Construction of an immune-related LncRNA signature with prognostic significance for bladder cancer.

Bladder cancer (BLCA) is one of the most common urological cancer with increasing cases and deaths every year. In the present study, we aim to construct an immune-related prognostic lncRNA signature (IRPLS) in bladder cancer (BLCA) patients and explore its immunogenomic implications in pan-cancers. First, the immune-related differentially expressed lncRNAs (IRDELs) were identified by 'limma' R package and the score of IRPLS in every patient were evaluated by Cox regression. The dysregulation of IRDELs expression between cancer and para-cancer normal tissues was validated through RT-qPCR. Then, we further explore the biological functions of a novel lncRNA from IRPLS, RP11-89 in BLCA using CCK8 assay, Transwell assay and Apoptosis analysis, which indicated that RP11-89 was able to promote cell proliferation and invasive capacity while inhibits cell apoptosis in BLCA. In addition, we performed bioinformatic methods and RIP to investigate and validate the RP11-89/miR-27a-3p/PPARγ pathway in order to explore the mechanism. Next, CIBERSORT and ESTIMATE algorithm were used to evaluate abundance of tumour-infiltrating immune cells and scores of tumour environment elements in BLCA with different level of IRPLS risk scores. Finally, multiple bioinformatic methods were performed to show us the immune landscape of these four lncRNAs for pan-cancers. In conclusion, this study first constructed an immune-related prognostic lncRNA signature, which consists of RP11-89, PSORS1C3, LINC02672 and MIR100HG and might shed lights on novel targets for individualized immunotherapy for BLCA patients.

Identification and validation of novel metastasis-related signatures of clear cell renal cell carcinoma using gene expression databases.

Patients with clear cell renal cell carcinoma (ccRCC) typically face aggressive disease progression when metastasis occurs. Here, we screened and identified differentially expressed genes in three microarray datasets from the Gene Expression Omnibus database. We identified 112 differentially expressed genes with functional enrichment as candidate prognostic biomarkers. Lasso Cox regression suggested 10 significant oncogenic hub genes involved in earlier recurrence and poor prognosis of ccRCC. Receiver operating characteristic curves validated the specificity and sensitivity of the Cox regression penalty used to predict prognosis. The area under the curve indexes of the integrated genes scores were 0.758 and 0.772 for overall and disease-free survival, respectively. The prognostic values of ADAMTS9, C1S, DPYSL3, H2AFX, MINA, PLOD2, RUNX1, SLC19A1, TPX2, and TRIB3 were validated through an analysis of 10 hub genes in 380 patients with ccRCC from a real-world cohort. The expression levels of were of high prognostic value for predicting metastatic potential. These findings will likely significantly contribute to our understanding of the underlying mechanisms of ccRCC, which will enhance efforts to optimize therapy.

Extended versus non-extended lymphadenectomy during radical cystectomy for patients with bladder cancer: a meta-analysis of the effect on long-term and short-term outcomes.

BACKGROUND: Pelvic lymphadenectomy (PLND) is an integral part of curative surgery for high-risk non-muscle invasive and muscle-invasive bladder cancer. The therapeutic value of extended PLND is controversial. METHODS: We conducted a comprehensive online search in PubMed, EMBASE, and the Cochrane Library databases for relevant literature directly comparing extended PLND (e-PLND) with non-extended PLND (ne-PLND) from database inception to June 2019. We performed the meta-analysis to evaluate the impact of PLND templates on recurrence-free survival (RFS), disease-specific survival (DSS), overall survival (OS), rates of postoperative major complications, and mortality within 90 days of surgery. RESULTS: A total of 10 studies involving 3979 patients undergoing either e-PLND or ne-PLND were included. The results showed that e-PLND was significantly associated with better RFS (HR 0.74, 95% CI 0.62-0.90, p = 0.002) and DSS (HR 0.66, 95% CI 0.55-0.79, p < 0.001). However, no correlation was found between e-PLND template and a better OS (HR 0.93, 95% CI 0.55-1.58, p = 0.79). Postoperative major complications were similar between e-PLND group and ne-PLND group, as was mortality within 90 days of surgery. CONCLUSION: e-PLND template is correlated with favorable RFS and DSS outcomes for patients with bladder cancer. e-PLND did not have more postoperative major complications than did ne-PLND.

