Jong-Khing Huang

THE ROLE OF BCL-2, p53, AND KI-67 INDEX IN PREDICTING TUMOR RECURRENCE FOR LOW GRADE SUPERFICIAL TRANSITIONAL CELL BLADDER CARCINOMA

PURPOSEnWe assess the prognostic significance of bcl-2 expression, p53 mutation and ki-67 index for low grade, superficial transitional cell bladder carcinoma.nnnMATERIALS AND METHODSnThe medical records of 93 cases of primary, low grade (24 G1, 69 G2), superficial (70 pTa, 23 pT1) transitional cell carcinoma of the bladder were reviewed. Association of bcl-2, p53 and ki-67 index immunoreactivity with tumor grade and stage was examined. Prognostic significance of tumor grade, pathological stage, bcl-2 expression, p53 mutation and ki-67 index in predicting tumor recurrence was assessed.nnnRESULTSnOf the tumors 60 (70%) had p53 mutation and 9 (10.5%) expressed bcl-2. These 2 markers did not relate to tumor grade or pathological stage. Median ki-67 index was 10.9% and positively correlated with tumor grade. Recurrence was noted in 34.9% of patients with a median followup of 26 months (range 1 to 84). The ki-67 index was the only significant prognostic indicator in univariate and multivariate analyses. This marker can further distinguish grade 2 tumors with a favorable prognosis from those with an unfavorable outcome.nnnCONCLUSIONSnThe ki-67 labeling index is an independent predictor of tumor recurrence for patients with primary superficial, low grade bladder cancers.

Acupuncture in the Treatment of Renal Colic

A prospective randomized study was performed to compare the effect of acupuncture and intramuscular Avafortan injection in the treatment of renal colic. Our results showed that acupuncture is as effective in relieving renal colic as Avafortan but it had a more rapid analgesic onset (3.14 +/- 2.88 minutes versus 15.44 +/- 7.55 minutes, p less than 0.05). Of the patients in the Avafortan group 7 (43.8%) had side effects, including skin rash in 3, tachycardia in 2, drowsiness in 1 and facial flush in 1. No side effects were noted in the acupuncture group. During 2 hours of observation acupuncture and Avafortan seemed to be ineffective in promoting stone passage. However, patients receiving Avafortan treatment were more likely to have paralytic ileus. In summary, acupuncture can be a good alternative for the treatment of renal colic.

Risk Factors for Individual Domains of Female Sexual Function

INTRODUCTIONnFemale sexual function contains four major subtypes of desire, arousal, orgasm, and pain. Few studies used validated instruments to determine the dysfunction in these areas and assess their risk factors.nnnAIMnTo assess the prevalence of and risk factors for individual components of sexual difficulty in women.nnnMETHODSnA self-administered questionnaire containing the Female Sexual Function Index (FSFI) was given to 2,159 woman employees of two hospitals to assess their sexual function and its correlates.nnnMAIN OUTCOME MEASURESnThe associations between female sexual difficulty in individual domains defined by the FSFI domain scores and potential risk factors assessed by simple questions.nnnRESULTSnAmong the 1,580 respondents, 930 womens data were eligible for analysis with a mean age of 36.1 years (range 20-67). Of them, 43.8% had sexual difficulty in one or more domains, including low desire in 31.3%; low arousal, 18.2%; low lubrication, 4.8%; low orgasmic function, 10.4%; low satisfaction, 7.3%; and sexual pain, 10.5%. Compared with the younger women (20-49 years), the oldest age group (50-67 years) had a significantly higher prevalence in low desire, low arousal, and low lubrication, but not in the other domains. Based on multivariate logistic regression analyses, poor relationship with the partner and perception of partners sexual dysfunction were major risk factors for low desire, low arousal, low orgasmic function, and low satisfaction. Age and urge urinary incontinence were associated with low lubrication and sexual pain. Most comorbidities were not related to these difficulties, except diabetes being related to low desire.nnnCONCLUSIONSnRelationship factors had substantial impact on female sexual function in desire, arousal, orgasm, and satisfaction. On the other hand, womens lubrication problem and sexual pain were related predominantly with biological factors. These are initial results and future research is needed to confirm them.

