Metagenomics in diagnosis and improved targeted treatment of UTI.

INTRODUCTION: The genomic revolution has transformed our understanding of urinary tract infection. There has been a paradigm shift from the dogmatic statement that urine is sterile in healthy people, as we are becoming forever more familiar with the knowledge that bacterial communities exist within the urinary tracts of healthy people. Metagenomics can investigate the broad populations of microbial communities, analysing all the DNA present within a sample, providing comprehensive data regarding the state of the microenvironment of a patient's urinary tract. This permits medical practitioners to more accurately target organisms that may be responsible for disease-a form of 'precision medicine'. METHODS AND RESULTS: This paper is derived from an extensive review and analysis of the available literature on the topic of metagenomic sequencing in urological science, using the PubMed search engine. The search yielded a total of 406 results, and manual selection of appropriate papers was subsequently performed. Only one randomised clinical trial comparing metagenomic sequencing to standard culture and sensitivity in the arena of urinary tract infection was found. CONCLUSION: Out of this process, this paper explores the limitations of traditional methods of culture and sensitivity and delves into the recent studies involving new high-throughput genomic technologies in urological basic and clinical research, demonstrating the advances made in the urinary microbiome in its entire spectrum of pathogens and the first attempts of clinical implementation in several areas of urology. Finally, this paper discusses the challenges that must be overcome for such technology to become widely used in clinical practice.

Antibiotic resistance, hospitalizations, and mortality related to prostate biopsy: first report from the Norwegian Patient Registry.

BACKGROUND: A 68-year-old man died of cerebral arterial embolism 6 days after transrectal prostate biopsy with a single p.o. dose of trimethoprim sulfamethoxazole (TMP-SMX) as prophylaxis. The case precipitated analysis of local antibiotic resistance and complication rates. MATERIALS AND METHODS: Data on E. coli resistance from Oslo University Hospital and national data on hospitalizations and mortality after biopsy were retrieved from local microbiology files and the Norwegian Patient Registry (NPR) 2011-2017. RESULTS: Urine E. coli resistance against TMP-SMX increased from 35% in 2013 to more than 60% in 2015. For ciprofloxacin, the resistance increased from 15% in 2013 to about 45% in 2016. The highest annual E. coli resistance in blood cultures for TMP-SMX and ciprofloxacin was 37% and 28%, respectively. 10% of patients were hospitalized with a diagnosis of infection within the first 60 days after biopsy and there was a relative increase in mortality rate of 261% within the first 30 days. Due to the severity of the figures, the story and the NPR data were published in Norway's leading newspaper and were succeeded by a series of chronicles and commentaries. CONCLUSIONS: Several critical points of the biopsy procedure were not performed according to current standards. We believe that the patient might have died of septic embolism after biopsy. As a result of the findings and the debate, local practice was changed from transrectal to transperineal prostate biopsies.

An implementation of next generation sequencing for prevention and diagnosis of urinary tract infection in urology.

INTRODUCTION: The changing face of current infection phenotypes from planktonic to biofilm type has been developed implicating bacterial biofilms in recurrent infection. To date, no specific medical treatment exists to specifically target biofilms in the human host. Similarly, the identification of a biofilm has relied upon the analysis of tissue samples with electron microscopy or DNA identification with polymerase chain reaction (PCR) and sequencing. Standard culture and sensitivity test is not able to detect a presence of biofilms. MATERIALS AND METHODS: Two types of molecular microbial diagnostic testing 'levels' are performed as noted below. In both types of analysis, the microbial DNA is extracted from the patient's sample. The patient report contains information about the pathogenic bacterial and fungal microorganisms detected, bacterial load and resistance genes to different antibiotics. Once the bacteria have been identified antibiotic recommendations are made based on research confirming the effectiveness of treatment. The technique was tested in 112 patients in different areas of urology for prevention and treatment purpose. RESULTS: The clinical application of next generation sequence in different clinical phase I-II trials (acute cystitis in 56 patients, rectal swabs before transrectal prostate biopsy in 32 men, neurogenic bladder in 13 patients, chronic bacterial prostatitis in 17 men) demonstrated that this novel approach extends our knowledge about the microbiome of the urogenital tract in both men and women. DNA sequence has a high sensitivity to detect a bacterial and fungal association with resistant genes to antibiotics revealed allowing to implement a targeted and individual prevention and treatment of urinary tract infection (UTI) with improved efficacy compared to standard culture and sensitivity technique. CONCLUSION: The next generation DNA sequence technology enables the discovery of new concepts regarding the role of microorganisms in diseases of the urinary tract with an individualized approach for a more accurate diagnosis, prevention, prophylaxis and treatment of UTI.

