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OBJECTIVES: To prospectively assess the safety, functional- and oncological-outcomes of irreversible electroporation (IRE) as salvage therapy for radio-recurrent focal prostate cancer in a multicenter setting. PATIENTS AND METHODS: Men with focal recurrent PCa after external beam radiation or brachytherapy without metastatic disease on staging imaging and co-registration between mpMRI and biopsies were prospectively included in this multicenter trial. Adverse events were reported following the Clavien-Dindo classification. Validated questionnaires were used for patient-reported functional outcomes. Follow-up consisted of 3 monthly prostate specific antigen (PSA) levels, a 6-month mpMRI and standardised transperineal template mapping biopsies at 12-months. Thereafter follow-up was guided by MRI and/or PSMA-PET/CT and PSA. Local recurrence was defined as any ISUP score ≥2 on biopsies. RESULTS: 37 patients were analysed with a median (interquartile range (IQR)) follow up of 29 (22-43) months. Median age was 71 (53-83), median PSA was 3.5 ng/mL (2.7-6.1). 28 (75.5%) patients harboured intermediate risk and 9 patients (24.5%) high risk PCa. Seven patients (19%) reported self-limiting urgency, frequency, or hematuria (grade 1-2). Seven patients (19%) developed a grade 3 AE; urethral sludge requiring transurethral resection. At 12 months post treatment 93% of patients remained continent and erectile function sufficient for intercourse deteriorated from 35% to 15% (4/27). Local control was achieved in 29 patients (78%) and 27 patients (73%) were clear of local and systemic disease. Four (11%) patients had local recurrence only. Six (16%) patients developed metastatic disease with a median time to metastasis of 8 months. CONCLUSION: The FIRE trial shows that salvage IRE after failed radiation therapy for localised PCa is safe with minimal toxicity, and promising functional and oncological outcomes. Salvage IRE can offer a possible solution for notoriously difficult to manage

PURPOSE: To assess whether completeness of pelvic lymph node dissection (PLND) as measured by lymph node yield reduces biochemical recurrence (BCR) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa), stratified according to Briganti nomogram-derived risk (≥5% vs. < 5%) of lymph node invasion (LNI). METHODS: Retrospective study of 3724 men who underwent RP between January 1995 and January 2015 from our prospectively collected institutional database. All men included had minimum five years follow-up and were not given androgen deprivation therapy or radiotherapy prior to BCR. Primary endpoint was time to BCR as defined by PSA > 0.2ng/ml. Patients were analysed according to Briganti Nomogram derived risk of 'low-risk' (< 5%) vs. 'high-risk' (≥ 5%). Extent of PLND was analysed using number of nodes yielded at dissection as a continuous variable as well as a categorical variable: Group 1 (limited, 1-4 nodes), Group 2 (intermediate, 5-8 nodes) and Group 3(extensive, ≥9 nodes). RESULTS: Median follow-up in the overall cohort was 79.7 months and 65% of the total cohort underwent PLND. There were 2402 patients with Briganti risk of LNI < 5% and 1322 with a Briganti risk of LNI ≥5%. At multivariate analysis, only PSA (HR1.01, p < 0.001), extracapsular extension at RP (HR 1.86, p < 0.001), positive surgical margin (HR 1.61, p < 0.001) and positive lymph node on pathology (HR 1.52, p = 0.02) were independently associated with BCR. In the high-risk group, increased nodal yield at PLND was associated with reduction in risk of BCR (HR 0.97, 95%CI 0.95-1.00 p = 0.05, Cochran Mantel Haenszel test, p < 0.05: respectively). In the low-risk group increased number of nodes at PLND did not reduce risk of BCR. CONCLUSIONS: In this study of extent of PLND at RP, higher nodal yield did not reduce risk of BCR in low-risk men (Briganti risk < 5%), however there was a weak benefit in terms of reduced long-term risk of BCR in high-risk men (Briganti risk ≥5%).