Determinant Role of Testosterone in the Pathogenesis of Urolithiasis in Rats

By using an ethylene glycol-induced urolithiasis model, we assessed the role of testosterone in the pathogenesis of urolithiasis. The intact and castrated male and female rats were fed with 0.5% ethylene glycol in drinking water for four weeks. The renal excretions of oxalate, citrate and other electrolytes were measured, and the stone and crystal deposit were examined microscopically. The results showed that drinking a loading of 0.5% ethylene glycol for four weeks produced hyperoxaluria in all rats, but the intact male rats excreted more urinary oxalate than any other groups of rats. The ethylene glycol-fed rats exhibited hypocitraturia except the castrated male rats. However, urolithiasis occurred in intact male but not female rats. Castration in male rats fed with ethylene glycol dramatically decreased the incidence of renal stone from 71.4% (5/7) to 14.3% (1/7). On the other hand, there was still no renal stone formed in the oophorectomized female rats which received ethylene glycol treatment. These data indicate that serum testosterone level plays a determinant role in urolithiasis formation.

The Incidence and Prognostic Significance of Humoral Hypercalcemia in Renal Cell Carcinoma

This retrospective study was conducted to evaluate the incidence and prognostic significance of humoral hypercalcemia in 218 renal cell carcinoma patients during the last 20 years. Of 218 patients 20 (9.2%) were hypercalcemic, with serum calcium levels ranging from 10.7 to 16.0 mg./dl. The respective incidence of humoral hypercalcemia was 3% in patients with stage I, 5.9% with stage II, 14.1% with stage III and 18.9% with stage IV disease without bone metastasis. The survival curves between the hypercalcemic and eucalcemic groups among stages I to III cancer patients showed no statistical significance (p greater than 0.05). The survival curve deteriorated significantly in stage IV cancer patients with humoral hypercalcemia (p less than 0.005), with a median survival of 45.0 +/- 39.7 days versus 286.4 +/- 27.6 days in eucalcemic patients. No specific correlation was found between pathological cell type and humoral hypercalcemia.

Peritoneal nitric oxide is a marker of peritonitis in patients on continuous ambulatory peritoneal dialysis

Nitric oxide plays an important role in mediating the inflammatory process. The aim of this study was to evaluate if nitric oxide production was increased during peritonitis in patients receiving continuous ambulatory peritoneal dialysis (CAPD), and the association with the prognosis. The study population comprised 21 patients with 22 episodes of peritonitis. Fifteen patients without peritonitis were controls. Nitrate was measured by HPLC and nitrite by the Griess method, to reflect nitric oxide production. Peritoneal dialysate effluent and plasma were collected from six patients during peritonitis and 1 week after treatment to study changes in dialysate:plasma ratio. In 15 patients, nitrite was measured during peritonitis and every 3 days for 2 weeks or until normalized for evolutional changes. The dialysate:plasma ratios of nitrate and nitrite during peritonitis were reduced 26% and 41.5%, respectively, after 1 week of treatment, indicating the peritoneal production of nitric oxide during peritonitis. In the evolutional study, a 5.1-fold increase of peak nitrite levels in bacterial peritonitis (n = 13) and a 2.5-fold increase in fungal peritonitis (n = 3) were observed compared to controls. Nitrite gradually declined to control levels (9.3 +/- 7.2 days) after effective antibiotic treatment, but took longer than to normalize leukocyte count in the peritoneal dialysate effluent (3.9 +/- 1.9 days). In four patients with refractory peritonitis (Candida infection in three, Acinetobacter infection in one), the nitrite levels remained elevated 2-fold despite treatment, and the catheters were removed. It is concluded that nitrite levels in peritoneal dialysate effluent may serve as a marker to assess treatment efficacy in CAPD patients with peritonitis.

