Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

Survival outcomes and prognostic factors for first-line abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer.

PURPOSE: To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted therapies (ARATs) and prognostic factors for patient survival. METHODS: This retrospective study obtained data from 202 patients who started abiraterone acetate or enzalutamide as first-line therapy for mCRPC between 2016 and 2021 from a single academic center. The primary endpoint was overall survival (OS) defined as the interval from the start of ARAT to death, loss to follow-up, or the end of the study period. The secondary endpoints were PSA decline, PSA nadir, and time to nadir (TTN) after ARATs. Kaplan-Meier survival analyses were applied for depicting OS. Cox proportional hazards model with inversed probability of treatment weighing-adjustment was used to validate the effect of patient, disease, and treatment response factors on OS. RESULTS: Among 202 patients, 164 patients were treated with first-line ARATs alone and 38 patients received second-line chemotherapy. The median OS was not reached in patients with first-line ARATs alone and was 38.8 months in those with subsequent chemotherapy after failure from ARATs. OS was not different between the use of abiraterone and enzalutamide, though enzalutamide showed a higher rate of PSA decline ≧ 90% (56% versus 40%, p = 0.021) and longer TTN (5.5 versus 4.7 months, p = 0.019). Multivariable analysis showed that PSA nadir > 2 ng/mL [hazard ratio (HR) 7.04, p < 0.001] and TTN<7 months (HR 2.18, p = 0.012) were independently associated with shorter OS. Patients with both of these poor prognostic factors had worse OS compared to those who had 0-1 factors (HR 9.21, p < 0.001). CONCLUSIONS: Patients with mCRPC who received first-line ARATs had better survival if they had a PSA nadir[Formula: see text]2 ng/mL or a TTN[Formula: see text]7 months. Further study is needed to determine if an early switch in therapy for those in whom neither is achieved may impact OS.

Aristolochic acid-containing Chinese herbal medicine and upper urinary tract urothelial carcinoma in Taiwan: a narrative review.

PURPOSE: The high incidence of upper urinary tract urothelial carcinoma (UTUC) in Taiwan is largely due to exposure to aristolochic acid (AA), a principal component of Aristolochia-based herbal medicines. Here we systematically review the molecular epidemiology, clinical presentation and biomarkers associated with AA-induced UTUC. METHODS: This is a narrative review. Medline, Embase, and Web of Science were searched from inception to December 31, 2021. Studies evaluating the association, detection, and clinical characteristics of AA and UTUC were included. RESULTS: A nationwide database revealed 39% of the Taiwanese population had been exposed to AA-containing herbs between 1997 and 2003. Epidemiological reports revealed AA posed a significantly higher hazard for renal failure and UTUC in herbalists and the general population who ingested AA-containing herbs. The presence of aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, located predominantly on the non-transcribed DNA strand, with a strong preference for deoxyadenosine in a consensus sequence (CAG), was observed in many UTUC patients. Clinically, AA-related UTUC patients were characterized by a younger age, female gender, impaired renal function and recurrence of contralateral UTUC. To date, there are no preventive measures, except prophylactic nephrectomy, for subjects at risk of AA nephropathy or AA-related UTUC. CONCLUSION: AA exposure via Aristolochia-based herbal medicines is a problem throughout Taiwan, resulting in a high incidence of UTUC. Aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, can be used as biomarkers to identify AA-related UTUC. AA-related UTUC is associated with a high recurrence rate of contralateral UTUC.

Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis.