BACKGROUND:Focal irreversible electroporation (IRE) can be used to treat men with localised prostate cancer (PCa) with reduced impact on quality of life (QoL). OBJECTIVE:To assess oncological and functional outcomes. DESIGN, SETTING, AND PARTICIPANTS:To report on a prospective database of patients undergoing primary IRE between February 2013 and August 2018. A minimum of 12-mo follow-up was available for 123 patients. Median follow-up was 36 mo (interquartile range [IQR] 24-52 mo). A total of 112 (91%) patients had National Comprehensive Cancer Network intermediate risk and 11 (9%) had low risk. A total of 12 (9.8%) had International Society of Urological Pathology (ISUP) grade 1, 88 (71.5%) had ISUP 2, and 23 (18.7%) had ISUP 3. INTERVENTION:Focal IRE ablation of PCa lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Follow-up involved serial prostate-specific antigen (PSA), multiparametric magnetic resonance imaging (mpMRI), and transperineal template mapping biopsy (TTMB) at 12 mo. Failure-free survival (FFS) was defined as progression to whole-gland or systemic treatment or metastasis/death. Functional outcomes were assessed. RESULTS AND LIMITATIONS:Median age was 68yr (IQR 62-73yr). Median preoperative PSA was 5.7ng/ml (IQR 3.8-8.0ng/ml). On post-treatment TTMB, in-field recurrence was present in 2.7-9.8% of patients. FFS at 3yr was 96.75%, metastasis-free survival 99%, and overall survival 100%. A total of 18 patients required salvage treatment (12 had repeat IRE; six had whole-gland treatment). The negative predictive value of mpMRI was 94% and sensitivity 40% for detecting in-field residual disease 6 mo after treatment. Among patients who returned questionnaires, 80/81 (98.8%) remained pad free and 40/53 (76%) had no change in erectile function. CONCLUSIONS:Focal IRE in select patients with localised clinically significant PCa has satisfactory short-term oncological outcomes with a minimal impact on patient QoL. PATIENT SUMMARY:In this study, 123 patient

A plethora of individual candidate biomarkers for predicting biochemical relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with biochemical relapse. In the current study, these biomarkers were re-analyzed for biochemical relapse, metastatic relapse and PCa death with extended follow-up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n = 324) was based on 12 biomarkers with a median follow-up of 16 years. Seven biomarkers were significantly associated with biochemical relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6-32; p = 0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2-25; p = 0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, p < 0.001). Our findings indicate that biochemical relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.

Background: The development, monitoring, and reporting of indicator measures that describe standard of care provide the gold standard for assessing quality of care and patient outcomes. Although indicator measures have been reported, little evidence of their use in measuring and benchmarking performance is available. A standard set, defining numerator, denominator, and risk adjustments, will enable global benchmarking of quality of care. Objective(s): To develop a set of indicators to enable assessment and reporting of quality of care for men with localised prostate cancer (PCa). Design, setting, and participants: Candidate indicators were identified from the literature. An international panel was invited to participate in a modified Delphi process. Teleconferences were held before and after each voting round to provide instruction and to review results. Outcome measurements and statistical analysis: Panellists were asked to rate each proposed indicator on a Likert scale of 1-9 in a two-round iterative process. Calculations required to report on the endorsed indicators were evaluated and modified to reflect the data capture of the Prostate Cancer Outcomes Registry-Australia and New Zealand (PCOR-ANZ). Results and limitations: A total of 97 candidate indicators were identified, of which 12 were endorsed. The set includes indicators covering pre-, intra-, and post-treatment of PCa care, within the limits of the data captured by PCOR-ANZ. Conclusion(s): The 12 endorsed quality measures enable international benchmarking on the quality of care of men with localised PCa. Reporting on these indicators enhances safety and efficacy of treatment, reduces variation in care, and can improve patient outcomes. Patient Summary: PCa has the highest incidence of all cancers in men. Early diagnosis and relatively high survival rates mean issues of quality of care and best possible health outcomes for patients are important. This paper identifies 12 important measurable quality indica

Background: The development, monitoring, and reporting of indicator measures that describe standard of care provide the gold standard for assessing quality of care and patient outcomes. Although indicator measures have been reported, little evidence of their use in measuring and benchmarking performance is available. A standard set, defining numerator, denominator, and risk adjustments, will enable global benchmarking of quality of care. Objective: To develop a set of indicators to enable assessment and reporting of quality of care for men with localised prostate cancer (PCa). Design, setting, and participants: Candidate indicators were identified from the literature. An international panel was invited to participate in a modified Delphi process. Teleconferences were held before and after each voting round to provide instruction and to review results. Outcome measurements and statistical analysis: Panellists were asked to rate each proposed indicator on a Likert scale of 1–9 in a two-round iterative process. Calculations required to report on the endorsed indicators were evaluated and modified to reflect the data capture of the Prostate Cancer Outcomes Registry–Australia and New Zealand (PCOR-ANZ). Results and limitations: A total of 97 candidate indicators were identified, of which 12 were endorsed. The set includes indicators covering pre-, intra-, and post-treatment of PCa care, within the limits of the data captured by PCOR-ANZ. Conclusions: The 12 endorsed quality measures enable international benchmarking on the quality of care of men with localised PCa. Reporting on these indicators enhances safety and efficacy of treatment, reduces variation in care, and can improve patient outcomes. Patient summary: PCa has the highest incidence of all cancers in men. Early diagnosis and relatively high survival rates mean issues of quality of care and best possible health outcomes for patients are important. This paper identifies 12 important measurable quality indicators

© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd Objective: To develop and externally validate a predictive model for detection of significant prostate cancer. Patients and Methods: Development of the model was based on a prospective cohort including 393 men who underwent multiparametric magnetic resonance imaging (mpMRI) before biopsy. External validity of the model was then examined retrospectively in 198 men from a separate institution whom underwent mpMRI followed by biopsy for abnormal prostate-specific antigen (PSA) level or digital rectal examination (DRE). A model was developed with age, PSA level, DRE, prostate volume, previous biopsy, and Prostate Imaging Reporting and Data System (PIRADS) score, as predictors for significant prostate cancer (Gleason 7 with >5% grade 4, ≥20% cores positive or ≥7 mm of cancer in any core). Probability was studied via logistic regression. Discriminatory performance was quantified by concordance statistics and internally validated with bootstrap resampling. Results: In all, 393 men had complete data and 149 (37.9%) had significant prostate cancer. While the variable model had good accuracy in predicting significant prostate cancer, area under the curve (AUC) of 0.80, the advanced model (incorporating mpMRI) had a significantly higher AUC of 0.88 (P < 0.001). The model was well calibrated in internal and external validation. Decision analysis showed that use of the advanced model in practice would improve biopsy outcome predictions. Clinical application of the model would reduce 28% of biopsies, whilst missing 2.6% significant prostate cancer. Conclusions: Individualised risk assessment of significant prostate cancer using a predictive model that incorporates mpMRI PIRADS score and clinical data allows a considerable reduction in unnecessary biopsies and reduction of the risk of over-detection of insignificant prostate cancer at the cost of a very small increase in the number of

© 2016 Pim J. van Leeuwen et al. Introduction. To assess the performance of five previously described clinicopathological definitions of low-risk prostate cancer (PC). Materials and Methods. Men who underwent radical prostatectomy (RP) for clinical stage ≤T2, PSA <10 ng/mL, Gleason score <8 PC, diagnosed by transperineal template-guided saturation biopsy were included. The performance of five previously described criteria (i.e., criteria 1-5, criterion 1 stringent (Gleason score 6 + ≤5 mm total max core length PC + ≤3 mm max per core length PC) up to criterion 5 less stringent (Gleason score 6-7 with ≤5% Gleason grade 4) was analysed to assess ability of each to predict insignificant disease in RP specimens (defined as Gleason score ≤6 and total tumour volume <2.5 mL, or Gleason score 7 with ≤5% grade 4 and total tumour volume <0.7 mL). Results. 994 men who underwent RP were included. Criterion 4 (Gleason score 6) performed best with area under the curve of receiver operating characteristics 0.792. At decision curve analysis, criterion 4 was deemed clinically the best performing transperineal saturation biopsy-based definition for low-risk PC. Conclusions. Gleason score 6 disease demonstrated a superior trade-off between sensitivity and specificity for clarifying low-risk PC that can guide treatment and be used as reference test in diagnostic studies.

In applications involving large tissue specimens that have been sectioned into smaller tissue fragments, manual reconstruction of a "pseudo whole-mount" histological section (PWMHS) can facilitate (a) pathological disease annotation, and (b) image registration and correlation with radiological images. We have previously presented a program called HistoStitcher, which allows for more efficient manual reconstruction than general purpose image editing tools (such as Photoshop). However HistoStitcher is still manual and hence can be laborious and subjective, especially when doing large cohort studies. In this work we present AutoStitcher, a novel automated algorithm for reconstructing PWMHSs from digitized tissue fragments. AutoStitcher reconstructs ("stitches") a PWMHS from a set of 4 fragments by optimizing a novel cost function that is domain-inspired to ensure (i) alignment of similar tissue regions, and (ii) contiguity of the prostate boundary. The algorithm achieves computational efficiency by performing reconstruction in a multi-resolution hierarchy. Automated PWMHS reconstruction results (via AutoStitcher) were quantitatively and qualitatively compared to manual reconstructions obtained via HistoStitcher for 113 prostate pathology sections. Distances between corresponding fiducials placed on each of the automated and manual reconstruction results were between 2.7%-3.2%, reflecting their excellent visual similarity.