Tumor growth velocity: A modified tumor growth rate defining tumor progression during sorafenib treatment in patients with metastatic renal cell carcinoma.

OBJECTIVES: To investigate the role of tumor growth velocity in defining tumor progression in metastatic renal cell carcinoma patients treated with the vascular endothelial growth factor tyrosine kinase inhibitor, sorafenib. METHODS: A modified calculation for tumor growth velocity was introduced to evaluate the tumor growth velocity, before and after sorafenib withdrawal. Known prognostic factors together with tumor growth velocity before drug withdrawal and tumor growth velocity after drug withdrawal were compared using a χ2 -test from a contingency table, and partial likelihood test from a Cox regression model for overall survival. RESULTS: A total of 114 patients who reached progressive disease and withdrew from sorafenib were enrolled after a median follow-up period of 107.8 months. Tumor growth velocity before drug withdrawal was 7.347 ± 4.040, and tumor growth velocity after drug withdrawal was 11.647 ± 5.937 (P < 0.001). Higher tumor growth velocity before drug withdrawal was correlated with a higher risk Memorial Sloan Kettering Cancer Center score (P = 0.022), Karnofsky Performance Status <80 (P = 0.028), non-clear cell carcinoma (P = 0.037), higher tumor nucleus grade (P < 0.001) and best treatment response (P < 0.001). Patients with tumor growth velocity before drug withdrawal >5.0 had shorter overall survival (P < 0.001). On multivariate analysis, factors associated with overall survival were high/intermediate Memorial Sloan Kettering Cancer Center risk score (hazard ratio 2.119, P = 0.006), non-clear histological subtype (hazard ratio 1.900, P = 0.031), tumor growth velocity before drug withdrawal ≥5.0 (hazard ratio 2.758, P < 0.001) and progressive disease as best response (hazard ratio 2.069, P = 0.001). CONCLUSIONS: Significantly faster tumor growth can be observed if sorafenib is discontinued in the case of disease progression. Thus, we suggest not to withdraw targeted agents until tumor growth velocity is >5.0.

Nephrometry score-guided off-clamp laparoscopic partial nephrectomy: patient selection and short-time functional results.

BACKGROUND: Laparoscopic partial nephrectomy (LPN) is not a novel but a relatively technically challenging surgical procedure. Off-clamp LPN with zero ischemia can completely eliminate ischemic reperfusion injury to the kidney. The purpose of this study was to evaluate the safety and functional outcome of nephrometry score-guided off-clamp technique in LPN. METHODS: A total of 44 patients underwent LPN between January 2015 and July 2015 for renal mass with radius, exophytic/endophytic, nearness to sinus, anterior/posterior location (RENAL) score 4 were enrolled. Twenty-two of them underwent off-clamp LPN with zero ischemia, and the other 22 received standard LPN with common renal artery clamp. Estimate blood loss (EBL), total operation time, resection time, renorrhaphy time, preoperative estimated glomerular filtration rate (eGFR), postoperative eGFR, eGFR change, and drainage after surgery were compared between these two groups using t test. RESULTS: Patients' characteristics including gender, age, BMI, tumor size, and RENAL score were balanced between the two groups. Average EBL was more in the off-clamp group than in the on-clamp group (134.32 versus 70.23 ml, p = 0.001). Average eGFR change was less in the off-clamp group than in the on-clamp group (-1.56 versus -6.45, p < 0.001). Average drainage after surgery was 203.41 ml for the off-clamp group and 145.46 ml for the on-clamp group, p = 0.062. No urinary leakage and hematuria occurred in both groups. There were no statistical difference in total operation time, resection time, renorrhaphy time, preoperative eGFR, and postoperative eGFR between the two groups. CONCLUSIONS: Off-clamp LPN is a safe and feasible approach to excise certain kidney tumors with RENAL score 4. This technique can better preserve kidney function without ischemic reperfusion injury.

Clinicopathological and prognostic factors for long-term survival in Chinese patients with metastatic renal cell carcinoma treated with sorafenib: a single-center retrospective study.

