Active Surveillance for Taiwanese Men with Localized Prostate Cancer: Intermediate-Term Outcomes and Predictive Factors.

PURPOSE: Active surveillance (AS) is one of the management options for patients with low-risk and select intermediate-risk prostate cancer (PC). However, factors predicting disease reclassification and conversion to active treatment from a large population of pure Asian cohorts regarding AS are less evaluated. This study investigated the intermediate-term outcomes of patients with localized PC undergoing AS. MATERIALS AND METHODS: This cohort study enrolled consecutive men with localized non-high-risk PC diagnosed in Taiwan between June 2012 and Jan 2023. The study endpoints were disease reclassification (either pathological or radiographic progression) and conversion to active treatment. The factors predicting endpoints were evaluated using the Cox proportional hazards model. RESULTS: A total of 405 patients (median age: 67.2 years) were consecutively enrolled and followed up with a median of 64.6 months. Based on the National Comprehensive Cancer Network (NCCN) risk grouping, 70 (17.3%), 164 (40.5%), 140 (34.6%), and 31 (7.7%) patients were classified as very low-risk, low-risk, favorable-intermediate risk, and unfavorable intermediate-risk PC, respectively. The 5-year reclassification rates were 24.8%, 27.0%, 18.6%, and 25.3%, respectively. The 5-year conversion rates were 20.4%, 28.8%, 43.6%, and 37.8%, respectively. A prostate-specific antigen density (PSAD) of ≥0.15 ng/mL² predicted reclassification (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.17-2.88) and conversion (HR 1.56, 95% CI 1.05-2.31). A maximal percentage of cancer in positive cores (MPCPC) of ≥15% predicted conversion (15% to <50%: HR 1.41, 95% CI 0.91-2.18; ≥50%: HR 1.97, 95% CI 1.1453-3.40) compared with that of <15%. A Gleason grade group (GGG) of 3 tumor also predicted conversion (HR 2.69, 95% CI 1.06-6.79; GGG 3 vs 1). One patient developed metastasis, but none died of PC during the study period (2,141 person-years). CONCLUSIONS: AS is a viable option for Taiwanese men with non-high-risk PC, in terms of reclassification and conversion. High PSAD predicted reclassification, whereas high PSAD, MPCPC, and GGG predicted conversion.

Effect of plasma selenium, red blood cell cadmium, total urinary arsenic levels, and eGFR on renal cell carcinoma.

High total urinary arsenic concentrations and low estimated glomerular filtration rate (eGFR) increase the risk of renal cell carcinoma (RCC). This study aimed to determine whether other metals or metalloids can affect RCC. A total of 401 patients with RCC and 774 age- and sex-matched controls were recruited between November 2006 and December 2012 in Taiwan. Surgical resection or image-guided biopsy of renal tumors was performed to pathologically verify RCC. High-performance liquid chromatography linked to a hydride generator and atomic absorption spectrometer were used to measure the urinary arsenic species concentrations. Inductively coupled plasma mass spectrometry was used to determine plasma selenium and red blood cell cadmium and lead concentration. Plasma selenium levels were inversely related to RCC, whereas red blood cell cadmium levels were directly related to RCC. The odds ratio (OR) and 95% confidence interval (CI) were 0.14 (95% CI, 0.10-0.20) and 1.33 (95% CI, 1.03-1.72), respectively. A low plasma selenium level tended to interact with high total urinary arsenic levels or with high red blood cell cadmium concentration to increase the OR of RCC. In particular, low eGFR multiplicatively interacted with high red blood cell cadmium concentration to increase the OR of RCC (Pinteraction=0.003). This study was the first to find a significant multiplicative interaction between eGFR and the red blood cell cadmium levels on the increased OR of RCC.

Levels of plasma selenium and urinary total arsenic interact to affect the risk for prostate cancer.