Androgen receptor gene polymorphism and prostate cancer in Taiwan

BACKGROUND AND PURPOSEnThe length of polymorphic CAG trinucleotide repeats in the polyglutamine region of the androgen receptor (AR) gene has been suggested to be inversely correlated with the transactivation function of the AR. An increase in androgen activity may be associated with prostate cancer, and ethnic variations in CAG repeat length may contribute to varying prostate cancer risks in different populations. This case-control study investigated the potential role of AR polymorphism in prostate cancer risk in Taiwanese.nnnMETHODSnSixty six pathologically-confirmed prostate cancer patients and 104 controls were studied. CAG repeat polymorphism was genotyped by a polymerase chain reaction (PCR)-based direct sequencing method. Logistic regression was used to determine the relative risk of AR gene CAG number on prostate cancer risk. The associations of AR-CAG polymorphism with disease stage, pathologic grade, and age at diagnosis were assessed. AR-CAG repeat number was first treated as a continuous variable, then was divided into short and long groups (n < 23 vs n > or = 23) for categorical analysis. The extreme groups of AR-CAG distribution were also analyzed for these associations (n < or = 20 vs n > or = 26 and n = 21-25 vs n > or = 26).nnnRESULTSnThe mean number of CAG repeats in patients and controls was similar: 23.2 +/- 3.0 (range, 15 to 31) and 22.9 +/- 3.1 (range, 15 to 31), respectively. No association was found between AR-CAG repeat polymorphism and disease stage (p = 0.30), histological grade (p = 0.49), or age at diagnosis (p = 0.51). After adjusting for other covariates (age, body mass index, education level, smoking, and alcohol status), the number of AR-CAG repeats was not significantly associated with prostate cancer risk [odds ratio (OR) = 0.97, 95% confidence interval (95% CI) = 0.72 to 1.31; p = 0.84]. In categorical analysis, men with short CAG repeats (n < 23) did not have increased risk for prostate cancer (OR = 0.45, 95% CI = 0.29 to 1.05) compared to those with long CAG repeats (n > or = 23). Non-significant differences in prostate cancer risk were also found when comparing the extreme short group (n < or = 20) and the intermediate group (n = 21-25) to the extreme long group (n > or = 26) [n < or = 20 vs n > or = 26: OR = 1.00, 95% CI = 0.34 to 3.00; n = 21-25 vs n > or = 26: OR = 0.82, 95% CI = 0.37 to 1.81].nnnCONCLUSIONSnThe results of this study do not support an important effect of AR-CAG repeat polymorphism on prostate cancer risk. A large-scale study is needed to clarify genetic components of prostate cancer risk in the Taiwanese population.

Effect of Thymol on Ca2+ Homeostasis and Viability in MG63 Human Osteosarcoma Cells

Aims: The effect of the natural product thymol on cytosolic Ca²⁺ concentrations ([Ca²⁺]_i) and viability in MG63 human osteosarcoma cells was examined. Methods: The Ca²⁺-sensitive fluorescent dye fura-2 was applied to measure [Ca²⁺]_i. Results: Thymol at concentrations of 200–1,000 µmol/l induced a [Ca²⁺]_i rise in a concentration-dependent fashion. The response was decreased partially by removal of extracellular Ca²⁺. Thymol-induced Ca²⁺ entry was inhibited by nifedipine, econazole, SK&F96365 and protein kinase C modulators. When extracellular Ca²⁺ was removed, incubation with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) inhibited the thymol-induced [Ca²⁺]_i rise. Incubation with thymol also inhibited the thapsigargin or BHQ-induced [Ca²⁺]_i rise. Inhibition of phospholipase C with U73122 abolished the thymol-induced [Ca²⁺]_i rise. At concentrations of 100–600 µmol/l, thymol killed cells in a concentration-dependent manner. This cytotoxic effect was not changed by chelating cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid/AM. Annexin V/propidium iodide staining data suggest that thymol (200 and 400 µmol/l) induced apoptosis in a concentration-dependent manner. Thymol (200 and 400 µmol/l) also increased levels of reactive oxygen species. Conclusions: In MG63 cells, thymol induced a [Ca²⁺]_i rise by inducing phospholipase C-dependent Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ entry via protein kinase C-sensitive store-operated Ca²⁺ channels. Thymol induced cell death that may involve apoptosis via mitochondrial pathways.

