Focal laser ablation as clinical treatment of prostate cancer: report from a Delphi consensus project.

PURPOSE: To define the role of focal laser ablation (FLA) as clinical treatment of prostate cancer (PCa) using the Delphi consensus method. METHODS: A panel of international experts in the field of focal therapy (FT) in PCa conducted a collaborative consensus project using the Delphi method. Experts were invited to online questionnaires focusing on patient selection and treatment of PCa with FLA during four subsequent rounds. After each round, outcomes were displayed, and questionnaires were modified based on the comments provided by panelists. Results were finalized and discussed during face-to-face meetings. RESULTS: Thirty-seven experts agreed to participate, and consensus was achieved on 39/43 topics. Clinically significant PCa (csPCa) was defined as any volume Grade Group 2 [Gleason score (GS) 3+4]. Focal therapy was specified as treatment of all csPCa and can be considered primary treatment as an alternative to radical treatment in carefully selected patients. In patients with intermediate-risk PCa (GS 3+4) as well as patients with MRI-visible and biopsy-confirmed local recurrence, FLA is optimal for targeted ablation of a specific magnetic resonance imaging (MRI)-visible focus. However, FLA should not be applied to candidates for active surveillance and close follow-up is required. Suitability for FLA is based on tumor volume, location to vital structures, GS, MRI-visibility, and biopsy confirmation. CONCLUSION: Focal laser ablation is a promising technique for treatment of clinically localized PCa and should ideally be performed within approved clinical trials. So far, only few studies have reported on FLA and further validation with longer follow-up is mandatory before widespread clinical implementation is justified.

Does mpMRI improve clinical criteria in selecting men with prostate cancer for active surveillance?

BACKGROUND: Active surveillance (AS) has excellent short to medium term outcomes in well-selected prostate cancer patients. Traditional biopsy-based selection criteria have been criticized for inaccurate determination of cancer grade and extent. We evaluated the incremental benefit of multiparametric magnetic resonance imaging (mpMRI) in patient selection using various AS criteria. METHODS: We retrospectively evaluated men who received mpMRI before radical prostatectomy between 2011 and 2014. Patients were classified as suitable for AS using four criteria: (1) Epstein, (2) National Comprehensive Cancer Network (NCCN) low-risk or (3) extended criteria (Gleason ⩽3+4, PSA ⩽15 ng/ml, clinical stage ⩽T2b) using clinical parameters. The incremental value of mpMRI was evaluated against the referent standard of surgical pathology in determining suitability for AS using sensitivity, specificity, likelihood ratios (LRs) and area under receiver operating curves (AUCs). RESULTS: We evaluated 208 men. Only one man fulfilled Epstein criteria (1) at pathology, who was neither identified using clinical criteria nor mpMRI. Using (2), clinical criteria had a sensitivity of 80%, specificity 75%, LR+ 3.3, LR- 0.3, AUC 0.78, while combined clinical-mpMRI criteria achieved a sensitivity of 80%, specificity 99.5% (P<0.01), LR+ 162, LR- 0.2 and AUC 0.90 (P<0.01 compared to clinical). Using (3), clinical criteria had a sensitivity of 74%, specificity 47%, LR+ 1.4, LR- 0.6, AUC 0.60, while combined clinical-mpMRI criteria achieved a sensitivity of 26% (P<0.01), specificity 97% (P<0.01), LR+ 8.3, LR- 0.8 and AUC 0.62 (P=0.85). CONCLUSIONS: Addition of mpMRI significantly improved selection of men for AS using NCCN low-risk criteria. For selecting men with limited prognostic grade group 2, mpMRI significantly improved specificity at the expense of sensitivity.

Patient selection for prostate focal therapy in the era of active surveillance: an International Delphi Consensus Project.