BACKGROUND: The Phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control; randomized 2:1 to olaparib or control) in men with homologous recombination repair gene alterations and metastatic castration-resistant prostate cancer whose disease progressed on prior next-generation hormonal agent. METHODS: We present efficacy and safety data from an exploratory post hoc analysis of olaparib in the PROfound Asian subset. Analyses were not planned, alpha controlled or powered. Of 101 Asian patients enrolled in Japan (n=57), South Korea (n=29) and Taiwan (n=15), 66 and 35 patients received olaparib and control, respectively. RESULTS: Radiographic progression-free survival (rPFS) and overall survival (OS) favored olaparib versus control in Cohort A [rPFS 7.2 vs. 4.5 months, HR 0.58, 95% CI 0.29-1.21, P = 0.14 (nominal); OS 23.4 vs. 17.8 months, HR 0.81, 95% CI 0.40-1.74, P = 0.57 (nominal)] and Cohorts A+B [rPFS 5.8 vs. 3.5 months, HR 0.69, 95% CI 0.42-1.16, P = 0.13 (nominal); OS 18.6 vs. 16.2 months, HR 0.96, 95% CI 0.56-1.70, P = 0.9 (nominal)]. Olaparib showed greatest improvement in patients harboring BRCA alterations [rPFS 9.3 vs. 3.5 months, HR 0.17, 95% CI 0.06-0.49, P = 0.0003 (nominal); OS 26.8 vs. 14.3 months, HR 0.62, 95% CI 0.24-1.79, P = 0.34 (nominal)]. Safety data were consistent with the known profile of olaparib, with no new safety signals identified. CONCLUSION: In PROfound, there was a statistically significant improvement in outcomes reported in the global population of patients with metastatic castration-resistant prostate cancer and alterations in homologous recombination repair genes whose disease progressed on prior next-generation hormonal agent compared with control. For the subset of Asian patients reported here, exploratory analysis suggested that there was also an improvement in outcomes versus control. The safety and tolerability of olaparib in Asian patients were similar to that of the PROfound global population. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02987543.

Comparison of oncological outcomes for hand-assisted and pure laparoscopic radical nephroureterectomy: results from the Taiwan Upper Tract Urothelial Cancer Collaboration Group.

PURPOSE: Laparoscopic radical nephroureterectomy (LNU) has gradually become the new standard treatment for localized upper tract urothelial cancer (UTUC). With more blunt dissection and tactile sensation, hand-assisted LNU might shorten the operative time compared with the pure laparoscopic approach. However, whether the use of the hand-assisted or the pure laparoscopic approach has an effect on oncological outcomes remains unclear. METHODS: We retrospectively identified 629 patients with non-metastatic UTUC who underwent hand-assisted (n = 515) or pure LNU (n = 114) at 9 hospitals in Taiwan between 2004 and 2019. Overall survival, cancer-specific survival, recurrence-free survival, and bladder recurrence-free survival were compared between these two groups using inverse-probability of treatment weighting (IPTW) derived from the propensity scores for baseline covariate adjustment. RESULTS: The median follow-up period was 32.9 and 28.7 months in the hand-assisted and the pure groups, respectively. IPTW-adjusted Cox proportional hazards models showed that the laparoscopic approach (pure vs. hand-assisted) was not significantly associated with all-cause mortality (HR 0.79, 95% CI 0.49-1.24, p = 0.304), cancer-specific mortality (HR 0.88, 95% CI 0.51-1.51, p = 0.634), or extra-vesical recurrence (HR 0.65, 95% CI 0.41-1.04, p = 0.071). However, the pure laparoscopic approach was significantly associated with lower intra-vescial recurrence (HR 0.64, 95% CI 0.43-0.96, p = 0.029) for patients who underwent LNU. Kaplan-Meier curves also revealed that the pure laparoscopic approach was associated with better bladder recurrence-free survival compared with the hand-assisted laparoscopic approach in both the original cohort and the IPTW-adjusted cohort (log-rank p = 0.042 and 0.027, respectively). CONCLUSIONS: The performance of hand-assisted or pure LNU does not significantly affect the all-cause mortality, cancer-specific mortality, or extra-vesical recurrence for patients with non-metastatic UTUC. However, the hand-assisted laparoscopic approach could increase the risk of intra-vesical recurrence for patients who undergo LNU.

Clinical characteristics and survival outcomes in patients with a high PSA and non-metastatic prostate cancer.

BACKGROUND/PURPOSE: To investigate the clinical presentation and survival outcomes of patients with both a high prostate-specific antigen (PSA) value and non-metastatic prostate cancer (PC). METHODS: In total, 2053 PC patients were managed in our institute between January 2008 and December 2014. A total of 343 (16.7%) patients who presented with PSA values > 100 ng/mL were enrolled. Non-metastatic and metastatic PC were identified in 67 (group 1) and 276 (group 2) patients, respectively. Furthermore, 75 metastatic PC patients with PSA values < 20 ng/mL were included (group 3) for comparison. All demographics and survival outcomes were retrospectively reviewed by a questionnaire. RESULTS: Group 2 patients had a higher PSA level than did group 1 (median: 1095 vs. 283 ng/mL, p < 0.001), and a higher Gleason grade than did groups 1 and 3 (grade group 4 plus 5: 60%, 77%, and 56%, for groups 1, 2, and 3, respectively; p < 0.001). Other demographics were similar among groups. Group 1 patients survived significantly longer than group 2 and 3 in terms of overall and cancer-specific survival rates (5-year overall survival rates: 87.5%, 46.3%, and 66.9%; 5-year cancer-specific survival rates: 94.7%, 52.7%, and 68.7% for groups 1, 2, and 3, respectively). Group 1 patients receiving local definitive treatments, such as radiation therapy or cryoablation, received survival and metastasis-free benefits compared to those without local treatment. CONCLUSION: Patients with a high PSA value were not destined to have metastatic PC. Non-metastatic PC patients with a high PSA level obtained a survival benefit from local prostate-definitive treatments.

Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation.

Loss of fatty acid ß-oxidation (FAO) in the proximal tubule is a critical mediator of acute kidney injury and eventual fibrosis. However, transcriptional mediators of FAO in proximal tubule injury remain understudied. Krüppel-like factor 15 (KLF15), a highly enriched zinc-finger transcription factor in the proximal tubule, was significantly reduced in proximal tubule cells after aristolochic acid I (AAI) treatment, a proximal tubule-specific injury model. Proximal tubule specific knockout of Klf15 exacerbated proximal tubule injury and kidney function decline compared to control mice during the active phase of AAI treatment, and after ischemia-reperfusion injury. Furthermore, along with worsening proximal tubule injury and kidney function decline, knockout mice exhibited increased kidney fibrosis as compared to control mice during the remodeling phase after AAI treatment. RNA-sequencing of kidney cortex demonstrated increased transcripts involved in immune system and integrin signaling pathways and decreased transcripts encompassing metabolic pathways, specifically FAO, and PPARα signaling, in knockout versus control mice after AAI treatment. In silico and experimental chromatin immunoprecipitation studies collectively demonstrated that KLF15 occupied the promoter region of key FAO genes, CPT1A and ACAA2, in close proximity to transcription factor PPARα binding sites. While the loss of Klf15 reduced the expression of Cpt1a and Acaa2 and led to compromised FAO, induction of KLF15 partially rescued loss of FAO in AAI-treated cells. Klf15, Ppara, Cpt1a, and Acaa2 expression was also decreased in other mouse kidney injury models. Tubulointerstitial KLF15 independently correlated with eGFR, PPARA and CPT1A appearance in expression arrays from human kidney biopsies. Thus, proximal tubule-specific loss of Klf15 exacerbates acute kidney injury and fibrosis, likely due to loss of interaction with PPARα leading to loss of FAO gene transcription.

Tumor location on MRI determines outcomes of patients with prostate cancer after total prostate cryoablation.

We investigated the association between tumor location on multiparametric magnetic resonance imaging (mpMRI) and outcomes of prostate cancer patients after primary total prostate cryoablation (PTPC). Between March 2010 and December 2012, consecutive 192 prostate cancer patients receiving PTPC were enrolled. Tumor locations were determined and classified as anterior apex (AA), anterior midgland (AM), anterior base (AB), posterior apex (PA), posterior midgland (PM) and posterior base (PB) using mpMRI. Midline location, central location, seminal vesicle invasion, extraprostatic extension, multiple tumors, and tumor volume were also identified. Prostate local recurrence and biochemical failure were considered as primary and secondary endpoints, respectively. Tumors on mpMRI were identified in 148 (77.1%) patients. Tumor locations were most frequently noted in PM (89, 46.4%), followed by AM (55, 28.6%), PB (53, 27.6%), PA (46, 24%), AA (35, 18.2%) and AB (31, 16.1%). Midline and central tumors were observed in 34 (17.7%) and 14 (7.3%) patients, respectively. During a median follow-up duration of 81 months (range, 2-114 months), 71 (37.0%) and 29 (40.8%) patients experienced biochemical failure and local recurrence, respectively. Multivariable analyses revealed only AA tumors increased the risk of local recurrences (HR = 2.98, 95% CI. 1.36-6.49). None of location-related parameters was associated with biochemical failure. Tumor location on mpMRI has a significant association with local tumor recurrence in patients receiving PTPC. Physicians should be cautious when conducting cryoablation for prostate tumors in AA location.

Association between low prostate-specific antigen levels and greater disease progression in high-grade locally-advanced prostate cancer.