A pretreatment nomogram for prediction of biochemical failure after primary cryoablation of the prostate.

BACKGROUND: To create a predictive nomogram for biochemical failure following primary whole-gland cryoablation of the prostate for localized prostate cancer (LPCa). METHODS: We retrospectively analyzed 2,242 patients from the Cryo On-Line Database (COLD) who were treatment naive and had undergone primary whole gland cryoablation of the prostate for biopsy-confirmed LPCa. Kaplan-Meier (KM) curves estimating 5 year biochemical progression-free survival (bPFS) were generated. Multivariable Cox proportional hazards analysis (CoxPH) was performed in order to construct the nomogram. The nomogram was internally validated using the bootstrap technique. RESULTS: Overall, the KM estimated 5 year bPFS was 72.8%. Stratified by D'Amico risk, The KM estimated 5 year bPFS was 82.6%, 71.1%, and 57.8% for low-, intermediate-, and high-risk groups, respectively. Statistically significant predictors of biochemical outcomes from CoxPH analysis were pre-treatment prostate specific antigen (PTPSA) (P < 0.001), total prostate volume (P = 0.004), clinical stage (P = 0.034), and Gleason score (0.004). A nomogram for predicted 5 year biochemical progression free probability was constructed with a concordance index of 0.652. An online risk calculator was also generated. CONCLUSIONS: To the best of our knowledge, this is the first predictive nomogram for biochemical outcomes after primary whole gland cryoablation of the prostate using socio-demographic, pretreatment, clinical, and prostate biopsy data. Our nomogram and online risk calculator can guide both patients and urologists for shared decision making regarding definitive treatment options.

Predictors of biochemical failure in patients undergoing prostate whole-gland salvage cryotherapy: a novel risk stratification model.

UNLABELLED: What's known on the subject? and what does the study add?: Previous studies have identified the most important prognostic factors of the likely outcomes of salvage prostate whole-gland ablation, including initial clinical stage, biopsy Gleason score, and PSA (total and doubling time). There is potential for further optimization of candidate selection for salvage cryoablation with curative intent and nadir PSA achieved after whole-gland cryotherapy may provide additional prognostic value. The study shows that the most important prognostic factors of biochemical progression-free survival for patients who have undergone whole-gland salvage prostate cryotherapy are nadir PSA achieved after therapy and pre-therapy biopsy Gleason score. Based on these two prognostic variables, we have identified risk stratification groups (low, intermediate and high) which help predict the expected outcomes of salvage whole-gland prostate cryotherapy in a given patient. This risk stratification constitutes a useful clinical tool in defining which patients maybe best suited for this local salvage treatment method. OBJECTIVE: To assess the prognostic variables predicting the risk of biochemical progression-free survival (bPFS) after salvage prostate whole-gland cryotherapy using the Phoenix definition of bPFS. PATIENTS AND METHODS: A total of 132 patients underwent prostate whole-gland salvage cryotherapy with curative intent. No patient underwent neoadjuvant/adjuvant hormonal ablative therapy, and all had extended post-salvage prostate-specific antigen (PSA) follow-up data. Cox univariate and multivariate logistic regression analyses of potential predictors of bPFS were conducted. Kaplan-Meier analyses of bPFS was also performed. RESULTS: At a mean (range) follow-up of 4.3 (0.9-12.7) years, the median (range) post-cryotherapy nadir PSA achieved was 0.17 (0-33.9) ng/mL. On multivariate analysis, predictors of bPFS were nadir PSA post-cryotherapy and pre-salvage biopsy Gleason score (P < 0.001 and 0.009, respectively). Risk stratification groups (low, intermediate and high) were developed based on the presence of zero, one or two adverse risk factors, the risk factors being either a nadir PSA >2.5 ng/mL or biopsy Gleason score ≥ 7, with the Kaplan-Meier bPFS curves of these risk groups being significantly different (P = 0.02 and <0.001, respectively). CONCLUSIONS: Post-salvage nadir PSA and pre-salvage biopsy Gleason score are important predictors of outcome in this patient cohort. Low-, intermediate- and high-risk groups can be determined based on these variables and can define patients best suited for prostate cryotherapy.