BACKGROUND: Whole-gland extirpation or irradiation is considered the gold standard for curative oncological treatment for localized prostate cancer, but is often associated with sexual and urinary impairment that adversely affects quality of life. This has led to increased interest in developing therapies with effective cancer control but less morbidity. We aimed to provide details of physician consensus on patient selection for prostate focal therapy (FT) in the era of contemporary prostate cancer management. METHODS: We undertook a four-stage Delphi consensus project among a panel of 47 international experts in prostate FT. Data on three main domains (role of biopsy/imaging, disease and patient factors) were collected in three iterative rounds of online questionnaires and feedback. Consensus was defined as agreement in ⩾80% of physicians. Finally, an in-person meeting was attended by a core group of 16 experts to review the data and formulate the consensus statement. RESULTS: Consensus was obtained in 16 of 18 subdomains. Multiparametric magnetic resonance imaging (mpMRI) is a standard imaging tool for patient selection for FT. In the presence of an mpMRI-suspicious lesion, histological confirmation is necessary prior to FT. In addition, systematic biopsy remains necessary to assess mpMRI-negative areas. However, adequate criteria for systematic biopsy remains indeterminate. FT can be recommended in D'Amico low-/intermediate-risk cancer including Gleason 4+3. Gleason 3+4 cancer, where localized, discrete and of favorable size represents the ideal case for FT. Tumor foci <1.5 ml on mpMRI or <20% of the prostate are suitable for FT, or up to 3 ml or 25% if localized to one hemi-gland. Gleason 3+3 at one core 1mm is acceptable in the untreated area. Preservation of sexual function is an important goal, but lack of erectile function should not exclude a patient from FT. CONCLUSIONS: This consensus provides a contemporary insight into expert opinion of patient selection for FT of clinically localized prostate cancer.

Utilization of multiparametric prostate magnetic resonance imaging in clinical practice and focal therapy: report from a Delphi consensus project.

PURPOSE: To codify the use of multiparametric magnetic resonance imaging (mpMRI) for the interrogation of prostate neoplasia (PCa) in clinical practice and focal therapy (FT). METHODS: An international collaborative consensus project was undertaken using the Delphi method among experts in the field of PCa. An online questionnaire was presented in three consecutive rounds and modified each round based on the comments provided by the experts. Subsequently, a face-to-face meeting was held to discuss and finalize the consensus results. RESULTS: mpMRI should be performed in patients with prior negative biopsies if clinical suspicion remains, but not instead of the PSA test, nor as a stand-alone diagnostic tool or mpMRI-targeted biopsies only. It is not recommended to use a 1.5 Tesla MRI scanner without an endorectal or pelvic phased-array coil. mpMRI should be performed following standard biopsy-based PCa diagnosis in both the planning and follow-up of FT. If a lesion is seen, MRI-TRUS fusion biopsies should be performed for FT planning. Systematic biopsies are still required for FT planning in biopsy-naïve patients and for patients with residual PCa after FT. Standard repeat biopsies should be taken during the follow-up of FT. The final decision to perform FT should be based on histopathology. However, these consensus statements may differ for expert centers versus non-expert centers. CONCLUSIONS: The mpMRI is an important tool for characterizing and targeting PCa in clinical practice and FT. Standardization of acquisition and reading should be the main priority to guarantee consistent mpMRI quality throughout the urological community.

Focal Cryotherapy for Localized Prostate Cancer.

OBJECTIVE: To systematically review the oncological and functional outcomes of contemporary primary prostate focal cryotherapy for localized prostate cancer in the context of current developments in prostate focal therapy. METHODS: We performed a systematic search of the Pubmed, Cochrane and Embase databases to identify studies where primary prostate focal cryotherapy was performed to treat prostate cancer. These included reports on focal/ lesion/ sector ablation, hemi-ablation and partial prostate ablation. We excluded salvage focal therapy studies. Where multiple reports were published over time from a single cohort, the latest one was used. RESULTS: Our search yielded 290 publications, including 17 primary reports on eight single-center cohort studies and one multi-center registry report. Of 1,595 men identified, mean age was 60.5-69.5 years and mean PSA 5.1-7.8 ng/ml. When stratified by D'Amico risk criteria, 52% of the aggregate total number of men were low-risk, 38% intermediate-risk and 10% high-risk. Besides 12-core TRUS biopsy, 3 cohorts reported using TTMB and one included mpMRI to select men for focal treatment. Median follow-up ranged from 13-63 months. BPFS ranged from 71-98%. The overall post-treatment positive biopsy rate was 8-25%. Among 5 cohorts with a mandatory 6-12 month posttreatment biopsy, 216 of 272 men (79%) did undergo biopsy, with 47 positive (21.8%). Of these, 15 were infield, 26 outfield, 2 bilateral and 4 undeclared. Ten upgraded to Gleason≥7. Overall, two men had metastatic disease and none died of prostate cancer. Post-treatment continence rates were 96-100% and rates of erectile dysfunction ranged from 0-42%. The rate of post-treatment urinary retention ranged from 0-15%. The rate of recto-urethral fistula was 0-0.1%. CONCLUSION: Focal cryotherapy for localized prostate cancer is a safe and provides good preservation of sexual and urinary function. Accurate cancer localization and risk stratification is key to patient selection. In highly selected patients, focal therapy has good short to medium term oncological efficacy.

Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project.

PURPOSE: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa). METHODS: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated. RESULTS: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text. CONCLUSION: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice.

Follow-up modalities in focal therapy for prostate cancer: results from a Delphi consensus project.

INTRODUCTION: Focal therapy can offer the middle ground for treatment between active surveillance and radical therapy in patients with low- and intermediate-risk prostate cancer. Factors that prohibit focal therapy from being standard of care are numerous. Several consensus projects have been conducted to position the utilization of imaging and trial design in focal therapy. However, the literature is still scarce on patient follow-up after focal therapy. For these reasons, an international multidisciplinary consensus project was established in order to reach consensus about a uniform follow-up protocol after focal therapy. OBJECTIVE: To standardize patient follow-up after focal therapy. MATERIALS AND METHODS: A literature study was performed, and a questionnaire was constructed. The questionnaire was sent out to 76 participants (70 % urologists, 28 % radiologists and 2 % biomedical engineers) in three consecutive rounds according to the Delphi method. In each round, the panelists were presented with the results of the previous round. Participants each had the opportunity to adapt, delete or add questions. The topics discussed pertaining to follow-up after focal therapy were as follows: (1) general,(2) biopsies, (3) PSA, (4) digital rectal examination (DRE), (5) imaging, (6) quality of life (QoL) and (7) registration and pooling of data. The project was concluded with a face-to-face meeting in which final conclusions were formulated. RESULTS: The follow-up after focal therapy should be a minimum of 5 years. The following modalities should be included in assessing post-treatment outcomes: multiparametric MRI (mpMRI), biopsies, assessment of erectile function, QoL, urinary symptoms and incontinence. A systematic 12-core TRUS biopsy combined with 4-6 targeted biopsy cores of the treated area and any suspicious lesion(s) should be performed after 1 year, and thereafter only when there is suspicion on imaging. The ideal way to perform targeted biopsies is to use TRUS-MRI fusion technology. PSA should be performed for research purposes, in the first year, every 3 months, and after the first year, every 6 months. mpMRI is the optimal imaging modality for follow-up after focal therapy. On a 1.5T scanner, an endorectal coil is strongly advised by the panel, whereas on a 3T machine, it is optional, however, it will improve image quality. The following sequences should be included: T2WI, DWI including high b values of >1,000 and ADC maps of DWI, DCE and T1WI. Imaging should be performed at 6 months and at 1 year following treatment; after the first year post-treatment, it should be performed every year until 5 years following treatment. All data should ideally be pooled in a common global database. CONCLUSION: Focal therapy is a relatively new form of treatment for prostate cancer. In order to include focal therapy as a standard of care treatment, consistent follow-up is necessary. By implementing the results of this consensus study, focal therapy users will be able to provide important and standardized outcome data.

Re-purposing cryoablation: a combinatorial 'therapy' for the destruction of tissue.

It is now recognized that the tumor microenvironment creates a protective neo-tissue that isolates the tumor from the various defense strategies of the body. Evidence demonstrates that, with successive therapeutic attempts, cancer cells acquire resistance to individual treatment modalities. For example, exposure to cytotoxic drugs results in the survival of approximately 20-30% of the cancer cells as only dividing cells succumb to each toxic exposure. With follow-up treatments, each additional dose results in tumor-associated fibroblasts secreting surface-protective proteins, which enhance cancer cell resistance. Similar outcomes are reported following radiotherapy. These defensive strategies are indicative of evolved capabilities of cancer to assure successful tumor growth through well-established anti-tumor-protective adaptations. As such, successful cancer management requires the activation of multiple cellular 'kill switches' to prevent initiation of diverse protective adaptations. Thermal therapies are unique treatment modalities typically applied as monotherapies (without repetition) thereby denying cancer cells the opportunity to express defensive mutations. Further, the destructive mechanisms of action involved with cryoablation (CA) include both physical and molecular insults resulting in the disruption of multiple defensive strategies that are not cell cycle dependent and adds a damaging structural (physical) element. This review discusses the application and clinical outcomes of CA with an emphasis on the mechanisms of cell death induced by structural, metabolic, vascular and immune processes. The induction of diverse cell death cascades, resulting in the activation of apoptosis and necrosis, allows CA to be characterized as a combinatorial treatment modality. Our understanding of these mechanisms now supports adjunctive therapies that can augment cell death pathways.

