Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with prostate cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of prostate cancer was published in 2020. It was therefore decided, by both the ESMO and the Singapore Society of Oncology (SSO), to convene a special, virtual guidelines meeting in November 2021 to adapt the ESMO 2020 guidelines to take into account the differences associated with the treatment of prostate cancer in Asia. These guidelines represent the consensus opinions reached by experts in the treatment of patients with prostate cancer representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with prostate cancer across the different regions of Asia.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with renal cell carcinoma.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of renal cell carcinoma was published in 2019 with an update planned for 2021. It was therefore decided by both the ESMO and the Singapore Society of Oncology (SSO) to convene a special, virtual guidelines meeting in May 2021 to adapt the ESMO 2019 guidelines to take into account the ethnic differences associated with the treatment of renal cell carcinomas in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with renal cell carcinoma representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate.

Computational hemodynamics of portal vein hypertension in hepatic cirrhosis patients.

Portal vein hypertension generally occurs in liver diseases like hepatic cirrhosis. It causes hemodynamic changes that are closely related to liver disease. At advanced stages of hepatic cirrhosis, portal vein hypertension leads to the atrophy of the right lobe of the liver and the hypertrophy of the left lobe through a process that has not yet been fully explained. Based on the hemodynamic changes that are known to occur, we hypothesize that liver volume is related to the distribution of blood flowing from the splenic vein (SV) that carries hepatotrophic factors from the spleen and pancreas. We studied blood flow in the portal vein system to validate this hypothesis through in vitro experimentation and a computational fluid dynamics (CFD) analysis involving both simplified and patient-specific models based on four healthy subjects and two patients with liver cirrhosis. The results confirmed the hypothesis that right-lobe atrophy is significantly influenced by the distribution of blood from the SV. Moreover, the patients with liver cirrhosis had a significantly larger mass fraction of spleen-derived blood in the left portal vein branch (LPV) than healthy subjects, a result consistent with right-lobe atrophy and left-lobe hypertrophy.

An improved high performance liquid chromatography-diode array detection-mass spectrometry method for determination of carotenoids and their precursors phytoene and phytofluene in human serum.

An improved high performance liquid chromatography-diode array detection-mass spectrometry method was developed for determination of various carotenoids and their precursors phytoene and phytofluene in human serum. A polymeric C30 column and mobile phase of (A) methanol/acetonitrile/water (84:14:4, v/v/v) and (B) dichloromethane (100%) were employed with the gradient condition of 100% A and 0% B initially, raised to 10% B at 4 min, 18% B at 12 min, 21% B at 17 min, 30% B at 20 min and maintained until 25 min and increased further to 39% B at 28 min, 60% B at 40 min and returned to 100% A and 0% B at 45 min. A total of 30 carotenoids, including 6 all-trans forms, 20 cis-isomers, 2 ß-carotene epoxides, phytoene and phytofluene, were resolved within 45 min at a flow-rate of 1 mL/min, column temperature 25 °C and detection wavelengths 450, 348 and 286 nm. Identification of carotenoids was carried out by comparing retention behavior, absorption and mass spectral data with those of reference standards, isomerized standards and reported values. An internal standard parared was found appropriate for quantitation of all the carotenoids. The developed method provided high sensitivity with low detection and quantitation limits (2-14 and 6-43 ng/mL), high recovery (91-99%), and small intra-day and inter-day variations (0.14-6.01% and 0.31-7.28%). Application of the developed method to Taiwan subjects supplemented with carotenoid-rich capsules revealed ß-carotene plus its cis isomers as well as epoxide derivatives to be present in largest amount (1069.8-2783.1 ng/mL) in serum, followed by lutein plus its cis isomers (511.6-2009.5 ng/mL), phytofluene plus its cis isomer (515.0-1765.0 ng/mL), lycopene plus its cis isomers (551.1-1455.1 ng/mL), ß-cryptoxanthin plus its cis isomers (458.0-965.0 ng/mL), all-trans-zeaxanthin (110.0-177.0 ng/mL), phytoene (41.8-165.0 ng/mL) and all-trans-α-carotene (37.5-95.9 ng/mL).

Genetic polymorphisms in androgen receptor-binding sites predict survival in prostate cancer patients receiving androgen-deprivation therapy.