Outcomes of salvage prostate cryotherapy stratified by pre-treatment PSA: update from the COLD registry.

OBJECTIVES: In this study, we evaluate the outcomes of salvage cryotherapy for locally recurrent prostate cancer within the COLD (cryo online data) Registry. Furthermore, we assess the results of salvage cryotherapy (with intermediate follow-up) stratified by pre-treatment prostate-specific antigen (PSA) levels to determine which patients may best be suited for treatment. METHODS: The COLD registry was developed as a prospective, centrally collected database among patients undergoing salvage cryoablation for locally recurrent prostate cancer following primary prostate radiotherapy with curative intent. Of the patients undergoing salvage cryotherapy (without neoadjuvant hormonal ablative therapy), complete medical records were available in 156 patients, with their mean follow-up being 3.8 years (0.9-12.7 years). The treatment outcomes of salvage cryotherapy were assessed using the Phoenix definition (nadir PSA + 2 ng/ml) of biochemical failure. RESULTS: Of our entire study population, the biochemical disease-free survival (bDFS) rates at 1, 2, and 3 years were 89.0, 73.7, and 66.7%, respectively. Stratification of our patients into two subgroups is based on their pre-treatment total serum PSA values <5 and ≥5 ng/ml, and bDFS rates at 3 years for these two subgroups were 78.3 and 52.9%, respectively. A Kaplan-Meier analysis of bDFS stratified by these same pre-treatment PSA values revealed that the subset of patients with a PSA ≥ 5 ng/ml had statistically significant poorer bDFS rates (P = 0.01). CONCLUSIONS: Salvage prostate cryotherapy is a potentially curative local salvage therapy. The importance of early referral when patients have a pre-treatment PSA < 5 ng/ml is essential to optimize treatment outcomes.

Complications and postoperative events after cryosurgery for prostate cancer.

OBJECTIVES: There has been a call in the urological literature for standardized reporting of complications. To use strict criteria aiming to report our complications and other postoperative events in a cohort of men undergoing third-generation prostate cryosurgery. PATIENTS AND METHODS: Demographic, clinical and pathological data were collected on men undergoing primary cryosurgery from 2002-2010, excluding those who had received neoadjuvant or adjuvant radiotherapy. Complications and events were broadly defined as any deviation from the expected postoperative course and any subjective complaint expressed during a follow-up visit. Descriptive statistics were generated and compared between groups using chi-squared and rank sum tests as appropriate. Logistic regression analyses were performed to assess the potential predictors of any complication or event. RESULTS: In total, 106 consecutive patients were identified. There were no intra-operative complications or instances of equipment failure. We observed 42 early complications, with 48 delayed and 10 late postoperative events. A total of five (4.7%) patients had persistent urge and/or stress incontinence. Thirty-one patients had International Prostate Symptom Score (IPSS) and bother index scores available before and after surgery; median scores decreased from 7 and 2 to 6 and 1, for IPSS and bother index, respectively. Twenty-four patients had Sexual Health Inventory for Men scores available before surgery and at 2-year follow-up; median scores decreased from 11 to 2. On multivariate analysis, there were no significant associations. CONCLUSIONS: Modern cryosurgery is safe, and most of the complications and postoperative events are transient. Erectile function, however, has marked deterioration. We were unable to identify significant risk factors for complications or postoperative events.