PURPOSE: In advanced or high-grade prostate cancer (PCa), prostate-specific antigen (PSA) is usually elevated, however, some patients may present with low initial PSA (iPSA) levels. The objective of this study was to evaluate whether different iPSA levels were associated with dissimilar clinical outcomes among men with high-grade PCa and advanced disease after robot-assisted laparoscopic radical prostatectomy (RaLRP). METHODS: This study enrolled 69 PCa patients with initial Gleason score ≥8 and pathologic T-stage ≥3a from April 2012 to December 2018. Patients were stratified into 3 groups based on iPSA levels at diagnosis: <5.0, 5.0-9.9, and ≥10.0. The patients' related parameters were compared among these groups. RESULTS: The median follow-up period was 33.1 months (IQR: 12.1-48.1). There was no difference in biochemical recurrence (BCR) between the 3 groups (Log-rank test, p = 0.484). We found a higher risk of biochemical recurrence in patients with positive surgical margins (HR: 5.04, 95% CI: 1.64-15.50, p = 0.005). In addition, patients with low iPSA levels (<5.0 ng/mL) had poor radiographic progression-free survival (Log-rank test, p = 0.001) and a higher risk of disease progression (HR: 12.2, 95% CI: 1.18-1260.99, p = 0.036) compared with patients with higher iPSA levels (≥10 ng/mL). CONCLUSION: In patients with high-grade locally-advanced PCa, a low iPSA level was associated with a higher risk of disease progression, but not with biochemical recurrence. In this unique population, serum PSA may not be a reliable marker to detect disease progression. Monitoring of these patients may warrant other biomarkers or imaging.

Trifecta outcome of ureteral reconstruction in iatrogenic injury and non-iatrogenic ureteral lesions: a 10-year experience at a tertiary referral center.

PURPOSE: To analyze the trifecta outcome (functional, anatomical, and surgical aspects) of surgical reconstruction for ureteral lesions and investigate the factors affecting the success rate of such reconstruction. METHODS: We retrospectively reviewed the data of patients who underwent ureteral reconstruction at our institute between March 2007 and November 2016. Patient profiles, surgical methods, complications, ureteral stenting, laboratory data, and image studies were collected. The trifecta outcome was defined as preserved renal function, no progression of hydronephrosis, and no long-term stenting. The primary endpoint was the percentage of patients who achieved the trifecta outcome. The secondary endpoint was risk factors for trifecta outcome failure. RESULTS: We retrospectively reviewed 178 adult patients who had undergone ureteral reconstruction. The median follow-up period was 37.4 months. In total, 70 (39.3%) patients had iatrogenic ureteral injuries and 108 (60.7%) patients had non-iatrogenic ureteral lesions. Overall, 70% of the patients achieved the trifecta outcome after ureteral reconstruction. A multivariate analysis revealed that risk factors for trifecta failure were malignant diseases [odds ratio (OR) 2.93, p = 0.005], a history of pelvic radiation (OR 3.08, p = 0.032), preoperative estimated glomerular filtration rate < 60 (OR 2.52, p = 0.039), and a type of reconstruction ureteroureterostomy (OR 2.99, p = 0.014). CONCLUSIONS: Trifecta outcome could be used to evaluate the ureteral reconstruction in iatrogenic injury and non-iatrogenic ureteral lesions. This study revealed several risk factors that affected the trifecta outcome.

Practice pattern of non-muscle invasive bladder cancer in Japan, Korea and Taiwan: A Web-based survey.

OBJECTIVES: To investigate the treatment pattern of non-muscle invasive bladder cancer patients among urologists in Japan, Korea and Taiwan, with emphasis on compliance with important treatment guidelines. METHODS: A Web-based questionnaire survey was conceived by representative members of each country's urological oncology society and was open from June 2016 to February 2017 to each society's members. Descriptive statistics and multinomial logistic regression analysis were used. RESULTS: A total of 2334 urologists were invited and 701 responded to the survey with a response rate of 30.0%. Instruments used during transurethral resection of bladder cancer varied significantly between countries and depended on their availability. The re-transurethral resection rate for pT1 or high-grade disease >50% of the time was significantly higher in Japan than in the other two countries, but the collective rate was just 49%. The frequency of intravesical therapy in intermediate- to high-risk disease was generally consistent across countries. However, the choice of agent between chemotherapy and bacillus Calmette-Guérin was significantly different between countries. Maintenance bacillus Calmette-Guérin was used <10% of the time by 45% of respondents, the most important reasons being fear of side-effects, followed by a lack of efficacy and shortage of drug supply. CONCLUSIONS: There are significant differences between Japan, Korea and Taiwan in the management of intermediate- to high-risk non-muscle invasive bladder cancer. The results of this survey can serve as the basis for joint efforts to develop common clinical guidelines.