BACKGROUND: Activated androgen receptor binds to androgen-responsive elements (AREs) in genome to regulate target gene transcription and, consequently, mediates physiological or tumorigenic processes of the prostate. Our aim was to determine whether genetic variants in AREs are associated with clinical outcomes after androgen-deprivation therapy (ADT) in prostate cancer patients. PATIENTS AND METHODS: We systematically investigated 55 common single-nucleotide polymorphisms (SNPs) in the genome-wide insilico-predicted AREs in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT was assessed by Kaplan-Meier analysis and Cox regression model. RESULTS: In univariate analysis, two, five, and four SNPs were associated with disease progression, PCSM, and ACM, respectively. After adjusting for known prognostic factors, ARRDC3 rs2939244, FLT1 rs9508016, and SKAP1 rs6504145 remained as significant predictors for PCSM and FBXO32 rs7830622 and FLT1 rs9508016 remained as significant predictors for ACM in multivariate analysis. Moreover, strong combined genotype effects on PCSM and ACM were also observed (P(trend) < 0.001). CONCLUSION: Our results suggest that SNPs in AREs influence prostate cancer survival and may further advance our understanding of the disease progression.

An audit of nephroureterectomy for upper tract urothelial carcinoma.

BACKGROUND: The boundary of nephroureterctomy has been revisited and lymph node dissection has been recommended recently. We investigated the role of synchronous ipsilateral adrenalectomy in treating patients with upper tract urothelial carcinoma. METHODS: 110 patients with clinically localized upper tract urothelial carcinoma treated by nephroureterectomy and bladder cuff resection were retrospectively evaluated. 70 patients underwent nephroureterectomy without concomitant ipsilateral adrenalectomy, whereas nephroureterectomy and ipsilateral adrenalectomy was performed in other 40 patients. Cancer specific, metastasis and local recurrence free survival during a follow-up of median 46 months were analyzed. RESULTS: No patient had adrenal metastasis among the 40 adrenalectomized patients. A total of 4 patients developed local recurrences; including 1 of the 70 adrenalectomy-sparing and 3 of the 40 adrenalectomized patients (p = 0.102, chi-square test). Five patients with adrenalectomy and four without adrenalectomy had distant metastases (p = 0.212, chi-square test). The five-year local recurrence free survival (p = 0.09, log-rank test), metastasis-free survival (p = 0.292, log-rank test), and cancer-specific survival (p = 0.117, log-rank test) did not have significant difference between both groups. CONCLUSIONS: This is the only study in recent 2 decades to evaluate the necessity of synchronous adrenalectomy in treating localized upper tract urothelial carcinoma. Adrenal-sparing nephroureterectomy seems justified for clinically localized upper tract urothelial carcinoma.

Diet, vegetarian food and prostate carcinoma among men in Taiwan.

In a case-control study in a veterans hospital in Taiwan, we compared 237 histology-confirmed prostate carcinoma cases with 481 controls, frequency matched by age, for their consumption of vegetarian food, namely soybean products, rice, wheat protein and other vegetables. The multivariable logistic regression analysis showed a significant association with such food (odds ratio (OR)=0.67, 95% confidence interval (CI)=0.47, 0.94). This beneficial effect presented for men with body mass index (BMI) < or =25 kg m(-2) (OR=0.50, 95% CI=0.32, 0.76) but not for men with greater BMI. The OR of prostate carcinoma for men with BMI < or =25 kg m(-2) was 1.74 (95% CI=1.21, 2.51), compared with men with higher BMI (>25 kg m(-2)). Other significant risk factors associated with the disease included higher income (OR=2.40, 95% CI=1.07, 5.42), physical activity (OR=1.75, 95% CI=1.08, 2.83), being married (OR=2.49, 95% CI=1.40, 4.43) and coffee consumption (OR=1.88, 95% CI=1.07, 3.30). Stratified analysis also showed that the consumption of fish/shellfish had an adverse association for men with higher BMI. This study suggests that the intake of the low fat local vegetarian food has a protective effect against prostate carcinoma for thin men in this study population.

An improved HPLC method for determination of carotenoids in human serum.