Data on long-term survival and prognostic significance of demographic factors and adverse events (AEs) associated with sorafenib, an orally administered multikinase inhibitor in Chinese population with advanced renal cell carcinoma (RCC) are limited. Outcome data from adult patients (n = 256) with advanced RCC who received sorafenib (400 mg twice daily) either as first-line or second-line therapy between April 2006 and May 2013 were analyzed retrospectively. The primary endpoint was median overall survival (OS), determined to be 22.2 (95% CI: 17.1-27.4) months, and the secondary endpoint was overall median progression-free survival (PFS), determined to be 13.6 (95% CI: 10.7-16.4) months at a median follow-up time of 61.8 (95% CI: 16.2-97.4) months. Analysis of the incidence of AEs revealed the most common side effect as hand-foot skin reactions (60.5%) followed by diarrhea (38.7%), fatigue (35.5%), alopecia (34.0%), rash (24.6%), hypertension (21.5%) and gingival hemorrhage (21.1%). Multivariate regression analysis revealed older age (≥ 58 years), lower Memorial Sloan-Kettering Cancer Center score, time from nephrectomy to sorafenib treatment, number of metastatic tumors and best response as significant and independent demographic predictors for improved PFS and/or OS (p ≤ 0.05). Alopecia was identified as a significant and independent predictor of increased OS, whereas vomiting and weight loss were identified as significant predictors of decreased OS (p ≤ 0.05). Sorafenib significantly improved OS and PFS in Chinese patients with advanced RCC. Considering the identified significant prognostic demographic factors along with the advocated prognostic manageable AEs while identifying treatment strategy may help clinicians select the best treatment modality and better predict survival in these patients.

Association of glutathione S-transferase T1 and M1 polymorphisms with prostate cancer susceptibility in populations of Asian descent: a meta-analysis.

BACKGROUND: Genetic polymorphism was hypothesized to be reason of variation in prostate cancer incidence among different racial group. Based on that published data on the association of prostate cancer susceptibility with polymorphisms in genes encoding Glutathione S-transferases (GSTs) were inconclusive, the aim of this study was to more precisely address the role of GSTs polymorphisms (especially, GSTT1 and GSTM1 deletions) on prostate cancer risk in Asian descent. METHODS: A meta-analysis including 8 articles with 711 cases and 1122 controls for GSTT1 and 1098 cases and 1588 controls for GSTM1 was performed. RESULTS: Significantly increased prostate cancer risk was found among subjects carrying GSTM1 null genotype (odds ratio (OR) = 1.403; 95% confidence interval (CI) = 1.088 - 1.808) but not among subjects carrying GSTT1 deletion genotype (OR = 0.959; 95%CI = 0.709 - 1.297). When stratified by country, the null genotype of GSTT1 neither increased nor decreased prostate cancer risk significantly in China (OR = 1.355; 95%CI = 0.895 - 2.049), Japan (OR = 0.812; 95%CI = 0.545 - 1.211), and Korea (OR = 1.056; 95%CI = 0.727 - 1.534). While significant association of elevated prostate cancer risk with GSTM1 deletion were found in China (OR = 1.665; 95%CI = 1.324 - .094) and Korea (OR = 1.914; 95%CI = 1.311 - 2.793) but not in Japan (OR = 0.980; 95%CI = 0.726 - 1.321). CONCLUSIONS: In summary, this meta-analysis suggested that the null genotype of GSTM1 rather than GSTT1 may be involved in the etiology of prostate cancer in Asian population.

Evaluation of fine particles in surgical smoke from an urologist's operating room by time and by distance.