Objective. To compare the performance of multiparametric resonance imaging/ultrasound fusion targeted biopsy (MRI/US-TBx) to a combined biopsy strategy (MRI/US-TBx plus 24-core transperineal template saturation mapping biopsy (TTMB)). Methods. Between May 2012 and October 2015, all patients undergoing MRI/US-TBx at our institution were included for analysis. Patients underwent MRI/US-TBx of suspicious lesions detected on multiparametric MRI +/-simultaneous TTMB. Subgroup analysis was performed on patients undergoing simultaneous MRI/US-TBx + TTMB. Primary outcome was PCa detection. Significant PCa was defined as ≥Gleason score (GS) 3 + 4 = 7 PCa. McNemar's test was used to compare detection rates between MRI/US-TBx and the combined biopsy strategy. Results. 148 patients underwent MRI/US-TBx and 80 patients underwent MRI/US-TBx + TTMB. In the MRI/US-TBx versus combined biopsy strategy subgroup analysis (n = 80), there were 55 PCa and 38 significant PCa. The detection rate for the combined biopsy strategy versus MRI/US-TBx for significant PCa was 49% versus 40% (p = 0.02) and for insignificant PCa was 20% versus 10% (p = 0.04), respectively. Eleven cases (14%) of significant PCa were detected exclusively on MRI/US-TBx and 7 cases (8.7%) of significant PCa were detected exclusively on TTMB. Conclusions. A combined biopsy approach (MRI/US-TBx + TTMB) detects more significant PCa than MRI/US-TBx alone; however, it will double the detection rate of insignificant PCa.

© 2016 Lawson, Glenn, Salyakina, Clay, Delprado, Cheerala, Tran, Ngan, Miyauchi, Karim, Antonsson and Whitaker.Purpose: Women with human papilloma virus (HPV)-associated cervical neoplasia have a higher risk of developing breast cancer than the general female population. The purpose of this study was to (i) identify high-risk HPVs in cervical neoplasia and subsequent HPV positive breast cancers which developed in the same patients and (ii) determine if these HPVs were biologically active. Methods: A range of polymerase chain reaction and immunohistochemical techniques were used to conduct a retrospective cohort study of cervical precancers and subsequent breast cancers in the same patients. Results: The same high-risk HPV types were identified in both the cervical and breast specimens in 13 (46%) of 28 patients. HPV type 18 was the most prevalent. HPVs appeared to be biologically active as demonstrated by the expression of HPV E7 proteins and the presence of HPV-associated koilocytes. The average age of these patients diagnosed with breast cancer following prior cervical precancer was 51 years, as compared to 60 years for all women with breast cancer (p for difference = 0.001). Conclusion: These findings indicate that high-risk HPVs can be associated with cervical neoplasia and subsequent young age breast cancer. However, these associations are unusual and are a very small proportion of breast cancers. These outcomes confirm and extend the observations of two similar previous studies and offer one explanation for the increased prevalence of serious invasive breast cancer among young women.

PURPOSE: Human papillomaviruses (HPV) may have a role in some breast cancers. The purpose of this study is to fill important gaps in the evidence. These gaps are: (i) confirmation of the presence of high risk for cancer HPVs in breast cancers, (ii) evidence of HPV infections in benign breast tissues prior to the development of HPV-positive breast cancer in the same patients, (iii) evidence that HPVs are biologically active and not harmless passengers in breast cancer. METHODS: RNA-seq data from The Cancer Genome Atlas (TCGA) was used to identify HPV RNA sequences in breast cancers. We also conducted a retrospective cohort study based on polymerase chain reaction (PCR) analyses to identify HPVs in archival specimens from Australian women with benign breast biopsies who later developed breast cancer. To assess whether HPVs in breast cancer were biologically active, the expression of the oncogenic protein HPV E7 was assessed by immunohistochemistry (IHC). RESULTS: Thirty (3.5%) low-risk and 20 (2.3%) high-risk HPV types were identified in 855 breast cancers from the TCGA database. The high risk types were HPV 18 (48%), HPV 113 (24%), HPV 16 (10%), HPV 52 (10%). Data from the PCR cohort study indicated that HPV type 18 was the most common type identified in breast cancer specimens (55% of 40 breast cancer specimens) followed by HPV 16 (13%). The same HPV type was identified in both the benign and subsequent breast cancer in 15 patients. HPV E7 proteins were identified in 72% of benign breast specimens and 59% of invasive breast cancer specimens. CONCLUSION: There were four observations of particular interest: (i) confirmation by both NGS and PCR of the presence of high-risk HPV gene sequences in breast cancers, (ii) a correlation between high-risk HPV in benign breast specimens and subsequent HPV-positive breast cancer in the same patient, (iii) HPVs in breast cancer are likely to be biologically active (as shown by transcription of HPV DNA to RNA plus the expression of