An HPLC method was developed to determine the various carotenoids in human serum. A C-30 column and a mobile phase of 100% methanol (A) and 100% methylene chloride (B) with the following gradient elution were used: 90% A and 10% B in the beginning, maintained for 5 min, decreased to 78% A at 15 min, 62% A at 30 min, 52% A at 40 min, 41% A at 50 min, 38% A at 55 min, maintained for 3 min, and returned to 100% A at 65 min. A total of 21 carotenoids, including all-trans forms of lutein, zeaxanthin, alpha-cryptoxanthin, beta-cryptoxanthin, alpha-carotene, beta-carotene and lycopene, as well as their 14 cis-isomers were resolved within 51 min at a flow rate of 1.0 mL/min and detection at 476 nm. all-trans-beta-Carotene was found to be present in highest amount (256.3-864.2 ng/mL), followed by all-trans-lycopene (64.4-569.2 ng/mL), all-trans-lutein (137.9-450.3 ng/mL), all-trans-alpha-cryptoxanthin (55.7-188.2 ng/mL), all-trans-beta-cryptoxanthin (43.1-134.5 ng/mL), all-trans-alpha-carotene (20.0-122.1 ng/mL) and all-trans-zeaxanthin (9.1-21.3 ng/mL). Similar trend was observed for cis-isomers of carotenoids.

Changing trends of prostate cancer in Asia.

Although Asian people have the lowest incidence and mortality rates of prostate cancer in the world, these rates have risen rapidly in the past two decades in most Asian countries. Prostate cancer has become one of the leading male cancers in some Asian countries. In 2000, the age-adjusted incidence was over 10 per 100000 men in Japan, Taiwan, Singapore, Malaysia, the Philippines and Israel. Although some of the increases may result from enhanced detection, much of the increased incidence may be associated with westernization of the lifestyle, with increasing obesity and increased consumption of fat. The differences in incidences between native Americans and Asian immigrants are getting smaller, reflecting a possible improvement of diagnostic efforts and changes of environmental risk factors in Asian immigrants. Nevertheless, the huge variations in incidences among ethnic groups imply that there are important genetic risk factors. The stage distributions of prostate cancer in Asian populations are still unfavorable compared to those of Western developed countries. However, a trend towards diagnosing cancer with more favorable prognosis is seen in most Asian countries. Both genetic and environmental risk factors responsible for elevated risks in Asian people are being identified, which may help to reduce prostate cancer incidence in a chemopreventive setting.

Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.

Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.

A pilot study of AFL-T (doxorubicin, 5-fluorouracil, leucovorin, and tamoxifen) combination chemotherapy for hormone-refractory prostate cancer.

BACKGROUND: Tamoxifen had been used to treat advanced prostate cancer with limited success. In vitro data suggested that tamoxifen could enhance the cytotoxic effect of chemotherapeutic agents, including doxorubicin, on prostate cancer cell lines. We applied this observation into a phase II trial for patients with hormone refractory prostate cancer (HRPC). PATIENTS AND METHODS: The AFL-T regimen consisted of doxorubicin 30 mg/m2/day on day 1; 5-FU 2,000 mg/m2/day 24-hour infusion and leucovorin 200 mg/m2/day 24-hour infusion on days 15 and 29; tamoxifen 50 mg/m2 four times daily on days 1, 2, 16, 17, 30, and 31. The protocol was designed to be of low dose-intensity and tolerable to most HRPC patients who may have reduced bone marrow reserve and poor renal function. Between Feb. 1994 and April 1999, 17 patients (median age 67, range 60-81) with HRPC were enrolled. Extensive hormonal manipulations had been done prior to the chemotherapy. Three patients had measurable diseases, 14 had only bone metastases, and all had elevated PSA levels (median 498 ng/ml, range 7.4-3,970 ng/ml). RESULTS: All 17 patients were eligible for analysis of toxicity. ECOG Grade III/IV leukopenia and thrombocytopenia occurred in 1 and 3 patients, respectively. There was no febrile neutropenia; there was no treatment-related mortality. Grade III/IV nausea, vomiting, mucositis, and diarrhea were noted in 0, 0, 1 and 0 patient, respectively. There was no venous thrombosis. One partial response, 1 stable disease, and 1 progressive disease were found in the three patients with measurable lesions. Eleven of the 17 patients (64.7%, 95% confidence interval: 41-88%) who were eligible for the evaluation of PSA response (PSA decrease > 50% for at least 6 weeks) were responders. The median overall and progression-free survivals were 13 and 7 months, respectively. Seventy-six percent of patients showed decreased analgesic usage or enhanced performance status. CONCLUSION: AFL-T, that has a low toxicity profile, is comparable to most other active regimens in terms of the PSA response rate. Randomized trials are needed to determine if there exists a survival benefit for patients with HRPC.