INTRODUCTION: Electrocautery, harmonic scalpel tissue dissection and other surgical techniques can generate surgical smoke with high proportion of 'fine particles' (PM(2.5)) <2.5 µm, which is known to have adverse effects on human health. The high-risk zone for PM(2.5) during surgeries by time and by distance has not been well evaluated. METHODS: The study included open superficial, open abdominal, open pelvic, laparoscopic and transurethral urology surgeries, five of each. A particle counter was placed at three different distances from the incision site, and the real-time PM(2.5) concentration was displayed after each cut. Air Quality Index (AQI) revised by the US Environmental Protection Agency and the calculated inhalation dose were used to evaluate the severity of PM(2.5). RESULTS: In superficial, abdominal and pelvic surgeries, the peak PM(2.5) concentration may reach 245.7, 149.4 and 165.1 µg/m(3) 3-6 s after a single cut 40 cm from the incision site. By the time, AQI usually turns to 'unhealthy' or 'very unhealthy.' In laparoscopic surgeries, 40 cm from the trocar, the air quality reached 'hazardous' in 3 s after opening of the trocar valve with a peak concentration of 517.5 µg/m(3). In transurethral surgeries, the AQI 40 cm away from the resectoscope is generally at moderate level. In each surgery, the chief surgeon may inhale most of the PM(2.5), while the assistant will inhale less than half the dose, and the scrub nurse may inhale nearly none. The use of wall suction may induce a 48-65 % decrease in fine particle inhalation. CONCLUSIONS: During surgeries, the concentration of PM(2.5) could reach a very unhealthy status, especially for the chief surgeon who is the nearest to the incision site. Surgical smoke evacuation in the first few seconds of a cut is essential; however, using smoke evacuators such as a wall suction alone may not be enough.

Development of a preliminary nomogram to predict progression of bone scan for castration-resistant prostate cancer.

The optimal time to perform bone scan to detect new metastasis during the castration-resistant prostate cancer (CRPC) stage remains undefined. This study attempted to identify predictors of progression of bone scan for CRPC, and use such information to develop a nomogram to predict the optimal time of examinations for bone scan. The analysis included 167 CRPC patients. Progression of bone lesion, as evaluated by bone scan, occurred in 64 (38.3%) cases. A logistic regression identified the following three risk factors: short time to prostate-specific antigen (PSA) progression, severe pain, and short PSA doubling time (PSADT) (P<0.05 for all). A nomogram model was constructed to predict progression of bone scan using time to PSA progression and severe pain as dichotomized variables and PSADT as a continuous variable. The result indicated that a predictive nomogram model showed a bootstrap-corrected concordance index of 0.762 and good calibration using the three readily available variables, and there were worse prognosis and higher progression rate of bone scan for patients with time to PSA progression <6.6 months, severe pain, and short PSADT (<2 months). In conclusion, short time to PSA progression, severe pain, and short PSADT are three risk factors of progression of bone scan for CRPC patients. The predictive nomogram model may be a valuable numerical assessment tool for patient consultation and treatment decision.

A Phase II trial of dosage escalation of sorafenib in Asian patients with metastatic renal cell carcinoma.

AIM: To investigate the role of sorafenib dosage escalation in Asian patients with metastatic renal cell carcinoma that had progressed after routine dosages. PATIENTS & METHODS: Sorafenib dosage escalation to 600 or 800 mg twice a day was offered to 41 patients with metastatic renal cell carcinoma who had progressed on normal dosages. Clinical outcome, toxicity and favorable clinical covariables for progression-free survival (PFS) were evaluated. RESULTS: The median PFS with dosage-escalated therapy was 7 months. Drug-related adverse events were tolerable. The pre-escalation Karnofsky performance status, serum calcium concentration, neutrophil/lymphocyte ratio, PFS and the highest toxicity grade at the routine dosage were associated with a longer PFS in the dosage-escalation period. CONCLUSION: Sorafenib dosage escalation was efficacious and tolerable in Asian patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry (no. ChiCTR-ONRC-12002088).

Visceral fat accumulation is associated with different pathological subtypes of renal cell carcinoma (RCC): a multicentre study in China.