This study investigated whether plasma selenium levels modified the risk for prostate cancer (PC) related to arsenic exposure. We conducted a case-control study that included 318 PC patients and 318 age-matched, healthy control subjects. Urinary arsenic profiles were examined using HPLC-HG-AAS and plasma selenium levels were measured by ICP-MS. We found that plasma selenium levels displayed a significant dose-dependent inverse association with PC. The odds ratio (OR) and 95% confidence interval (CI) for PC was 0.07 (0.04-0.13) among participants with a plasma selenium level >28.06 µg/dL vs. ≤19.13 µg/dL. A multivariate analysis showed that participants with a urinary total arsenic concentration >29.28 µg/L had a significantly higher OR (1.75, 1.06-2.89) for PC than participants with ≤29.89 µg/L. The combined presence of a low plasma selenium level and a high urinary total arsenic concentration exponentially increased the OR for PC, and additively interacted with PSA at levels ≥20 ng/mL. This is the first epidemiological study to examine the combined effects of plasma selenium and urinary total arsenic levels on the OR for PC. Our data suggest a low plasma selenium level coupled with a high urinary total arsenic concentration creates a significant risk for aggressive PC.

Association between levels of urinary heavy metals and increased risk of urothelial carcinoma.

OBJECTIVES: To evaluate possible sources of exposure to heavy metals in the general population, and to determine the association between urinary heavy metals and urothelial carcinoma risk. METHODS: We recruited 205 patients with urothelial carcinoma and 406 control participants for a case-control study between June 2011 and December 2013. The control participants were frequency-matched with cases according to sex and age. We measured the urinary levels of arsenic, cadmium, chromium, nickel and lead by using inductively coupled plasma mass spectrometry. We collected environmental exposure-related information through questionnaires. Multivariate logistic regression and 95% confidence intervals were applied to estimate the urothelial carcinoma risk and potential effects of urothelial carcinoma-related risk factors on the levels of urinary heavy metals. RESULTS: Patients with urothelial carcinoma showed higher urinary levels of arsenic, cadmium, chromium, nickel and lead than the controls. After considering other potential risk factors, a significantly increased risk for urothelial carcinoma was observed in patients with increased urinary levels of cadmium, chromium, nickel and lead. Smokers showed a high urinary cadmium level. In addition to cadmium, a high urinary lead level was associated with cumulative cigarette smoking and herbal medicine use. CONCLUSION: Environmental factors might contribute to higher urinary levels of heavy metals and ultimately result in urothelial carcinoma carcinogenesis. These findings can promote proper environmental surveillance of exposure to heavy metals in the general population.

[Clinical Efficacy and Safety of Heat-sensitive Moxibustion Therapy for Lumbar Disc Herniation:A Meta-analysis].

OBJECTIVE: To systematically review the effectiveness and safety of heat-sensitive moxibustion (HSM) therapy in the treatment of lumbar disc herniation (LDH). METHODS: Papers of randomized clinical trials (RCTs) concerning the effectiveness and safety of HSM therapy for LDH published in both Chinese and English before November 17, 2015 were collected from PubMed, EMBase, Cochrane library, CNKI, CBM, WanFang Data and VIP databases according to the inclusion and exclusion criteria and by using key words of "thermal moxibustion" "heat-sensitive acupoint" "lumbar intervertebral disc herniation (LIDH)" "lumbar disc herniation (LDH)" and "lumbago backache", followed by screening, data extracting and methodological quality assessing. Then, the Meta-analysis was performed using RevMan 5.3 software. RESULTS: Twenty RCTs were included eventually, containing a total of 1 861 cases treated by HSM therapy in the treatment of LDH patients. The Meta-analysis shows that the effectiveness and safety of HSM therapy for LDH are superior to those of other therapies, which is drawn from total effective rate of treatment group[RR=1.13, 95%CI(1.09,1.18), P<0.001], M-JOA score[MD=-3.17, 95%CI(-3.88, -2.47), P<0.001], M-JOA score difference of various subgroups:daily life ability effect difference[MD=1.04, 95%CI(0.44, 1.64), P<0.001], subjective effect symptoms difference[MD=0.58, 95%CI (0.23, 0.92),P=0.001], objective effect symptoms difference[MD=1.12, 95%CI(0.58, 1.65),P<0.001], VAS score[MD=-1.17,95%CI(-1.78, -0.57), P<0.001], the recurrence rate[RR=0.54, 95%CI(0.37, 0.80), P=0.002], and no adverse reactions mentioned in the reported results. The sensitivity analysis showed a greater homogeneity in literature and the results were stable, but funnel plot analysis showed a publication bias. CONCLUSIONS: The HSM therapy is effective and safe in the treatment of LDH patients.