Effect of percent free prostate-specific antigen measurement on improving the specificity of serum prostate-specific antigen testing in Taiwanese patients.

BACKGROUND AND PURPOSE: Measurement of percent free prostate-specific antigen (fPSA) has been shown to enhance the diagnostic performance of traditional serum PSA determination. We sought to determine whether measurement of percent fPSA could improve the specificity of serum total PSA testing in the detection of prostate cancer in Taiwanese patients with intermediate serum PSA concentrations. METHODS: The medical records of 211 patients examined from March 1998 through March 2000 were analyzed retrospectively; all had a serum total PSA concentration of between 4.1 and 20.0 ng/mL and negative digital rectal examination (DRE) findings, and had undergone a prostate biopsy. Biopsy results were correlated with the serum total PSA concentration and percent fPSA, which were determined using a microparticle enzyme immunoassay. Percent fPSA was calculated as the ratio of fPSA to total PSA multiple by 100. The sensitivity and specificity were calculated and the receiver operating characteristic (ROC) curves were generated from different cutoff values of percent fPSA and total PSA. RESULTS: Thirty-four patients (16.1%) had positive biopsy results (prostate cancer). Patients with positive biopsy results had significantly lower percent fPSA values than those with negative results (11.7% vs 16.0%, p < 0.001). Patients with a lower percent fPSA (< 10%) had a higher probability of a positive biopsy result than those with a high percent fPSA (> 20%) (positive biopsy rate, 29% vs 10%, p < 0.05). Using a cutoff value of 25% fPSA or below, the sensitivity, specificity, and positive predictive value in differentiating patients with positive biopsy results from those with negative results were 97%, 13%, and 18%, respectively. Consequently, 27 unnecessary biopsies could have been avoided at the cost of missing one cancer. The area under the ROC curve was 0.68 for percent fPSA and 0.63 for total PSA (p > 0.05). CONCLUSIONS: For Taiwanese patients with a serum PSA concentration of between 4.1 and 20.0 ng/mL, the incidence of prostate cancer is relatively low; measurement of percent fPSA only weakly enhances the specificity of serum PSA testing in detecting prostate cancer.

Cross-resistance and combined cytotoxic effects of paclitaxel and cisplatin in bladder cancer cells.

PURPOSE: We studied the cross-resistance and combined cytotoxic effects of cisplatin and paclitaxel in bladder cancer cells in vitro. MATERIALS AND METHODS: The cytotoxicity of the 2 agents alone or in combination were studied in the bladder cancer cell line NTUB1 and the 2 sublines NTUB1/P, which is cisplatin resistant, and NTUB1/T, which is paclitaxel resistant, using the microculture tetrazolium assay. Schedule dependence of the 2-drug combination was assayed using 3 treatment schedules, including 1 concurrent and 2 sequential exposures. RESULTS: The mean cisplatin concentration plus or minus standard error of the means inhibiting 50% of the growth of NTUB1, NTUB1/P and NTUB1/T was 1.9 +/- 0.19, 19.3 +/- 2.33 and 2.1 +/- 0.15 microM., respectively, and the mean paclitaxel concentration inhibiting 50% of the growth of the 3 cell lines was 30 +/- 3.9, 1,033 +/- 120 and 110 +/- 15 nM., respectively. NTUB1/P had strong cross-resistance to paclitaxel. In contrast, NTUB1/T was as sensitive as NTUB1 to cisplatin. On median effect analysis the combined effects of the 2 agents given concurrently were sub-additive in the low fraction affected range of 0.1 to 0.3 and additive in the median to high fraction affected range of 0.4 to 1.0 in the 3 cell lines. Combined cytotoxicity was more synergistic when paclitaxel was given 24 hours earlier than cisplatin. The effects were less synergistic when cisplatin was given before paclitaxel. This phenomenon was noted in sensitive and resistant cells. CONCLUSIONS: In our bladder cancer cell model cisplatin resistant cells have strong cross-resistance to paclitaxel, whereas paclitaxel resistant cells are sensitive to cisplatin. The combined effects may be optimized by sequential use of the 2 agents, preferably paclitaxel given 24 hours before cisplatin. Our results have clinical implications for the treatment of bladder cancer.