OBJECTIVE: To investigate whether visceral obesity is associated with certain histological subtypes of renal cell carcinoma (RCC) ina multicentre Chinese cohort. PATIENTS AND METHODS: A kidney tumour database was created using three tertiary centres in China; 487 patients were enrolled presenting with localised RCC and complete computer tomography(CT)/magnetic resonance imaging (MRI) information. A single-slice CT image was used to measure the area of visceral and subcutaneous adipose tissues in each patient. Statistical methods were used to analyse clear-cell RCC (ccRCC) and non-clear-cell RCC (non-ccRCC) as they relate to visceral fat area (VFA) and other risk factors, such as age, gender, tumour size, diabetes, hypertension, total fat area (TFA) and body mass index (BMI). RESULTS: In all, 418 patients had a ccRCC subtype and 69 had a non-ccRCC subtype. For all the patients with RCC, the mean VFA was 102 cm2, while mean BMI was 24 kg/m2. The mean VFA was greater in ccRCC than non-ccRCC patients by 25 cm2. There were significant differences in the mean VFA and TFA between patients with ccRCC and those with non-ccRCC.Multivariate analysis showed that the presence ofVFA was more important than the effects of BMI and Type 2 diabetes on pathology prediction. In patients with a normal BMI, those with a higher quartile of VFA were more likely to develop ccRCC than those with a low VFA. CONCLUSIONS: Increased visceral fat was found to be associated with ccRCC and the significance of VFA outweighed the effects of BMI and Type 2 diabetes for the prediction of RCC pathology in multivariate analyses. As a result, VFA could constitute a primary explanation for the link between obesity and ccRCC.

[Exploratory analysis of the effect of toxicity of sunitinib on the clinical outcome of patients with advanced renal cell carcinoma].

OBJECTIVE: To explore the effect of toxicity of sunitinib on the clinical outcome of patients with advanced renal cell carcinoma (RCC) . METHODS: A total of 136 patients with advanced RCC were treated with sunitinib from 2008 to 2011. There were 91 males and 45 females with an average age of 56 years. Their 6-week therapy cycle was 4 weeks of sunitinib 50 mg daily followed by 2-week off-treatment (schedule 4/2). The median follow-up time was 15 months. Correlation between toxicities and overall survival (OS) was evaluated in a Cox model using log-transformed levels after adjusting for MSKCC model.Log-rank test and Cox proportional hazard model were used to assess the value of drug toxicity as the prognostic factors. RESULTS: The increased hemoglobin on cycle 1 day 14 (HR:0.950, 95%CI:0.923-0.978) and the increased lymphocytes on cycle 1 days 28 and 42 (HR:0.405, 95%CI:0.203-0.809, HR:0.394, 95%CI:0.179-0.867) were significantly associated with OS (P adj = 0.001, 0.014 and 0.022 respectively). Hypertension class III/IV (HR:0.066, 95%CI:0.008-0.582), and the number of neutrophils screening and lymphocyte count ratio (HR:2.537, 95%CI:1.182-5.404) were the survival prognosis independent predictors. CONCLUSION: Early hematopoietic toxicities may potentially predict the outcomes of advanced RCC after a therapy of sunitinib.

The effectiveness of the TAX 327 nomogram in predicting overall survival in Chinese patients with metastatic castration-resistant prostate cancer.

Based on the results of TAX 327, a nomogram was developed to predict the overall survival of metastatic castration-resistant prostate cancer (mCRPC) after first-line chemotherapy. The nomogram, however, has not been validated in an independent dataset, especially in a series out of clinical trials. Thus, the objective of the current study was to validate the TAX 327 nomogram in a community setting in China. A total of 146 patients with mCRPC who received first-line chemotherapy (docetaxel or mitoxantrone) were identified. Because clinical trials are limited in mainland China, those patients did not receive investigational treatment after the failure of first-line chemotherapy. The predicted overall survival rate was calculated from the TAX 327 nomogram. The validity of the model was assessed with discrimination, calibration and decision curve analysis. The median survival of the cohort was 21 months (docetaxel) and 19 months (mitoxantrone) at last follow-up. The predictive c-index of the TAX 327 nomogram was 0.66 (95% CI: 0.54-0.70). The calibration plot demonstrated that the 2-year survival rate was underestimated by the nomogram. Decision curve analysis showed a net benefit of the nomogram at a threshold probability greater than 30%. In conclusion, the present validation study did not confirm the predictive value of the TAX 327 nomogram in a contemporary community series of men in China, and further studies with a large sample size to develop or validate nomograms for predicting survival and selecting therapies in advanced prostate cancer are necessary.

[Hematologic adverse effects in patients with renal cell carcinoma treated with sunitinib].

