical nephrectomy were followed for 38 to 156 months (median 86 months). Seventy-three survived without any recurrent disease, five survived with metastasis, and no patient died of metastatic disease. The 4-year disease-free and overall survival rates were 93% and 100%, respectively. CONCLUSIONS: Hand-assisted laparoscopic surgical management of T(1)/T(2) renal-cell carcinoma is feasible and safe. At our institution, HALRN confers long-term oncologic effectiveness equivalent to that of open radical nephrectomy.