Combination chemotherapy of cisplatin, methotrexate, vinblastine, and high-dose tamoxifen for transitional cell carcinoma.

BACKGROUND: We have previously demonstrated that tamoxifen enhanced the chemosensitivity of bladder cancer cells in vitro. In this pilot study, we tested the modulating effect of high-dose tamoxifen to conventional cisplatin, methotrexate, and vinblastine combination chemotherapy (CMV-T) for transitional cell carcinoma (TCC). PATIENTS AND METHODS: Between Nov. 1994 and Mar. 1999, 30 TCC patients were enrolled. Nine patients had muscle-invasive bladder TCC; 21 patients had either unresectable locally advanced diseases or distant metastases. CMV-T consisted of cisplatin 50 mg/m2/day, day 1 & 2; methotrexate 30 mg/m2/day, day 1 & 8; vinblastine 3 mg/m2/day, day 1 & 8; and tamoxifen 200 mg/m2/day, days 1 through 4. RESULTS: A total of 98 courses had been given with an average of 3.27 courses per patient (range: 1-7). Grade III/IV leukopenia and thrombocytopenia occurred in 18% and 21% of total courses, respectively. There were 7 episodes of neutropenic fever, and 3 patients died of sepsis. Non-haematologic toxicities were generally mild. There was no venous thrombosis. Out of 26 patients eligible for evaluation of response, 1 complete and 14 partial responses with an overall response rate of 58% (95% confidence interval: 38-75%) were observed. The mean survival of all patients was 8 months. CONCLUSIONS: The toxicity of CMV-T chemotherapy is moderate, but generally manageable. The response rate of CMV-T for patients with advanced TCC seems to be only comparable to most conventional cisplatin-based combinations. The possible benefit of tamoxifen to enhance chemosensitivity of TCC needs further investigation.

Characterization of chemoresistance mechanisms in a series of cisplatin-resistant transitional carcinoma cell lines.

We explored the mechanisms of cisplatin resistance in a series of bladder transitional carcinoma cells that are either sensitive or progressively resistant to cisplatin. Resistant lines were raised by chronic exposure of the parental cells to progressively increased concentrations of cisplatin. The cisplatin IC50s of the sensitive and the three resistant cells were 4.3, 25.0, 40.4, and 52.2 microM, respectively. The expressions of glutathione S-transferase pi (GST-pi) and multidrug resistance-associated protein (MRP) were enhanced in a dose-response manner as cells acquired progressive cisplatin resistance. Expression of mdr-1 transcript was detected in the three resistant lines but not in the sensitive line. Glutathione contents were increased in resistant cells, yet the trend of increase did not reach statistical significance (p = 0.061). In conclusion, transitional carcinoma cells may gain cisplatin resistance through multiple pathways including up-regulation of GST-pi, MRP and possibly mdr-1. Glutathione contents may play a less significant role in cisplatin chemoresistance.

Prostate cancer in Taiwan: epidemiology and risk factors.

The incidence of prostate cancer (PC) has been rapidly increasing in the past 10 years in Taiwan. It became the sixth common cancer in males in 1996 and resulted in 540 deaths in 1998. It was estimated that the incidence of PC would be up to 14 per 105 in the year 2000, 3-fold higher than that in 1990. Three factors may be responsible for the increase of PC in Taiwan: use of prostate specific antigen, population aging and high fat diet. A case-control study on the risk factors of PC in a patient population comprised mainly of veterans (63%) in Taiwan showed that PC patients tended to have engaged in more physical activity (adjusted odds ratio (OR): 2.16), have a lower body mass index (OR 2.0) and be less likely to consume vegetables cooked with pork lard (OR 0.47). About half of our patients had locally advanced or metastatic diseases upon diagnosis. This staging distribution was consistent in most major institutions in Taiwan and was fairly unchanged over time in the past two decades. The incidence of latent PC in Taiwan was not investigated until a pathological review of 49 cystoprostatectomy specimens recently revealed unsuspected PC in 32.7% and high-grade prostate intra epithelial neoplasia in 49% of the prostates removed. As the incidence of PC grows rapidly in Taiwan, this disease warrants more attention from the public and the authorities. More efforts should also be directed to the investigation on the risk factors for PC in the new millennium.