Vitamin D(3) cryosensitization increases prostate cancer susceptibility to cryoablation via mitochondrial-mediated apoptosis and necrosis.

OBJECTIVES: To investigate the effect and molecular mechanisms of action of Vitamin D(3) (VD(3) ) as a neo-adjunctive agent before cryosurgery in an effort to increase treatment efficacy for prostate cancer (CaP). To eliminate the potential for disease recurrence that exists at the periphery of the freeze lesion, where temperatures may be insufficient to destroy both androgen-sensitive (AS) and androgen-insensitive (AI) CaP. METHODS: Human CaP cells, LNCaP, were each genetically altered to express the AS and AI phenotypes and subjected to VD(3) treatment and freezing in an in vitro and tissue-engineered model. Cell viability, caspase inhibitor and western blot studies were used to determine the basis of the different responses of AI and AS cells to VD(3) cryosensitization. RESULTS: VD(3) was found to be a highly effective cryosensitizer, resulting in a >50% overall increase in cell death after -15 °C freezing. Fluorescence microscopy, western blot analysis and caspase protease assays confirmed that the increased activation of apoptosis was modulated through a mitochondrial-mediated pathway. Caspase inhibition studies showed that apoptosis played an integral role in cell death, with VD(3) cryosensitivation-induced apoptotic events responsible for >30% of the overall cell death after -15 °C freezing. CONCLUSIONS: The present study suggests that the use of VD(3) as a cryosensitizer increases cryoablation efficacy through the increased activity of apoptosis as well as through necrosis. The data show that through VD(3) treatment the overall level of AI CaP cell tolerance to freezing is reduced to a level similar to that of AS CaP. VD(3) pre-treatment in conjunction with cryoablation may increase treatment efficacy and reduce disease recurrence for CaP patients.

Urinary bladder cancer: role of MR imaging.

Urinary bladder cancer is a heterogeneous disease with a variety of pathologic features, cytogenetic characteristics, and natural histories. It is the fourth most common cancer in males and the tenth most common cancer in females. Urinary bladder cancer has a high recurrence rate, necessitating long-term surveillance after initial therapy. Early detection is important, since up to 47% of bladder cancer-related deaths may have been avoided. Conventional computed tomography (CT) and magnetic resonance (MR) imaging are only moderately accurate in the diagnosis and local staging of bladder cancer, with cystoscopy and pathologic staging remaining the standards of reference. However, the role of newer MR imaging sequences (eg, diffusion-weighted imaging) in the diagnosis and local staging of bladder cancer is still evolving. Substantial advances in MR imaging technology have made multiparametric MR imaging a feasible and reasonably accurate technique for the local staging of bladder cancer to optimize treatment. In addition, whole-body CT is the primary imaging technique for the detection of metastases in bladder cancer patients, especially those with disease that invades muscle.

Preoperative predictors of pathologic stage T2a in low-risk prostate cancer: implications for focal therapy.