BACKGROUND: Human papilloma viruses (HPVs) may act early in breast oncogenesis (“hit-and-run” phenomena). METHODS: The authors used immunohistochemistry for the identification of HPV E7 oncogenic protein expression in 32 sets of benign and subsequent breast cancer specimens from the same Australian patients. RESULTS: HPV E7 oncoprotein was clearly expressed in the nuclei of 23 (72%) of the 32 benign specimens and 20 (62.5%) of the subsequent 32 breast cancer specimens in the same patients. There was no HPV E7 protein expression in seven (30%) of the 23 breast cancer specimens that had prior HPV E7 protein-positive benign breast biopsies in the same patients. CONCLUSIONS: This observation suggests that HPV oncogenic influences occur early in some breast cancers. This finding confirms the previous observations. This early influence of HPVs may be the reason why there is no increase in the prevalence of HPV-associated breast cancer in immunocompromised patients as compared to HPV-associated cervical cancer.

Purpose Multiparametric magnetic resonance imaging appears to improve prostate cancer detection but prospective studies are lacking. We determined the accuracy of multiparametric magnetic resonance imaging for detecting significant prostate cancer before diagnostic biopsy in men with abnormal prostate specific antigen/digital rectal examination. Materials and Methods In this single center, prospective study men older than 40 years with abnormal prostate specific antigen/digital rectal examination and no previous multiparametric magnetic resonance imaging underwent T2-weighted, diffusion-weighted and dynamic contrast enhanced imaging without an endorectal coil. Imaging was allocated alternately to 1.5/3.0 Tesla. Imaging was double reported independently using PI-RADS (Prostate Imaging Reporting and Data System) by specialist radiologists. Transperineal grid directed 30-core biopsy was performed with additional magnetic resonance imaging directed cores for regions of interest outside template locations. Four significant cancer definitions were tested. Chi-square and logistic regression analysis was done. Men undergoing prostatectomy were analyzed. Results Of the 165 men who enrolled in the study 150 were analyzed. Median age was 62.4 years, median prostate specific antigen was 5.6 ng/ml, 29% of patients had an abnormal digital rectal examination and 88% underwent initial biopsy. Multiparametric magnetic resonance imaging was positive (PI-RADS 3 to 5) in 66% of patients, 61% had prostate cancer and 30% to 41% had significant prostate cancer (definitions 1 to 4). For significant cancer sensitivity was 93% to 96%, specificity was 47% to 53%, and negative and positive predictive values were 92% to 96% and 43% to 57%, respectively (definitions 1 to 4). Radical prostatectomy results in 48 men were similar. Aggregate PI-RADS (4 to 20) performed similarly to overall PI-RADS (1 to 5). Negative and positive predictive values (100% and 71%, respectively) were similar in men at h

BACKGROUND: There is increasing evidence that high-risk human papilloma virus (HPV) is involved in cancers in addition to cervical cancer. For example, it is generally accepted that HPV has a role in a significant proportion of head and neck tumours, and it has long been hypothesised that hormone dependent oncogenic viruses, such as HPV may have causal roles in some human breast cancers. A number of reports have identified HPV DNA in breast tissue and breast cancer specimens, but these rely on standard polymerase chain reaction (PCR), which is criticised for its propensity for contamination. METHODS: We have used two different technologies, in situ and standard PCR (with sequencing), and histology based on light microscopy. RESULTS: We unambiguously demonstrate the presence of high-risk HPV in the cells of breast cancer specimens and breast cancer cell lines. In addition, we also show that the oncogenic characteristics of HPV associated breast cancer are very similar to HPV-associated cervical cancer. Specifically, that putative koilocytes are present in some HPV associated breast cancers. INTERPRETATION: The above observations indicate a likely causal role for high-risk HPV in human breast cancer and offer the possibility of primary prevention of some breast cancers by vaccination against HPV.