Function and therapeutic implication of C-CAM cell-adhesion molecule in prostate cancer.

Human neoplasms are often caused by cumulative alterations in oncogenes and tumor-suppressor genes. By identifying the early genetic changes involved in tumorigenesis, one can develop strategies to prevent and detect cancers at early stages, when treatment is most effective. C-CAM1, a cell-adhesion molecule (CAM) isoform (I), was recently shown to play a critical role in prostate cancer initiation and progression. Loss of C-CAM1 expression occurs early in the development of prostate cancer, suggesting that C-CAM1 may help maintain the differentiated state of the prostate epithelium. Reintroduction of C-CAM1 into cancer cells can reverse their cancerous growth. Thus, the C-CAM1 molecule itself or drugs that increase C-CAM1 expression are promising agents for prostate cancer treatment. The mechanisms by which C-CAM1 suppresses tumorigenesis are different from those of p53 and Rb. Therefore, C-CAM1 therapy is a new form of prostate cancer treatment. To exploit C-CAM1's therapeutic potential, a human C-CAM1 adenovirus expression vector (Ad-hu-C-CAM1) has been used to treat prostate tumor xenografts in nude mice. The preliminary results have shown great promise. In addition, while C-CAM gene therapy may have immediate application in prostate cancer treatment, the knowledge to be learned from mechanistic studies of C-CAM1-mediated tumor suppression may also help us design better strategies for prevention and treatment for prostate cancer.

Genetic polymorphisms of N-acetyltransferase 1 and 2 and risk of cigarette smoking-related bladder cancer.

Aromatic amines from cigarette smoking or occupational exposure, recognized risk factors for bladder cancer, are metabolized by N-acetyltransferases (NAT). This study examined the association of (NAT) 1 and 2 genotypes with the risk of smoking-related bladder cancer. A total of 74 pathologically confirmed bladder cancer patients and 184 controls were serially recruited from the National Taiwan University Hospital. History of cigarette smoking and other risk factors for bladder cancer was obtained through standardized questionnaire interview. Peripheral blood lymphocytes were collected from each subject and genotyped for NAT1 and NAT2 by DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Allele frequency distributions of NAT1 and NAT2 were similar between cases and controls. There was a significant dose-response relationship between the risk of bladder cancer and the quantity and duration of cigarette smoking. The biological gradients were significant among subjects carrying NAT1*10 allele or NAT2 slow acetylators, but not among NAT2 rapid acetylators without NAT1*10 allele. The results are consistent with the hypothesis that NAT1 and NAT2 might modulate the susceptibility to bladder cancer associated with cigarette smoking.

Antiandrogen hepatotoxicity in patients with chronic viral hepatitis.

OBJECTIVE: To assess whether patients with chronic viral hepatitis are at an increased risk for antiandrogen hepatotoxicity. METHODS: We retrospectively reviewed 121 prostate cancer patients who received long-term antiandrogen, either flutamide (n = 56) or cyproterone acetate (n = 65), and had normal pretreatment serum alanine aminotransferase (ALT) levels. Serological markers of hepatitis B and C viruses (HBV and HCV) were checked in 42 of the 121 patients. RESULTS: Twenty-two (18%) of the 121 patients had ALT elevations during antiandrogen therapy. Thirteen (59%) of the 22 patients were positive for either one of the two viral markers, including 7 for HBV, 4 for HCV, and 2 for both. This percentage was higher than the combined prevalence rate of positivity for HBV and/or HCV markers (<20%) in Taiwan. There was no significant differences in the percentage of positive makers among the two antiandrogen groups (p = 0.092). Although a higher incidence of hepatotoxicity was noted in the flutamide (13/56, 23%) than in the cyproterone acetate group (9/65, 14%), there were no significant differences between the two groups (p = 0.27). The time period between initiation of antiandrogen and first ALT elevation varied significantly (from 4 to 1,398 days with a median of 151 days). Half of the 14 HBV carriers and all of the 6 patients with anti-HCV developed antiandrogen hepatotoxicity. CONCLUSION: Our limited data suggested that patients with chronic viral hepatitis probably are at a higher risk of developing antiandrogen hepatotoxicity. Close monitoring of liver functions in patients with chronic viral hepatitis is advised if antiandrogen therapy is necessary. However, a large-scale study is necessary for a definitive conclusion.