OBJECTIVE: To assess preoperative parameters that may be predictive of pathologic stage T2a disease in low-risk prostate cancer patients. METHODS: Data from a cohort of 1,495 consecutive men with low-risk prostate cancer who underwent a radical prostatectomy between 1993 and 2009 were evaluated. Preoperative parameter assessment focused on age, race, clinical stage, diagnostic PSA level, biopsy tumor laterality and diagnostic Gleason score. Preoperative parameters were analyzed by univariate and multivariate methods. Kaplan-Meier method was used to evaluate the biochemical disease-free survival. RESULTS: Among the 1,495 men, 236 (15.8%) had pT2a disease. In univariate analysis, biopsy tumor unilaterality (p < 0.001), diagnostic PSA ≤ 4 ng/ml (p < 0.001) and non-African-American race (p = 0.009) were significant variables. In multivariate analysis, biopsy tumor laterality (OR 0.377; p < 0.001), diagnostic PSA ≤ 4 ng/ml (OR 0.621; p = 0.002) and race (OR 0.583; p = 0.029) were independent predictors. Low-risk patients with pT2a disease showed a better PSA recurrence-free survival rate, compared with men with >pT2a diseases (p = 0.012). CONCLUSIONS: Biopsy tumor unilaterality, diagnostic PSA ≤ 4 ng/ml and race are independent predictors of pT2a in low-risk prostate cancer. These three preclinical variables may be a useful reference to begin the selection process for focal therapy in men with low-risk prostate cancer.

Understanding the pathological features of focality, grade and tumour volume of early-stage prostate cancer as a foundation for parenchyma-sparing prostate cancer therapies: active surveillance and focal targeted therapy.

OBJECTIVE: • To better understand the biology and incidence of the cancer foci within the prostate through a comprehensive literature review and a review of our own data, to establish the current level of knowledge regarding the pathological foundation for active surveillance (AS) or focal therapy (FT). PATIENTS AND METHODS: • A systematic review of the literature was performed, searching PubMed® from January 1994 to July 2009. • Electronic searches were limited to the English language using the keywords 'prostate cancer', 'histopathology', 'radical prostatectomy', 'pathological stage' and 'focal therapy'. • The authors' own data were also analysed and are presented. RESULTS: • Recent data have shown a significant pathological stage migration towards earlier disease comprising unilateral pT2a/b prostate cancer (PCa). • The cancer volume of the clinically significant tumour (index lesion) has been proposed as a driving force of PCa progression and therefore should be identified and treated at an early stage. • In general, most satellite lesions do not appear to be life-threatening. • Other pathological features, such as Gleason score, extraprostatic extension and the spatial distribution of PCa within the prostate, remain important selective criteria for AS or FT. CONCLUSION: • The present study reviews the current knowledge of cancer focality, aggression and tumour volume. Further research is needed to better understand the biologic behaviour of each of the tumour foci within a cancerous prostate, and to employ this information to selected patients for no therapy (AS), parenchyma-preserving approaches (FT) or whole gland radical therapy.

Predictors of prolonged operative time during robot-assisted laparoscopic radical prostatectomy.

OBJECTIVE: To determine risk factors for prolonged operative time (OT) during robot-assisted laparoscopic radical prostatectomy (RALP). Being able to predict prolonged OT is of pivotal importance both to the physician for patient counseling and to the hospital management. PATIENTS AND METHODS: Retrospective review of patient records undergoing RALP between 2003 and 2009 at a tertiary academic center with a structured teaching program. The following variables were recorded: age, race, body-mass index (BMI), previous abdominal surgery (yes/no), nerve-sparing technique (yes/no), lymph nodes dissection (yes/no), pathological stage (organ-confined versus non), cumulative surgical experience with RALP (expressed as number of years since introduction of RALP at our center), prostate weight and OT calculated skin-to-skin by the anesthesiologists. Prolonged OT was defined as the upper quintile (20%) according to the distribution. Multivariate regression model was generated to assess potential predictors of prolonged OT. RESULTS: A total of 523 records were retrieved. Caucasians accounted for 77.8% of the cohort. Median age was 60.3 years (interquartile range, IQR, 55.0-64.6 years), median BMI 28.1 (25.8-30.7 kg/m²), prostate weight 46.0 g (37.0-57.8 g). Eighty-six (16.4%) patients had previous abdominal surgery, lymph nodes dissection was performed in 341 (65.2%) and nerve-sparing technique was done in 310 (59.3%) cases. Median OT was 175 min (IQR 146-220 min). Prolonged OT was set at > 230 min, thereby 105 (20.1%) records were classified as such. On multivariate analysis, cumulative surgical experience with RALP (P < 0.001), nerve sparing (P = 0.023) and prostate weight (P < 0.001) were independent predictors of prolonged OT. CONCLUSIONS: Larger prostates are associated with longer OT and this effect is maintained independently of cumulative robotic experience that represents another independent factor in determining OT.