Adjuvant androgen-deprivation therapy following prostate total cryoablation in high-risk localized prostate cancer patients - Open-labeled randomized clinical trial.

PURPOSE: To investigate the efficacy and safety profile of 12-month adjuvant androgen-deprivation therapy (ADT) following total-gland cryoablation (TGC) in patients with high-risk localized prostate cancer (HRLPC). MATERIALS AND METHODS: This open-label randomized trial included 38 HRLPC patients who received TGC between July 2011 and March 2013. Within 4 weeks after TGC, subjects were randomly assigned (1:1) to either the 12-month adjuvant ADT or non-adjuvant ADT group. The primary outcome was biochemical failure measured by the Phoenix definition. Adverse events were measured at month 1, 2, 3, 6, 9 and 12. In addition, a cohort of 145 HRLPC patients was selected retrospectively for outcome validation. RESULTS: The adjuvant ADT and non-adjuvant ADT groups did't differ in peri-operative characters, such as age, preoperative PSA, tumor stages, Gleason score, prostate size and cryoprobe number. Four patients with adjuvant ADT withdrew from this trial for personal reasons (N = 2), elevated liver function (N = 1) and poorly controlled hyperglycemia (N = 1). In contrast, none in non-adjuvant ADT group experienced adverse events. Biochemical failures were identified in 5 (26%) patients in each group during a median follow-up duration of 45 months. The median times to biochemical failure were 25 and 5.5 months for adjuvant ADT and non-adjuvant ADT groups, respectively. Biochemical-failure survival curves converged 24 months after TGC. Univariable and multivariable analyses revealed adjuvant ADT was not associated with biochemical recurrences in the validation cohort. CONCLUSIONS: Adjuvant ADT does not reduce biochemical failure for HRPLC patients undergoing TGC. It should be further confirmed by a larger cohort.

Perioperative changes in TGF-ß1 levels predict the oncological outcome of cryoablation-receiving patients with localized prostate cancer.

PURPOSE: To evaluate the cytokine transforming growth factor beta 1 (TGF-ß1) as a predictor of oncological outcomes in patients after cryoablation. MATERIALS AND METHODS: Perioperative blood samples from prostate cancer (PC) patients who underwent total gland cryoablation between October 2011 and March 2013 were collected prospectively. Plasma TGF-ß1 levels were quantified using magnetic bead immunoassay. The perioperative change in TGF-ß1 was defined as the change in TGF-ß1 from before surgery to 1-2 months after surgery. Biochemical recurrence (BCR) was defined according to the Phoenix criteria. The Mann-Whitney U, Kruskal-Wallis rank sum, and Chi-square test were used to compare the clinical characteristics of the subsets. The Cox proportional hazard model was applied for the comparison of recurrence risk among the groups. RESULTS: A total of 75 PC patients were included. During a median follow-up period of 12 months (range: 2.5-47 months), 11 patients had BCR, and 64 patients did not. Significantly greater changes in the perioperative TGF-ß1 levels (median: 470.3 vs. 78.9 pg/ml) were observed in patients with than without BCR (p < 0.05). According to the changes in TGF-ß1 levels, the patients were further divided into 4 groups, which were determined in the quartile categories of perioperative TGF-ß1 levels. Group 4 (≥430) predicted the worst BCR outcome. CONCLUSIONS: Perioperative plasma TGF-ß1 levels were associated with BCR after prostate cryoablation for localized PC. Increase in postoperative plasma TGF-ß1 may be a novel predictor for poor oncological outcomes and prompt a more aggressive follow-up or earlier salvage treatment.

Diabetes mellitus with poor glycemic control increases bladder cancer recurrence risk in patients with upper urinary tract urothelial carcinoma.