Angiogenesis inhibitor therapies for advanced renal cell carcinoma: toxicity and treatment patterns in clinical practice from a global medical chart review.

The aim of this study was to assess the treatment patterns and safety of sunitinib, sorafenib and bevacizumab in real-world clinical settings in US, Europe and Asia. Medical records were abstracted at 18 community oncology clinics in the US and at 21 tertiary oncology centers in US, Europe and Asia for 883 patients ≥ 18 years who had histologically/cytologically confirmed diagnosis of advanced RCC and received sunitinib (n=631), sorafenib (n=207) or bevacizumab (n=45) as first-line treatment. No prior treatment was permitted. Data were collected on all adverse events (AEs) and treatment modifications, including discontinuation, interruption and dose reduction. Treatment duration was estimated using Kaplan-Meier analysis. Demographics were similar across treatment groups and regions. Median treatment duration ranged from 6.1 to 10.7 months, 5.1 to 8.5 months and 7.5 to 9.8 months for sunitinib, sorafenib and bevacizumab patients, respectively. Grade 3/4 AEs were experienced by 26.0, 28.0 and 15.6% of sunitinib, sorafenib and bevacizumab patients, respectively. Treatment discontinuations occurred in 62.4 (Asia) to 63.1% (US) sunitinib, 68.8 (Asia) to 90.0% (Europe) sorafenib, and 66.7 (Asia) to 81.8% (US) bevacizumab patients. Globally, treatment modifications due to AEs occurred in 55.1, 54.2 and 50.0% sunitinib, sorafenib and bevacizumab patients, respectively. This study in a large, global cohort of advanced RCC patients found that angiogenesis inhibitors are associated with high rates of AEs and treatment modifications. Findings suggest an unmet need for more tolerable agents for RCC treatment.

Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes.

Aristolochic acid (AA), a component of all Aristolochia-based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To investigate the clinical and pathological characteristics of AA-induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam-DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T-to-T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam-DNA adducts and A:T-to-T:A transversions in TP53 were defined as AA-UUC, whereas patients lacking both of these biomarkers were classified as non-AA-UUC. Cases with either biomarker were classified as possible-AA-UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA-UUC, possible-AA-UUC and non-AA-UUC, respectively. AA-UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end-stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible-AA-UUC and non-AA-UUC patients. All 14 patients who developed contralateral UUC had aristolactam-DNA adducts; ten of these also had signature mutations. The contralateral UUC-free survival period was shorter in AA-UUC compared to possible- or non-AA-UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA-UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC.

CKD as a risk factor for bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma.