Disparate results between proliferation rates of surgically excised prostate tumors and an in vitro bioassay using sera from a positive randomized controlled trial.

In vitro bioassay has been used extensively to test the effects of culturing cancer cells in sera from humans participating in dietary interventions, i.e, studies of modified intake of nutrients for the purpose of reducing cancer risk or progression. It has been hypothesized that cell proliferation rates determined by the in vitro bioassay indicate whether modification of dietary intake could decrease cancer cell growth in vivo. It has been suggested, however, that the in vitro bioassay may not correlate with tumor cell proliferation rates in prostate cancer. We investigated the concordance of cell proliferation rates from surgically excised prostate tumor tissue with the in vitro bioassay using sera from matched patients. We used samples from an earlier randomized clinical trial that showed that supplementation with flaxseed significantly inhibited prostate cancer cell proliferation rates in vivo as indicated by Ki67 staining in tumor specimens. Proliferation rates of LNCaP, DU145 and PC3 cell lines cultured in 10% human sera from participants in the flaxseed trial were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Spearman's Rho correlation coefficients (ρ) indicated no association between Ki67 staining in prostate tumors and the in vitro bioassay for the three cell lines. These disparate findings suggest that the in vitro bioassay may not provide an accurate assessment of the environment in vivo.

Sexual bother and function after radical prostatectomy: predictors of sexual bother recovery in men despite persistent post-operative sexual dysfunction.

Changes in sexual bother (SB) following radical prostatectomy (RP) negatively affect health-related quality of life (HRQoL) of prostate cancer survivors. However, post-operative SB tends to be neglected whereas sexual function (SF) is thoroughly assessed in clinical practice and few studies have focused on and evaluated patients' SB. We retrospectively reviewed 2 345 consecutive patients who underwent RP between 2001 and 2009 at a single institution. SF and SB were assessed using Expanded Prostate Cancer Index Composite (EPIC) questionnaires. We stratified our cohort by SB recovery and post-operative SF status, including a subset of men who recovered SB despite persistent post-RP sexual dysfunction. Multivariable logistic regression analyses were conducted to identify factors for men who have SB recovery. Of 319 eligible patients, 133 (41.7%) recovered their SB at a mean of 20 months after RP. Among the 133 men who demonstrated SB recovery, 109 had post-operative sexual dysfunction. Patients with SB recovery despite post-RP sexual dysfunction were more likely to be old (p = 0.004), to have higher clinical T stage (p < 0.001), to have more non-nerve-sparing RP (p < 0.001), to have lower pre-operative EPIC-SF/SB scores (p < 0.001), to have more extracapsular extension (p = 0.031) and to be PDE5i non-users after surgery (p < 0.001). In multivariable analysis, predictors for this subset were lower comorbidity (OR 0.62, p = 0.043), higher clinical cancer stage (OR 2.35, p = 0.026), worse pre-operative SF (OR 0.98, p = 0.010), SB (OR 0.98, p < 0.010) and no PDE5i use (OR 0.37, p = 0.002); age was not related (OR 0.99, p = 0.555). As SB can influence patients' overall HRQoL, expectations of SB recovery should be provided to patients in the same way that SF recovery is presented. This study may help clinicians to discuss SB with patients and assess their potential for SB recovery following RP.

Race is associated with discontinuation of active surveillance of low-risk prostate cancer: results from the Duke Prostate Center.