BACKGROUND: The association of diabetes mellitus and bladder cancer recurrence following radical nephroureterectomies (RNUs) in patients with upper urinary tract urothelial carcinoma (UTUC) was investigated. METHODS: Between January 1996 and March 2009, 538 patients with UTUC who received RNU and had no previous bladder cancer histories were enrolled. The clinicopathological characteristics were obtained and used for the analysis of metachronous bladder recurrence by using Cox proportional hazard model. RESULTS: The diabetic patients (N = 104, 19.3%) were elderly (72 vs 67 years, p < 0.001) and had more hypertension (56.7 vs 34.5%, p < 0.001) as compared with non-diabetic patients. There was no significant difference in the rest of clinicopathological characteristics between patient groups. During the median follow-up duration of 51 months, bladder recurrences were discovered in 47.1 and 33.1% of diabetic and non-diabetic patients with UTUC, respectively. Poorly controlled diabetic patients (HbA1c ≥ 7.0%) exhibited a shorter duration of bladder cancer recurrence-free survival as compared with those with good glycemic controlled diabetes mellitus and without diabetes mellitus (log-rank test, p < 0.001 and <0.001, respectively). In the multivariate analysis, male gender [hazard ratio (HR) = 1.67, p = 0.017], ureteral tumour (HR = 1.61, p = 0.020), end-stage renal disease (HR = 2.09, p = 0.030) and diabetes mellitus with poor glycemic control (HR = 2.10, p < 0.018) independently predicted bladder recurrence after RNU. CONCLUSIONS: Diabetes mellitus with poor glycemic control (HbA1c ≥ 7.0%) increases the risk of subsequent bladder cancer recurrence. These results underscore the need for intensive glycemic control and close follow-up for diabetic patients.

Prognostic value of saturated prostate cryoablation for localized prostate cancer.

PURPOSE: To evaluate the oncological outcomes and complications of patients with saturated prostate cryoablation. METHODS: A cohort of 208 patients cumulatively treated between June 2008 and December 2012 qualified for study inclusion, each undergoing total-gland cryoablation for prostate cancer. The degree of saturated prostate cryoablation was defined as the average prostate volume per cryoprobe (APVC), and divided into four groups (groups 1-4: <3 ml, 3 to <4 ml, 4 to <5 ml, ≧5 ml, respectively). Post-ablative complications were measured prospectively at weeks 1, 2, 4, 8, 12, and 24 by using the Common Terminology Criteria for Adverse Events. Biochemical failure was gauged by Phoenix criterion. The Kruskal-Wallis rank sum test and Chi-square test were used to compare clinical characteristics of therapeutic subsets. The Cox proportional hazard model was applied for comparison of recurrence risk between groups. RESULTS: APVC group 1 had the highest pre-operative PSA value and smallest prostate size among the groups. Multivariate analysis of risks of biochemical failures revealed that the larger the APVC, the higher the hazard (p for trend = 0.01). Compared to the group 1 patients, the hazard ratios of biochemical failures in groups 2-4 were 4.4 (confidence interval (CI): 0.5-37), 8.8 (CI 1.1-73), and 9.4 (CI 1.1-78), respectively. Nevertheless, the complication rate of APVC group 1 patients was similar to the other three groups. CONCLUSIONS: Saturated prostate cryoablation by reducing APVC would be beneficial for cancer control without compromising patient safety.

The outcome and prognostic factors for lymph node recurrence after node-sparing definitive external beam radiotherapy for localized prostate cancer.

BACKGROUND: The prognostic factors for the recurrence of lymph node (LN) metastasis after dose-escalated radiotherapy (RT) in prostate cancer patients have not been well investigated. We report the prognostic factors and outcomes in patients receiving salvage treatment for LN recurrence after high-dose intensity-modulated RT (IMRT). METHODS: We studied a cohort of 419 patients with localized prostate adenocarcinoma undergoing definitive IMRT (78 Gy). LN recurrence was diagnosed by size criteria using computed tomography (CT) or magnetic resonance imaging, or abnormal uptake of (18)F-fluorocholine by LNs on positron emission tomography/CT. Overall survival and LN recurrence-free survival (LNRFS) were calculated, and prognostic factors were evaluated. RESULTS: With a median follow-up of 60 months, 18 patients (4.3 %) had LN recurrence and a significantly lower 5-year overall survival rate (60 vs. 90 %, p = 0.003). Univariate analysis showed that T3/T4 stage (p = 0.003), Gleason score >7 (p < 0.001), and estimated risk of pelvic LN involvement of >30 % by the Roach formula (p = 0.029) were associated with significantly lower LNRFS. On multivariate analysis, high Gleason score (hazard ratio = 5.99, p = 0.007) was the only independent factor. The 1/2-year overall survivals after LN recurrence were 67/54 %. Patients with isolated LN recurrence (p = 0.003), prostate-specific antigen (PSA) doubling time >5 months (p = 0.009), interval between PSA nadir and biochemical failure >12 months (p = 0.035), and PSA <10 ng/ml at LN recurrence (p = 0.003) had significantly better survival. Patients with isolated LN recurrence had significantly better survival when treated with combined RT and hormones than when treated with hormones alone (p = 0.011). CONCLUSIONS: Gleason score of >7 may predict LN recurrence in prostate cancer patients treated with definitive IMRT. Small number of patients limits the extrapolation of this risk with the primary treatment strategy. Combined RT and hormones may prolong survival in patients with isolated LN recurrence.