BACKGROUND: The aim of this study is to examine chronic kidney disease (CKD) as a risk factor for bladder recurrence and cancer-specific and total mortality in a cohort of patients with upper urinary tract (UUT) urothelial carcinoma (UC) treated by means of nephroureterectomy. STUDY DESIGN: Cohort study. SETTINGS & PARTICIPANTS: 150 patients with primary UC of the ureter or renal pelvis treated by means of nephroureterectomy at a single center. PREDICTOR: Presence and severity of CKD according to preoperative markers of kidney damage, estimated glomerular filtration rate calculated using the Modification of Diet in Renal Disease Study equation, and other covariates. OUTCOMES & MEASUREMENTS: Subsequent bladder recurrences, cancer-specific survival, and overall survival. RESULTS: Of 150 patients, 37 (25%) had no CKD, 71 patients (47%) had CKD stages 1 to 4, and 42 patients (28%) had CKD stage 5. 41 (27%) and 31 patients (21%) reported exposure to herbal medicine or tobacco use, respectively. During a mean follow-up of 4 years, 53 patients (35%) developed bladder recurrence and 27 (18%) died, of whom 14 (9.3%) died of cancer. Overall 5-year bladder recurrence-free and cancer-specific survival rates were 62% and 89%, respectively (n = 150). Risks of bladder recurrence were 2.43 (95% confidence interval, 1.00 to 5.93) and 3.95 (95% confidence interval, 1.59 to 9.80), greater in patients with CKD stages 1 to 4 and CKD stage 5 compared with patients without CKD, respectively. Ureteral involvement of the primary tumor (hazard ratio, 1.97; 95% confidence interval, 1.12 to 3.48) also was associated significantly with an increased rate of bladder recurrence. The risk of death from all causes or UC was not significantly greater in patients with CKD stages 1 to 4 or CKD stage 5 compared with those without CKD. Higher tumor stage (pT2 to 4) was associated significantly with overall death (hazard ratio, 5.15; 95% confidence interval, 1.84 to 14.48). LIMITATIONS: A retrospective study in an area of high incidence of both UUT-UC and CKD. CONCLUSIONS: Advancing CKD stage of patients and positive ureteral involvement of the primary tumor (especially in the lower ureter) are associated with greater risk of subsequent bladder recurrence in patients with UUT-UC treated by means of radical surgery.

Weekly paclitaxel and high-dose 5-fluorouracil plus leucovorin in hormone-refractory prostate cancer: in vitro combined effects and a phase II trial.

PURPOSE: Paclitaxel and 5-fluorouracil have been used to treat hormone-refractory prostate cancer with some success. In vitro data suggest that the combined cytotoxicity may be sequence dependent. Thus, we explored the combined effects of the 2 agents, both in vitro and in vivo. PATIENTS AND METHODS: The combined cytotoxicity of paclitaxel and 5-fluorouracil, and the possible schedule dependence were studied in vitro using PC-3 and DU145 cells and the microculture tetrazolium assay. There were 23 patients with hormone-refractory prostate cancer treated with the regimen T-HDFL: paclitaxel 90 mg/m2 intravenously 1 hour on days 1 and 8; 5-fluorouracil 2000 mg/m2; and leucovorin 300 mg/m2 intravenous 24-hour infusion on days 2 and 9, which repeated every 21 days. The allowed percentage of bone marrow irradiation was 50%. RESULTS: Significant synergistic cytotoxicity was seen only when paclitaxel was given 24 hours before 5-fluorouracil. With the T-HDFL regimen, 11 (52%) of the 21 evaluable patients had > or = 50% reduction of prostate-specific antigen, lasting for 6 weeks. Of the 7 patients with measurable disease, 2 had a partial response. Median overall survival was 14.1 months. Grade III/IV leukopenia occurred in 2 patients. There was no treatment-related death. Toxicities were well tolerated. CONCLUSIONS: The combined cytotoxicity of paclitaxel and 5-fluorouracil is schedule dependent. It is feasible to administer weekly paclitaxel and high-dose 5-fluorouracil infusions in patients with hormone-refractory prostate cancer. Our findings may serve as an important rationale for future trial design.

Prognostic factors for metastatic urothelial carcinoma treated with cisplatin and 5-fluorouracil-based regimens.