Clinical predictors of renal mass pathological features.

OBJECTIVE: • To evaluate the influence of radiographic tumour size and other preoperative variables on the pathological characteristics of the lesion to determine the distribution of pathological features and assess preoperative risk factors for potentially aggressive versus probably indolent renal lesions. PATIENTS AND METHODS: • Retrospective review of records for 768 patients who underwent surgery for single, sporadic renal mass between 2000 and 2008 in a tertiary academic institution. • Demographic, radiographic and pathological variables were recorded and analysed with regression analyses for risk factors for potentially aggressive pathological features (malignant pathology, high Fuhrman grade, lymphovascular invasion and extracapsular extension). RESULTS: • Malignancy was pathologically confirmed in 628 (81.8%) specimens. • Radiographic size was significantly associated with malignancy (versus benign pathology; OR = 1.13, P= 0.001), high Fuhrman grade (OR = 1.21, P < 0.0001), vascular invasion (OR = 1.19, P < 0.0001) and extracapsular extension (OR = 1.23, P < 0.0001). • Age, symptomatic presentation, solid appearance and radiographic size were independent predictors of potentially aggressive disease, whereas for male gender (OR = 1.43, P= 0.062) a trend toward statistical significance was noted. CONCLUSIONS: • Age, male gender, radiographic size and appearance, as well as symptomatic presentation, are associated with an increased risk of malignant, potentially aggressive disease. • These factors should be considered when evaluating management options for a solitary enhancing renal mass.

Predicting unilateral prostate cancer on routine diagnostic biopsy: sextant vs extended.

OBJECTIVE: To compare the diagnostic properties of routine office-based sextant and extended biopsies for unilateral prostate cancer, as validated by final pathology, because focal therapy of prostate cancer is gaining acceptance as a viable treatment option and thus patient selection is of paramount consideration. PATIENTS AND METHODS: We retrospectively analysed records of patients who had a radical prostatectomy (RP) for biopsy confirmed prostate cancer at our institution between 1990 and 2007. Records with incomplete data were excluded. Diagnostic properties for sextant and extended biopsies were calculated and compared for diagnostic accuracy, sensitivity, specificity, positive and negative predictive values (PPV, NPV) and false-positive and -negative rates. RESULTS: We identified 882 records (729 sextant, 153 extended biopsies) matching our criteria. Overall, unilateral prostate cancer was confirmed in 151 (16%) of pathological RP specimens. The sensitivity improved from 84.1% to 88.0% on sextant and extended biopsy, respectively. Similarly, the PPV increased from 21.9% to 27.2%, specificity from 37.1% to 53.9% (P < 0.05), and NPV from 91.8% to 95.8% (P < 0.05). These changes are reflected in the decrease in false-positive rates (from 62.9% to 46.1%) and false-negative rates (from 15.9% to 12.0%). The overall diagnostic accuracy increased from 49% on sextant to 59% on extended biopsy (P < 0.05). CONCLUSIONS: Taking more prostate biopsy cores improves the diagnostic properties for identifying unilateral prostate cancer. However, a 12-core biopsy is not an ideal diagnostic test to select patients for focal therapy, and should be interpreted in conjunction with imaging and clinical variables. Additional research should investigate the diagnostic gain associated with a further increase in the number of biopsy cores.

Pathological T2 sub-divisions as a prognostic factor in the biochemical recurrence of prostate cancer.