Aristolochic acid-associated urothelial cancer in Taiwan.

Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of (5')AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.

Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients. METHODS: Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients. RESULTS: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17. CONCLUSIONS: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.

Proactive rectal warming during total-gland prostate cryoablation.

PURPOSE: Proactive rectal warming (PRW), as a modification of prostate cryoablation, was assessed in terms of rectal complications and therapeutic outcomes. MATERIALS AND METHODS: A cohort of 166 patients cumulatively treated between September, 2009 and November, 2012 qualified for study, each undergoing total-gland cryoablation (TGC) for prostate cancer. The initial 100 patients accrued submitted to TGC alone. PRW was administered to the final 66 patients. Preemptive warming is achieved by inserting a cryoprobe midline through perineal skin into anterior rectal wall under ultrasound guidance. The activated probe generates warmth as the ice ball encroaches on rectum. Prospective, post-ablative grading of rectal pain was measured at weeks 1, 2, 4, 8, 12, and 24 by using the Common Terminology Criteria for Adverse Events. Recurrent prostate cancer was gauged by Phoenix criterion (nadir+2 ng/ml). The Mann-Whitney U test and Chi-square test were used to compare clinical characteristics of therapeutic subsets. The Cox proportional hazard model was applied for comparison of cancer recurrence risk by group. RESULTS: Rectal pain (all grades) was experienced by patients treated with (62%) and without (74%) PRW. Although such pain typically resolved with time, it was milder (general lineal model, p=0.023) and less prolonged (median: 0.75 vs 1.5 months; log-rank test, p=0.002) in patients receiving PRW than in controls. Of note, PRW did not heighten cancer recurrence risk (hazard ratio=1.3 [95% CI, 0.3-5.0]). CONCLUSIONS: PRW helps to protect the rectum from freeze injury during prostate cryoablation, significantly reducing post-ablative rectal pain without compromising therapeutic outcomes.

Emphysematous pyelonephritis: clinical characteristics and prognostic factors.

OBJECTIVES: Emphysematous pyelonephritis is a severe necrotizing infection of the renal parenchyma and perirenal tissues that is caused by gas-producing bacterial pathogens. The aim of the present study was to determine the clinical characteristics and prognostic factors of patients with emphysematous pyelonephritis. METHODS: We retrospectively analyzed the clinical and laboratory data, imaging findings, and outcomes of 32 patients with emphysematous pyelonephritis. Receiver operating characteristic curve analysis was carried out on variables that were significantly associated with patient mortality. RESULTS: The overall survival rate was 87.5% (28/32). Escherichia coli (43.6%) was the most common organism cultured from urine and blood specimens. Hypoalbuminemia, shock as the presenting feature, bacteremia, need for hemodialysis and polymicrobial infection were significantly more common in cases resulting in death. The area under the receiver operating characteristic curve was 0.96. The cut-off point determined by the maximum Youden index (0.93) for three of these five factors yielded a sensitivity of 1.00 and specificity of 0.93. Shock as an initial presentation (P = 0.039) and polymicrobial infection (P = 0.010) were significantly associated with poor outcome. There were no significant differences in the clinical or laboratory features of the patients who did or did not undergo nephrectomy. CONCLUSION: Hypoalbuminemia, shock as an initial presentation, bacteremia, indications for hemodialysis and polymicrobial infection represent prognostic factors for mortality in patients with emphysematous pyelonephritis. Patients presenting with more than two of these prognostic factors carry the highest risk of mortality, and they require timely diagnosis and aggressive management.