BACKGROUND: Active surveillance (AS) is increasingly utilized in low-risk prostate cancer (PC) patients. Although black race has traditionally been associated with adverse PC characteristics, its prognostic value for patients managed with AS is unclear. METHODS: A retrospective review identified 145 patients managed with AS at the Duke Prostate Center from January 2005 to September 2011. Race was patient-reported and categorized as black, white or other. Inclusion criteria included PSA <10 ng ml(-1), Gleason sum ≤ 6, and ≤ 33% of cores with cancer on diagnostic biopsy. The primary outcome was discontinuation of AS for treatment due to PC progression. In men who proceeded to treatment after AS, the trigger for treatment, follow-up PSA and biopsy characteristics were analyzed. Time to treatment was analyzed with univariable and multivariable Cox proportional hazards models and also stratified by race. RESULTS: In our AS cohort, 105 (72%) were white, 32 (22%) black and 8 (6%) another race. Median follow-up was 23.0 months, during which 23% percent of men proceeded to treatment. The demographic, clinical and follow-up characteristics did not differ by race. There was a trend toward more uninsured black men (15.6% black, 3.8% white, 0% other, P = 0.06). Black race was associated with treatment (hazard ratio (HR) 2.93, P = 0.01) as compared with white. When the analysis was adjusted for socioeconomic and clinical parameters at the time of PC diagnosis, black race remained the sole predictor of treatment (HR 3.08, P = 0.01). Among men undergoing treatment, the trigger was less often patient driven in black men (8 black, 33 white, 67% other, P = 0.05). CONCLUSIONS: Black race was associated with discontinuation of AS for treatment. This relationship persisted when adjusted for socioeconomic and clinical parameters.

The use of mannitol in partial and live donor nephrectomy: an international survey.

PURPOSE: Animal studies have shown the potential benefits of mannitol as renoprotective during warm ischemia; it may have antioxidant and anti-inflammatory properties and is sometimes used during partial nephrectomy (PN) and live donor nephrectomy (LDN). Despite this, a prospective study on mannitol has never been performed. The aim of this study is to document patterns of mannitol use during PN and LDN. MATERIALS AND METHODS: A survey on the use of mannitol during PN and LDN was sent to 92 high surgical volume urological centers. Questions included use of mannitol, indications for use, physician responsible for administration, dosage, timing and other renoprotective measures. RESULTS: Mannitol was used in 78 and 64 % of centers performing PN and LDN, respectively. The indication for use was as antioxidant (21 %), as diuretic (5 %) and as a combination of the two (74 %). For PN, the most common dosages were 12.5 g (30 %) and 25 g (49 %). For LDN, the most common doses were 12.5 g (36.3 %) and 25 g (63.7 %). Overall, 83 % of centers utilized mannitol, and two (percent or centers??) utilized furosemide for renoprotection. CONCLUSIONS: A large majority of high-volume centers performing PN and LDN use mannitol for renoprotection. Since there are no data proving its value nor standardized indication and usage, this survey may provide information for a randomized prospective study.

African-American men with low-grade prostate cancer have higher tumor burdens: results from the Duke Prostate Center.

BACKGROUND: To investigate racial differences in tumor burden (cancer volume, cancer percentage and cancer to PSA ratios) in a large cohort of men undergoing radical prostatectomy (RP). METHODS: Demographic, clinical and pathological data of patients undergoing RP between 1993-2010 were reviewed and compared between African-American (AA) and non African-American (nAA) men. Further assessments of pathological tumor burden (estimated tumor volume, percent of cancer involvement, and estimated tumor volume/PSA ratios) were performed across Gleason score categories. RESULTS: Of 4157 patients in the analysis, 604 (14.5%) were AA. Overall, AA patients were younger, had higher Gleason scores, PSA levels and incidence of palpable disease (all P < 0.001). Despite comparable prostate weights (39.4 vs. 39.6 g), AA men had higher percent cancer involvement and estimated tumor volume (all P < 0.001) but similar estimated tumor volume/PSA ratios ( P> 0.05). When stratified by Gleason scores, prostate weights were comparable; however, estimated tumor volume, percent cancer involvement and estimated tumor volume/PSA ratios were higher in AA men with low grade (≤ 6) prostate cancer (PCa), similar in intermediate grade (7-8) and lower in high grade (9-10) PCa compared to nAA men. CONCLUSIONS: In this large series, AA patients had higher disease burden (estimated tumor volume, percent cancer involvement, estimated tumor volume/PSA ratios) compared to nAA but this association was especially pronounced in low grade (Gleason ≤ 6) cancers. These data depict a complex picture of relations between race and tumor burden across the spectrum of PCa aggressiveness. Further investigation is warranted to understand the mechanisms of racial disparities in PCa.

On-demand use of erectile aids in men with preoperative erectile dysfunction treated by whole gland prostate cryoablation.