OBJECTIVE: To explore the hematologic adverse effects in patients with renal cell carcinoma treated with sunitinib. METHODS: A total of 136 patients with advanced renal cell carcinoma were treated with sunitinib at our hospital from 2008 to 2011. There were 91 males and 45 females with an average age of 55.5 years. They received sunitinib in repeated 6-week cycles consisting of 4 weeks of sunitinib 50 mg per day followed by 2 weeks of treatment (schedule 4/2). The hematologic toxicities, collected at baseline and 14, 28, 42 (after a 2-week rest period) days, were graded according to the National Cancer Institute common terminology criteria for adverse events version 3.0. The paired Wilcoxon test was used to evaluate the kinetics of hematologic adverse effects at days 14, 28, and 42 post-treatment. RESULTS: The hematologic toxicities included leukopenia (n = 91, 66.9%), neutropenia (n = 95, 69.8%), lymphopenia (n = 58, 46.2%), thrombopenia (n = 89, 65.4%) and hypohemoglobinemia (n = 48, 35.3%). Among them, 31 cases (22.8%) had the high-grade (including grades 3 and 4) toxicity of thrombopenia. There were depressions in hematopoietic cell populations including leukocytes, neutrophils, and platelets at days 14, 28 and 42 versus the baseline level (all P < 0.05). The median hemoglobin level transiently increased at days 14 and 28 (both P < 0.01) and returned to the level of baseline at days 42 (P = 0.754). CONCLUSIONS: The incidence of hematologic adverse effects of sunitinib slightly varies with what have been observed in previous studies. And the incidence of high-grade toxicity of thrombocytopenia is higher than that reported in studies conducted in the US and Europe.

Prognostic factors in Chinese patients with metastatic castration-resistant prostate cancer treated with docetaxel-based chemotherapy.

This study aims to evaluate the potential value of patient characteristics in predicting overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel-based thermotherapy. A total of 115 patients with mCRPC undergoing a docetaxel q3w regimen were enrolled in this study. A survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models were used to evaluate the prognostic value of all covariates for OS. OS was also analysed after stratifying patients according to the results of multivariate analysis. The median OS for the entire cohort was 17.0 months. The multivariate analysis showed that the prostate-specific antigen doubling time (PSADT), baseline haemoglobin (Hb) concentration, alkaline phosphatase (ALP) concentration, cycles of chemotherapy and time to castration resistance were independent prognostic factors of OS. According to the presence of PSADT <46.3 days and baseline ALP ≥ 110 IU l(-1), all patients were divided into three risk groups: low-risk group (no risk factors), intermediate-risk group (one risk factor) and high-risk group (two risk factors). Median OSs for patients in low-, intermediate- and high-risk groups were 28.0 months (95% CI: 23.8-32.2), 21.0 months (95% CI: 18.9-23.1) and 11.0 months (95% CI: 7.6-14.4), respectively (P<0.001). In conclusion, PSADT, baseline Hb concentration, ALP concentration, cycles of chemotherapy and time to castration resistance were independent prognostic factors of OS in Chinese patients with mCRPC treated with docetaxel. PSADT combined with the baseline ALP concentration could be a useful risk stratification parameter for evaluating survival outcomes.

ADAM9 decreases in castration resistant prostate cancer and is a prognostic factor for overall survival.

BACKGROUND: A disintegrin and metalloprotease 9 (ADAM9) is a membrane-anchored enzyme which is considered to be involved in some diseases including tumor. However, the role of ADAM9 in castration resistant prostate cancer (CRPC) is not clear. This study aimed to explore the different expressions on protein and messenger RNA (mRNA) level of ADAM9 between hormonal sensitive prostate cancer (HSPC) and CRPC tissue, and find the correlation with prognosis. METHODS: Clinicopathologic characteristics of 106 HSPC and 76 CRPC cases were collected. The ADAM9 expressions were analyzed using immunohistochemistry. ADAM9 mRNA of 32 additional cases (16 HSPC and 16 CRPC patients) were analyzed via quantitative real-time polymerase chain reaction (RT-PCR). The prediction values of variables for overall survival (OS) of CRPC patients were analyzed using Cox regression. RESULTS: ADAM9 protein expression was significantly downregulated in CRPC compared with HSPC tissue (31.6% vs. 81.1%, P < 0.001). The relativity transcription level of ADAM9 mRNA was 0.45 for CRPC tissue and 1.0 for HSPC tissue (P = 0.002). In the CRPC group, patients with low ADAM9 protein expression were significantly associated with shorter OS than patients with high expression (38.6 months vs. 57.8 months, hazard rate (HR) = 2.638, P = 0.023). CONCLUSION: ADAM9 expression was low in CRPC, correlated with poor prognosis and might be involved in the succession from HSPC to CRPC by various functions.