OBJECTIVE: To determine the adequacy of T2 prostate cancer (PCa) sub-staging as an independent Predictor of biochemical disease-free survival (bDFS) after radical prostatectomy. MATERIALS AND METHODS: The Duke Prostate Center database was queried for patients who underwent radical prostatectomy between 1988 and 2007 and had pT2 PCa, identifying 1990 cases. Prostate-specific antigen (PSA) recurrence was defined as a single value ≥0.2 ng/mL. Kaplan-Meier curves compared differences in bDFS between T2 sub-divisions. Multivariate analysis was performed, adjusting for age, pathological Gleason sum, surgical margin status, preoperative PSA, race, total tumour percentage and prostate weight on biochemical recurrence. RESULTS: The mean age at surgery was 62 years, and 16% of patients were African-American. Median prostate weight was 40 g [interquartile range (IQR) 31-52] and median preoperative PSA was 5.6 (IQR 4.2-7.8). Pathological Gleason score was ≤6 in 57%, 7 in 38%, and ≥8 in 5%; pathological T stage distribution was 18% T2a, 6% T2b, and 76% T2c; and percentage tumour involvement was ≤5% in 43%, between 5.1 and 10% in 24%, between 10.1 and 15% in 10%, and >15% in 19%. 366 (18.4%) patients had a biochemical recurrence after a median of 4.6 years (IQR 2.1-8.2) follow-up. bDFS was significantly (P= 0.006) higher for pT2a disease than for pT2b and pT2c, which were comparable. Adjusting for demographic and other pathological variables, T2 sub-divisions lost statistical significance. CONCLUSIONS: Pathological T2a prostate cancer has significantly higher bDFS than the pT2b or pT2c sub-groups in univariate but not multivariate analyses. Different pathological features should be explored to create more meaningfully predictive pathological T2 sub-divisions.

Current salvage methods for recurrent prostate cancer after failure of primary radiotherapy.

We reviewed the current salvage methods for patients with local recurrent prostate cancer after primary radiotherapy (RT), using a search of relevant Medline/PubMed articles published from 1982 to 2008, with the following search terms: 'radiorecurrent prostate cancer, local salvage treatment, salvage radical prostatectomy (RP), salvage cryoablation, salvage brachytherapy, salvage high-intensity focused ultrasound (HIFU)', and permutations of the above. Only articles written in English were included. The objectives of this review were to analyse the eligibility criteria for careful selection of appropriate patients and to evaluate the oncological results and complications for each method. There are four whole-gland re-treatment options (salvage RP, salvage cryoablation, salvage brachytherapy, salvage HIFU) for RT failure, although others might be in development or investigations. Salvage RP has the longest follow-up with acceptable oncological results, but it is a challenging technique with a high complication rate. Salvage cryoablation is a feasible option, especially using third-generation technology, whereby the average biochemical disease-free survival rate is 50-70% and there are fewer occurrences of severe complications such as recto-urethral fistula. Salvage brachytherapy, with short-term cancer control, is comparable to other salvage methods but depends on cumulative dosage limitation to target tissues. HIFU is a relatively recent option in the salvage setting. Both salvage brachytherapy and HIFU require more detailed studies with intermediate and long-term follow-up. As these are not prospective, randomized studies and the definitions of biochemical failure varied, there are limited comparisons among these different salvage methods, including efficacy. In the focal therapy salvage setting, the increased use of thermoablative methods for eligible patients might contribute to reducing complications and maintaining quality of life. The problem to effectively salvage patients with locally recurrent disease after RT is the lack of diagnostic examinations with sufficient sensitivity and specificity to detect local recurrence at an early curable stage. Therefore, a more strict definition of biochemical failure, improved imaging techniques, and accurate specimen mapping are needed as diagnostic tools. Furthermore, universal selection criteria and an integrated definition of biochemical failure for all salvage methods are required to determine which provides the best oncological efficacy and least comorbidity.

Adjuvant versus salvage radiation therapy for prostate cancer and the risk of death.