Prostate cryoablation is an established minimally invasive treatment for localized prostate cancer (PCa). However, the impairment of erectile function (EF) is considered a serious complication of the procedure. To investigate the efficacy of erectile aids following cryotherapy, 93 patients who underwent whole gland prostate cryoablation with required complete medical records were analyzed. The changes in postoperative EF were evaluated using the International Index of Erectile Function (IIEF-5) questionnaire. Additionally, independent factors that could have a correlation to the postoperative IIEF-5 score or postoperative Expanded Prostate Cancer Index Composite (EPIC) score were assessed. In the entire cohort, the mean preoperative IIEF-5 score was 7.0 ± 6.2. A total of 72 (77.4%) patients had moderate-to-severe preoperative erectile dysfunction. In longitudinal investigation, the patients using erectile aids showed the ability to recover to baseline after 24 months from cryoablation compared with the patients not using erectile aids. There were significant differences of IIEF-5 scores between these groups at 24 months (7.5 vs 3.0; P = 0.025) and 36 months (8.5 vs 3.5; P = 0.010). In multivariate analysis, the use of erectile aids correlated with restoration of IIEF-5 scores (odds ratio, 5.11; confidence interval (CI), 1.87-13.96; P < 0.001) and lower EPIC sexual bother (coef, 19.61; CI, 0.32-38.89; P = 0.046). Our data indicate that on-demand use of erectile aids could help restore EF and reduce sexual bother after whole gland prostate cryoablation. Although, erectile aids could not play a role as an adequate treatment for ED after whole gland prostate cryoablation, these results may aid in the decision-making process for PCa patients with preoperative and postoperative ED who have concern about sexual health-related quality of life.

Use of 1,25α dihydroxyvitamin D3 as a cryosensitizing agent in a murine prostate cancer model.

Cryotherapy has emerged as a primary treatment option for prostate cancer (CaP); however, incomplete ablation in the periphery of the cryogenic lesion can lead to recurrence. Accordingly, we investigated the use of a non-toxic adjunctive agent, vitamin D3 (VD3), with cryotherapy to sensitize CaP to low temperature-induced, non-ice rupture-related cell death. VD3 (calcitriol) has been identified as a possible adjunct in the treatment of cancer because of its antiproliferative and antitumorigenic properties. This study aimed to identify the cellular responses and molecular pathways activated when VD3 (calcitriol) is combined with cryotherapy in a murine CaP model. Single freeze-thaw events above -15 °C had little effect on cancer cell viability; however, pretreatment with calcitriol in conjunction with cryo significantly increased cell death. The -15 °C calcitriol combination increased cell death to 55% following a single freeze compared with negligible cell loss by freezing or calcitriol alone. Repeated cryo combination yielded 90% cell death compared with 65% in dual freeze-only cycles. Western blot analysis following calcitriol cryosensitization regimes confirmed the activation of apoptosis. Specifically, proapoptotic Bid and procaspase-3 were found to decrease at 1 h following combination treatment, indicating cleavage to the active forms. A parallel in vivo study confirmed the increased cell death when combining cryotherapy with calcitriol pretreatment. The development of an adjunctive therapy combining calcitriol and cryotherapy represents a potentially highly effective, less toxic, minimally invasive treatment option. These results suggest a role for calcitriol and cryo as a combinatorial treatment for CaP, with the potential for clinical translation.

Predicting non-organ-confined prostate cancer in men diagnosed after 2000.

The objective of this study was to preoperatively predict non-organ-confined disease in patients considering radical prostatectomy. To account for the stage migration seen in prostate cancer, we included only those patients who underwent prostatectomy after the year 2000. Information on a cohort of 1895 patients who underwent radical prostatectomy from 2000 to 2008 was retrieved from the Duke Prostate Center database. Race (African American, non-African American), body mass index, age at surgery, PSA, biopsy Gleason sum (<7, 7 and >7) and clinical tumor stage (cT1, cT2/3) were analyzed by univariate analysis followed by logistic regression analysis. The Duke Interactive Clinical Equation for staging (DICE-S score) was calculated from the logistic regression model. The model was then internally validated using a bootstrapping technique. Biopsy Gleason sums 7 and >7 were more likely to have non-organ-confined disease compared with <7 (OR=2.97, Gleason sum=7; OR=3.25, Gleason sum>7). Clinical tumor stage, cT2/3, predicted non-organ-confined disease (OR=1.58). Older age was associated with non-organ-confined disease (OR=1.02), as was greater PSA (OR=1.12). DICE-S equation x=ln (p/1-p)=-3.627+0.019 (age)+0.109 (PSA)+1.087 (bGleason=7)+1.180 (bGleason >7)+0.459 (clinical T stage >T1), where p=(e(x))/(1+e(x)). A concordance index (prediction accuracy) of 0.73 was reached on internal validation. Using the DICE-S score, age, PSA, biopsy Gleason sum and clinical tumor stage, we can predict non-organ-confined disease in radical prostatectomy at an acceptable accuracy. Preoperative information on disease stage may aid in treatment decisions and surgical approach.