OBJECTIVES: We have previously shown that a combination of infusion cisplatin and high-dose 5-fluorouracil/leucovorin (P-HDFL) has moderate activity and acceptable toxicity in patients with metastatic urothelial carcinoma. The present study sought to identify factors that predict for patient survival after treatment with P-HDFL-based regimens. METHODS: The outcomes of 79 patients (median age 69 years) with metastatic urothelial cancer treated in two Phase II trials, including P-HDFL and paclitaxel plus P-HDFL, were updated. The log-rank test and multivariate Cox proportional hazard models were used to identify the prognostic factors predicting for survival. RESULTS: The median follow-up duration was 38.9 months (range 10.2 to 89.0). A Karnofsky performance status scale of less than 80% (hazard ratio 2.6, 95% confidence interval 1.5 to 4.6), presence of visceral metastasis (hazard ratio 2.3, 95% confidence interval 1.3 to 4.1), and alkaline phosphatase level of 220 U/L or greater (hazard ratio 2.5, 95% confidence interval 1.3 to 4.5) were three significant risk factors predicting for poor survival in the Cox proportional hazard model. The three factors weighted approximately the same and were independent of each other. The median survival for patients with three, one or two, and no risk factors was 4.6, 13.2, and greater than 81.8 months, respectively (P <0.001). CONCLUSIONS: The Karnofsky performance status scale, presence of visceral metastasis, and alkaline phosphatase level were independent risk factors for survival in patients with metastatic urothelial carcinoma treated with cisplatin and 5-fluorouracil-based regimens.

Phase II trial of weekly paclitaxel, cisplatin plus infusional high dose 5-fluorouracil and leucovorin for metastatic urothelial carcinoma.

PURPOSE: Conventional chemotherapy for urothelial carcinoma, such as methotrexate, vinblastine, doxorubicin and cisplatin, is associated with significant toxicity. We have previously reported a low toxicity and yet moderately active regimen containing weekly infusional cisplatin and high dose 5-fluorouracil/leucovorin for advanced urothelial carcinoma. We tested the efficacy and toxicity of adding paclitaxel to that regimen. MATERIALS AND METHODS: Between April 2000 and December 2004, 44 patients with a median age of 66 years with metastatic urothelial carcinoma were enrolled. The paclitaxel, cisplatin and high dose 5-fluorouracil/leucovorin regimen consisted of 70 mg/m2 paclitaxel daily as a 1-hour infusion on days 1 and 8, 35 mg/m2 cisplatin daily as a 24-hour infusion on days 2 and 9, 2,000 mg/m2 5-fluorouracil daily and 300 mg/m2 leucovorin daily as a 24-hour infusion on days 2 and 9. The cycles repeated every 21 days. A total of 25 patients (64%) had a creatinine clearance of 35 to 60 ml per minute. RESULTS: A total of 210 cycles (mean 4.8 per patient) were administered. Of the 40 patients eligible for response evaluation 11 (28%) and 19 (48%) were complete and partial responders with an overall response rate of 75% (95% CI 61 to 89). Median overall and progression-free survival in the whole group was 17.0 (95% CI 13.7 to 20.3) and 8.3 months (95% CI 6.4 to 10.2), respectively. Two-year disease-free survival was 15%. Grade 3 or 4 anemia, leukopenia and thrombocytopenia occurred at 23, 30 and 12 cycles, respectively. Nonhematological toxicity included infection, vomiting and diarrhea, etc. There were 2 treatment related deaths. CONCLUSIONS: Paclitaxel, cisplatin and high dose 5-fluorouracil/leucovorin is an active regimen against metastatic urothelial carcinoma which has an acceptable toxicity profile.

Weekly cisplatin plus infusional high-dose 5-fluorouracil and leucovorin (P-HDFL) for metastatic urothelial carcinoma: an effective regimen with low toxicity.