The prognostic factors of effective ketoconazole treatment for metastatic castration-resistant prostate cancer: who can benefit from ketoconazole therapy?

We investigated the prognostic value of some variables of effective ketoconazole treatment for metastatic castration-resistant prostate cancer (mCRPC). In total, 163 patients with mCRPC were eligible, receiving ketoconazole 200-400 mg three times daily with replacement doses of prednisone. Progression-free survival (PFS) was calculated from the beginning of the ketoconazole therapy to the onset of disease progression. The prognostic value of different variables for PFS was assessed by Cox regression analysis. The median PFS was 2.6 months (0.5-8.6 months) for these patients. The serum testosterone level changed during therapy, which decreased when the prostate-specific antigen (PSA) declined; the serum testosterone level increased as the levels of PSA relapsed. The median PFS values for patients associated with different factors were the following: 1.4 and 3.5 months for a nadir PSA of ≥ 0.2 and <0.2 ng ml(-1), respectively (hazard rate (HR)=4.767, P<0.001); 3.1 and 1.6 months for a baseline testosterone of ≥ 0.1 and <0.1 ng ml(-1), respectively (HR=2.865, P=0.012); 2.8 and 1.9 months for a baseline haemoglobin of ≥ 120 and <120 g l(-1), respectively (HR=1.605, P<0.001); and 3.0 and 1.9 months for a PSA doubling time (PSADT) of ≥ 2.0 and <2.0 months, respectively (HR=1.454, P=0.017). A risk model was constructed according to the four factors that divided patients into three subgroups of low risk (0-1 factors), moderate risk (2 factors) and high risk (3-4 factors) with PFS values of 3.6, 3.0 and 1.4 months, respectively (HR=1.619, P<0.001). A nadir PSA of ≥ 0.2 ng ml(-1), a baseline testosterone of <0.1 ng ml(-1), a baseline haemoglobin of <120 g l(-1) and a PSADT of <2 months were associated with a poor PFS. This risk model could provide evidence to predict the survival benefit of ketoconazole therapy.

External validation of the Prostate Cancer Prevention Trial and the European Randomized Study of Screening for Prostate Cancer risk calculators in a Chinese cohort.

Several prediction models have been developed to estimate the outcomes of prostate biopsies. Most of these tools were designed for use with Western populations and have not been validated across different ethnic groups. Therefore, we evaluated the predictive value of the Prostate Cancer Prevention Trial (PCPT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators in a Chinese cohort. Clinicopathological information was obtained from 495 Chinese men who had undergone extended prostate biopsies between January 2009 and March 2011. The estimated probabilities of prostate cancer and high-grade disease (Gleason >6) were calculated using the PCPT and ERSPC risk calculators. Overall measures, discrimination, calibration and clinical usefulness were assessed for the model evaluation. Of these patients, 28.7% were diagnosed with prostate cancer and 19.4% had high-grade disease. Compared to the PCPT model and the prostate-specific antigen (PSA) threshold of 4 ng ml(-1), the ERSPC risk calculator exhibited better discriminative ability for predicting positive biopsies and high-grade disease (the area under the curve was 0.831 and 0.852, respectively, P<0.01 for both). Decision curve analysis also suggested the favourable clinical utility of the ERSPC calculator in the validation dataset. Both prediction models demonstrated miscalibration: the risk of prostate cancer and high-grade disease was overestimated by approximately 20% for a wide range of predicted probabilities. In conclusion, the ERSPC risk calculator outperformed both the PCPT model and the PSA threshold of 4 ng ml(-1) in predicting prostate cancer and high-grade disease in Chinese patients. However, the prediction tools derived from Western men significantly overestimated the probability of prostate cancer and high-grade disease compared to the outcomes of biopsies in a Chinese cohort.

[Efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer].

OBJECTIVE: To assess the efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer (CRPC) and explore possible prognosis factors. METHODS: From August 2006 to August 2011, 71 patients with CRPC were analyzed retrospectively, who received oral ketoconazole 200 mg, three times a day with prednisone 5 mg, twice a day. Prostate specific antigen (PSA) response rate was defined as the percentage of patients with PSA decline ≥ 50% compared to baseline PSA level during low dose ketoconazole therapy. Multivariate Logistic regression analysis and receiver operating characteristic curve were used to assess the prognostic factors and their accuracy. RESULTS: The mean initial serum PSA level was (205 ± 38) ng/ml for these patients with mean age (69 ± 1) years old. After first androgen deprivation therapy failure, the prostate cancer progressed into castration resistant stage. The baseline PSA was (93 ± 24) ng/ml and the baseline serum testosterone was (0.13 ± 0.02) ng/ml. During the low dose ketoconazole therapy, 31 patients (43.7%) had PSA decrease and 22 cases (31.0%) were effective with PSA decline more than 50%. PSA doubling time and baseline serum testosterone were positive correlation with PSA response rate by multivariate Logistic regression analysis. Patients with PSA doubling time of ≥ 3.0 months had a PSA response rate of 64.3% and the PSA response rate in those with < 3.0 months decreased to 22.8%, hazard rate (HR) = 0.149 (95% confidence interval [CI] 0.029 - 0.766), P = 0.023, area under the curve (AUC) = 0.707. The PSA response rate for patients with baseline serum testosterone ≥ 0.1 and < 0.1 µg/L were 55.6% and 5.7%, respectively, HR = 0.068 (95%CI 0.012 - 0.380), P = 0.002, AUC = 0.749. The common adverse reactions included liver dysfunction (17.9%), renal dysfunction (16.4%), fatigue (11.9%), nausea (6.0%) and anorexia (4.5%) and so on. CONCLUSIONS: Low dose ketoconazole therapy was a moderate, low toxicity hormonal therapy option for patients with CRPC. PSA doubling time ≥ 3 months and baseline serum testosterone ≥ 0.1 µg/L were predictors of desired effect for low dose ketoconazole therapy.

Tumor cytoreduction results in better response to androgen ablation--a preliminary report of palliative transurethral resection of the prostate in metastatic hormone sensitive prostate cancer.

OBJECTIVES: To investigate the oncologic influence of transurethral resection of the prostate (TURP) as a cytoreductive surgery in metastatic hormone sensitive prostate cancer (mHSPC), in the setting of continuous complete androgen blockade (CAB). MATERIALS AND METHODS: Medical histories of 146 consecutive Chinese males with newly diagnosed mHSPC, registered in our institution in 2006 and 2007, were reviewed. All of these patients received CAB as initial systematic therapy. Demographics and cancer control outcomes from 39 mHSPC patients who underwent TURP for a relief of bladder outlet obstruction were compared with those of the other 107 who received CAB only when they were still hormone-sensitive. Median follow-up was 15 months (3 to 27 months). RESULTS: Age at diagnosis, baseline PSA, and biopsy Gleason score were comparable between the 2 groups. Patients who underwent a TURP had lower PSA nadir (median 0.15 ng/ml vs. 0.82 ng/ml, P = 0.015) and longer time to PSA nadir (11.2 months vs. 6.4 months, P < 0.001). More patients in the non-TURP group developed hormone refractory prostate cancer (P = 0.007). The TURP group had a tendency towards longer disease-specific survival and overall survival (24.4 months vs. 24.1 months and 24.4 months vs. 22.9 months, respectively), though this did not reach statistical significance. CONCLUSIONS: TURP resulted in a better and more prolonged response to hormone therapy in mHSPC, with a trend towards positive influence in disease specific survival and overall survival. To date, our preliminary report is the first study regarding long-term survival of cytoreductive surgery in mHSPC, and further investigations are warranted.