OBJECTIVE: To investigate whether salvage radiation therapy (RT) for prostate-specific antigen (PSA) failure can provide the same result as adjuvant RT, which decreases the risk of all-cause mortality (ACM) for men with positive margins (R1), or extra-capsular or seminal vesicle extension (pT3). METHODS: We studied 1638 men at Duke University who underwent radical prostatectomy for unfavourable-risk prostate cancer and whose postoperative PSA was undetectable. Cox regression was used to evaluate whether salvage vs adjuvant RT in men with a rapid (<10 months) or slow (≥10 months) PSA doubling time (DT) was associated with the risk of ACM, adjusting for adverse features (pT3, R1, Gleason score 8-10), age, preoperative PSA level, comorbidity and hormonal therapy use. RESULTS: Despite fewer men with two or more adverse features (61 vs 82%; P=0.016), salvage for a rapid PSA DT vs adjuvant RT increased the risk of ACM [adjusted hazard ratio (AHR)=3.42; 95% confidence interval (CI)=1.27-9.20; P=0.015]. There was no difference (AHR=1.39; 95% CI=0.50-3.90; P=0.53) in the risk of ACM among men who received salvage for a slow PSA DT or adjuvant RT. Nearly all (90%) men with a slow PSA DT had Gleason score ≤7 and the majority (59%) had at most pT3 or R1 disease. CONCLUSION: Radiation therapy after PSA failure as compared with adjuvant RT was not associated with an increased risk of ACM in men with Gleason score ≤7 and pT3R0 or pT2R1 disease.

Morphology of hypoxia following cryoablation in a prostate cancer murine model: its relationship to necrosis, apoptosis and, microvessel density.

The aim of this study is to investigate the tumor tissue changes in terms of hypoxia and demonstrate its relationship to vascularity and apoptosis following therapeutic cryoablation in a prostate tumor murine model. Total 67 male C57BL/J6 mice were assigned into sham-operation group and cryoablation group. Murine prostate tumors (RM-9) were inoculated subcutaneously in a right hind leg and treated with cryotherapy. Of 30 mice, tumor volumes were measured for 12 days following operation. Of 37 mice, tumor tissues were harvested in 24h following operation, and histological/molecular changes were analyzed. Hematoxylin and eosin or immunohistochemical staining were utilized to quantify tumor necrosis, hypoxia (pimonidazole), vascularization (CD31), and apoptosis (cleaved caspase-3). The results showed that cryoablated tumors demonstrated significant delayed growth following treatment compared to controls. Pathological analysis revealed that the severity of hypoxia increased in the cryoablation arm compared to controls. Necrotic and apoptotic populations were also found to be increased in the cryoablation arm (P=0.028 and 0.021). Hypoxia demonstrated a positive correlation with necrosis (r=0.520, P=0.001) and apoptosis (r=0.474, P=0.003), while showing negative correlation with microvessel density (MVD) (r=-0.361, P=0.021). We concluded that in the peripheral areas from the cryoneedle impact site, strong hypoxic responses were found, which may play important role in tumor freezing injury. To our knowledge, this is the first report describing cryoablation-mediated changes of hypoxia at a molecular level in the prostate cancer murine model.

The human gastrointestinal microbiota and prostate cancer development and treatment.

The human gastrointestinal microbiome contains commensal bacteria and other microbiota that have been gaining increasing attention in the context of cancer development and response to treatment. Microbiota play a role in the maintenance of host barrier surfaces that contribute to both local inflammation and other systemic metabolic functions. In the context of prostate cancer, the gastrointestinal microbiome may play a role through metabolism of estrogen, an increase of which has been linked to the induction of prostatic neoplasia. Specific microbiota such as Bacteroides, Streptococcus, Bacteroides massiliensis, Faecalibacterium prausnitzii, Eubacterium rectalie, and Mycoplasma genitalium have been associated with differing risks of prostate cancer development or extensiveness of prostate cancer disease. In this Review, we discuss gastrointestinal microbiota's effects on prostate cancer development, the ability of the microbiome to regulate chemotherapy for prostate cancer treatment, and the importance of using Next Generation Sequencing to further discern the microbiome's systemic influence on prostate cancer.