BACKGROUND: Conventional systemic chemotherapy for metastatic urothelial carcinoma (UC) such as methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) or cisplatin, methotrexate, and vinblastine (CMV) is associated with significant dose-limiting toxicities and even treatment-related death. The authors developed a regimen that was designed to maintain efficacy, while reducing toxicities. METHODS: Between January 1998 and July 2003, 35 patients (median age, 71 yrs) with metastatic UC were treated with 4-week cycles of P-HDFL (cisplatin 35 mg/m(2), high-dose 5-fluorouracil [5-FU] 2,600 mg/m(2), and leucovorin 300 mg/m(2), on Days 1 and 8, all given by 24-hr infusion). On Day 15, only HDFL was given again. RESULTS: Among the 32 patients treated with > or = 2 cycles, 9 (28.1%) and 11 (34.4%) were complete and partial responders, respectively, with an overall response rate of 62.5% (95% confidence interval [CI], 45.9-79.2%). The median overall and progression-free survival was 12.3 months (95% CI, 8.2-16.4 mos) and 10.5 months (95% CI, 8.4-12.6 mos), respectively. Toxicity in a total of 121 courses (mean, 3.5 per patient) was modest, with WHO Grade 3 or 4 leukopenia and thrombocytopenia noted in only 1 and 0 patients, respectively. Grade 3 or 4 nausea, vomiting, mucositis, and diarrhea were noted in 3, 2, 0, and 2 patients, respectively. In general, patients tolerated the regimen very well. CONCLUSIONS: P-HDFL is a moderately active and considerably low-toxic regimen for metastatic UC. The excellent toxicity profile makes it a viable option for patients with poor general conditions. To reach any conclusion, randomized trials comparing P-HDFL with traditional cisplatin-based regimens are necessary.

Characterization of molecular events in a series of bladder urothelial carcinoma cell lines with progressive resistance to arsenic trioxide.

Our previous studies have shown that arsenic trioxide (As2O3), a novel anti-cancer agent, may be active against urothelial carcinomas. A series of bladder urothelial carcinoma cells with progressive As2O3 resistance were established and studied to reveal molecular events in relation to the mechanisms of resistance to As2O3. A sensitive parental line (NTUB1) and three As2O3-resistant sublines (NTUB1/As) were used with their IC50s being 0.9, 1.2, 2.5 and 4.9 microM, respectively. Cellular resistance to As2O3 was associated with a lowered proliferation profile (increased p53 and p21Waf1/Cip1 and decreased c-Myc levels) and a greater resistance to apoptosis (elevated Bcl-2 levels). Cells with a stronger resistance had higher expressions of superoxide dismutase (Cu/Zn) and hMSH2 (but not hMLH1). GSH contents were up-regulated in resistant cells in a dose-dependent manner. The DNA-binding activities of NF-kappaB and AP-1 were down-regulated in resistant cells in a dose-dependent manner. Profound molecular alterations occur during the acquisition of secondary As2O3 resistance. Our in vitro cellular model may help to reveal resistance mechanisms to As2O3 in bladder urothelial carcinoma cells.

Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21(WAF1/CIP1) and C/EBPbeta expressions and suppressing NF-kappaB activation.

BACKGROUND: The modulatory effects and molecular mechanisms of curcumin (CCM) on the cytotoxicity of chemotherapeutic agents to prostate cancer cells were explored. METHODS: The combined effects of CCM and chemotherapeutic agents were examined by three different administration schedules (one concurrent and two sequential treatments) in two androgen-independent prostate cancer (AIPC) cells (PC-3 and DU145). Alteration of cell cycle progression, protein levels, and transcriptional activation in PC-3 cells were assayed by flow cytometry, Western blotting, and gel shift assay, respectively. RESULTS: The combined effects of CCM --> chemotherapeutic agent schedule showed the greatest synergistic cytotoxicity when compared to the other two schedules in both cells. CCM induced a significant G1 arrest in PC-3, which may be mediated by the induction of p21(WAF1/CIP1) and C/EBPbeta. Moreover, CCM was able to inhibit both the constitutional and TNF-alpha-induced NF-kappaB activation in a time-dependent manner. CONCLUSIONS: The incorporation of CCM into cytotoxic therapies may be a promising strategy for the treatment of AIPC.