Focal therapy in prostate cancer-report from a consensus panel.

PURPOSE: To establish a consensus in relation to case selection, conduct of therapy, and outcomes that are associated with focal therapy for men with localized prostate cancer. MATERIAL AND METHODS: Urologic surgeons, radiation oncologists, radiologists, and histopathologists from North America and Europe participated in a consensus workshop on focal therapy for prostate cancer. The consensus process was face to face within a structured meeting, in which pertinent clinical issues were raised, discussed, and agreement sought. Where no agreement was possible, this was acknowledged, and the nature of the disagreement noted. RESULTS: Candidates for focal treatment should have unilateral low- to intermediate-risk disease with clinical stage

Integrin involvement in freeze resistance of androgen-insensitive prostate cancer.

Cryoablation has emerged as a primary therapy to treat prostate cancer. Although effective, the assumption that freezing serves as a ubiquitous lethal stress is challenged by clinical experience and experimental evidence demonstrating time-temperature-related cell-death dependence. The age-related transformation from an androgen-sensitive (AS) to an androgen-insensitive (AI) phenotype is a major challenge in the management of prostate cancer. AI cells exhibit morphological changes and treatment resistance to many therapies. As this resistance has been linked with alpha6beta4 integrin overexpression as a result of androgen receptor (AR) loss, we investigated whether alpha6beta4 integrin expression, as a result AR loss, contributes to the reported increased freeze tolerance of AI prostate cancer. A series of studies using AS (LNCaP LP and PC-3 AR) and AI (LNCaP HP and PC-3) cell lines were designed to investigate the cellular mechanisms contributing to variations in freezing response. Investigation into alpha6beta4 integrin expression revealed that AI cell lines overexpressed this protein, thereby altering morphological characteristics and increasing adhesion characteristics. Molecular investigations revealed a significant decrease in caspases-8, -9, and -3 levels in AI cells after freezing. Inhibition of alpha6beta4 integrin resulted in increased caspase activity after freezing (similar to AS cells) and enhanced cell death. These data show that AI cells show an increase in post-freeze susceptibility after inhibition of alpha6beta4 integrin function. Further understanding the role of androgen receptor-related alpha6beta4 integrin expression in prostate cancer cells responses to freezing might lead to novel options for neo-adjunctive treatments targeting the AR signaling pathway.

Concordance in the perception of couples recovering from primary surgical treatment of prostate cancer.

Although prostate cancer affects men, research shows effects on both members of the couple. We analyzed concordance in couples recovering from primary surgical treatment of prostate cancer when surveyed on psychological domains including emotional status, relationship, self-image, partnership quality and support. Retrospective Sexual Surveys were utilized to survey physiological changes as well as psychological effects. In total, 28 heterosexual couples (56 people) were enrolled. Patients were treated between February 2002 and March 2007 with a median follow-up of 26 (range: 4-59) months. When polled on psychological aspects that may have been affected by treatment, overall concordance was 75.0%. Partnership had the highest concordance (92.2%) with treatment satisfaction questions following in second (90.7%). Subcategories focused on self-image (77.5%), relationship (67.3%), support (66.4%) and emotional status (55.6%), were less concordant. Although couples report relationships as strong and team-like, misconception between partners is widespread. Further research with regards to the effect of such disparities in couples might provide additional insight into improving recovery.

WITHDRAWN: Can the conventional sextant prostate biopsy reliably diagnose unilateral prostate cancer in low-risk, localized, prostate cancer?

The authors hereby retract the e-publication dated 13 May 2008 and entitled, 'Can the conventional sextant prostate biopsy reliably diagnose unilateral prostate cancer in low-risk, localized, prostate cancer?' The authors are submitting a revised version with the same title. This article's statistics were performed for predicting bilateral prostate cancer outcomes. The article was written to help predict unilateral prostate cancer. Although the statistical numbers are correct, they are backwards. We apologize that the statistics indicate a contrary outcome (eg predicting bilateral cancer instead of unilateral disease).