Mechanisms of resveratrol-induced changes in [Ca2+]i and cell viability in PC3 human prostate cancer cells

Abstract Resveratrol is a natural compound that affects cellular Ca2+ homeostasis and viability in different cells. This study examined the effect of resveratrol on cytosolic free Ca2+ concentrations ([Ca2+]i) and viability in PC3 human prostate cancer cells. The Ca2+-sensitive fluorescent dye fura-2 was used to measure [Ca2+]i and WST-1 was used to measure viability. Resveratrol-evoked [Ca2+]i rises concentration-dependently. The response was reduced by removing extracellular Ca2+. Resveratrol-evoked Ca2+ entry was not inhibited by nifedipine, econazole, SKF96365 and the protein kinase C inhibitor GF109203X, but was nearly abolished by the protein kinase C activator phorbol 12-myristate 13 acetate. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone decreased resveratrol-evoked rise in [Ca2+]i. Conversely, treatment with resveratrol inhibited BHQ-evoked rise in [Ca2+]i. Inhibition of phospholipase C with U73122 did not alter resveratrol-evoked rise in [Ca2+]i. Previous studies showed that resveratrol between 10 and 100u2009µM induced cell death in various cancer cell types including PC3 cells. However, in this study, resveratrol (1–10u2009μM) increased cell viability, which was abolished by chelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid-acetoxymethyl ester (BAPTA/AM). Therefore, it is suggested that in PC3 cells, resveratrol had a dual effect on viability: at low concentrations (1–10u2009µM) it induced proliferation, whereas at higher concentrations it caused cell death. Collectively, our data suggest that in PC3 cells, resveratrol-induced rise in [Ca2+]i by evoking phospholipase C-independent Ca2+ release from the endoplasmic reticulum and Ca2+ entry, via protein kinase C-regulated mechanisms. Resveratrol at 1–10u2009µM also caused Ca2+-dependent cell proliferation.

The Clinical Usefulness of Prostate-Specific Antigen (PSA) Level and Age-Specific PSA Reference Ranges for Detecting Prostate Cancer in Chinese

Introduction: To determine the role of prostate-specific antigen (PSA) level and age-specific PSA reference ranges for detecting prostate cancer in Chinese. Material and Methods: We retrospectively reviewed the medical records of all 50- to 79-year-old men who had their first-time prostatic biopsy done at our institute between January 1998 and December 2000. We evaluated the effect on biopsy rate and cancer detection if the PSA cutoff was shifted from 4.0 ng/ml to the age-specific reference ranges. Also, we tried to develop age-adjusted PSA cutoffs for Chinese. Results: Among 1,236 men enrolled, 252 (20.4%) were diagnosed as prostate cancers. The positive predictive value was 22.2% for PSA >4.0 ng/ml. Using the traditional age-specific PSA reference ranges 134 (10.8%) biopsies could be avoided but five (1.98%) cancers would be missed. We proposed age-specific PSA reference ranges for Chinese as: 0–4.0 ng/ml for men in their 50s and 0–6.0 ng/ml for men between 60 and 79 years. Had we used these alternative cutoffs, 150 (12.1%) biopsies could be saved, of them 3 were cancers. Conclusions: The age-specific PSA reference ranges may help to avoid 12% of biopsies but 1.2% of prostate cancers would have gone undetected. Among population with low incidence of prostate cancer as Chinese, minimizing unnecessary biopsies might be more important issue than maximizing cancer detection rate.