Development and External Validation of a Novel Nomogram to Predict the Probability of Pelvic Lymph-node Metastases in Prostate Cancer Patients Using Magnetic Resonance Imaging and Molecular Imaging with Prostate-specific Membrane Antigen Positron Emission Tomography.

BACKGROUND: Preoperative assessment of the probability of pelvic lymph-node metastatic disease (pN1) is required to identify patients with prostate cancer (PCa) who are candidates for extended pelvic lymph-node dissection (ePLND). OBJECTIVE: To develop a novel intuitive prognostic nomogram for predicting pathological lymph-node (pN) status in contemporary patients with primary diagnosed localized PCa, using preoperative clinical and histopathological parameters, magnetic resonance imaging (MRI), and prostate-specific membrane antigen (PSMA) positron emission tomography (PET). DESIGN, SETTING, AND PARTICIPANTS: In total, 700 eligible patients who underwent robot-assisted radical prostatectomy and ePLND were included in the model-building cohort. The external validation cohort consisted of 305 surgically treated patients. Logistic regression with backward elimination was used to select variables for the Amsterdam-Brisbane-Sydney nomogram. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Performance of the final model was evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision-curve analyses. Models were subsequently validated in an external population. RESULTS AND LIMITATIONS: The Amsterdam-Brisbane-Sydney nomogram included initial prostate-specific antigen value, MRI T stage, highest biopsy grade group (GG), biopsy technique, percentage of systematic cores with clinically significant PCa (GG ≥2), and lymph-node status on PSMA-PET. The AUC for predicting pN status was 0.81 (95% confidence interval [CI] 0.78-0.85) for the final model. On external validation, the Amsterdam-Brisbane-Sydney nomogram showed superior discriminative ability to the Briganti-2017 and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms (AUC 0.75 [95% CI 0.69-0.81] vs 0.67 [95% CI 0.61-0.74] and 0.65 [95% CI 0.58-0.72], respectively; p < 0.05), and similar discriminative ability to the Briganti-2019 nomogram (AUC 0.78 [95% CI 0.71-0.86] vs 0.80 [95% CI 0.73-0.86]; p = 0.76). The Amsterdam-Brisbane-Sydney nomogram showed excellent calibration on external validation, with an increased net benefit at a threshold probability of ≥4%. CONCLUSIONS: The validated Amsterdam-Brisbane-Sydney nomogram performs superior to the Briganti-2017 and MSKCC nomograms, and similar to the Briganti-2019 nomogram. Furthermore, it is applicable in all patients with newly diagnosed unfavorable intermediate- and high-risk PCa. PATIENT SUMMARY: We developed and validated the Amsterdam-Brisbane-Sydney nomogram for the prediction of prostate cancer spread to lymph nodes before surgery. This nomogram performs similar or superior to all presently available nomograms.

The relationship between biochemical recurrence and number of lymph nodes removed during surgery for localized prostate cancer.

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%).

Sri Lankan Sloth Bear (Melursus ursinus inornatus) Attacks on Humans.

The sloth bear (Melursus ursinus) is an omnivore that has been reported around most parts of South Asia. Although rare, sloth bear attacks can inflict potentially life-threatening injuries. This cross-sectional study analyzed 10 patients who had been mauled by sloth bears and who presented to rural hospitals in the Anuradhapura district of Sri Lanka between 2015 and 2019. All of the patients were male farmers. The human-bear encounters occurred in the jungle during the daytime. Ten victims sustained multiple soft tissue and bone injuries, mainly to the face and arms. The injuries ranged from minor abrasions to extensive deep lacerations and bone fractures. All of the patients were managed in the tertiary care hospital by multidisciplinary surgical teams. Sloth bear-inflicted wounds must be treated as major trauma. There is a need to formulate guidelines and train medical officers in managing animal-inflicted injuries in Sri Lanka.

Prevalence and sequelae of penile lichen sclerosus in males presenting for circumcision in regional Australia: a multicentre retrospective cohort study.

Background: Lichen sclerosus (LS) in men commonly involves the external genitalia, with up to 20% of these patients developing urethral stricture disease, and a small group developing malignant transformation to penile squamous cell carcinoma (SCC). The objective of this study was to determine the prevalence of LS and its sequelae in males presenting for circumcision. Methods: A multicentre retrospective cohort study was conducted at 8 hospitals within 3 Australian regional centres. We identified males who underwent circumcision between January 2004 and November 2018 and obtained histological and clinical data. Histopathological confirmation of LS was the primary outcome. Development of urethral stricture disease and penile cancer were secondary outcomes. Results: Six hundred and eleven patients underwent circumcision, of which 313 (51.2%) had a specimen sent for histology. Of these, 199 (63.6%) had confirmed LS where the median age at diagnosis was 65 years [interquartile range (IQR), 40-77]. Even if the remainder of unsent specimens were free of LS, the prevalence would still be 32.6%. Amongst the patients with LS, 44 (22.1%) developed urethral strictures, 1 penile SCC (0.5%), and 1 penile intraepithelial neoplasia (0.5%). Conclusions: The prevalence of LS in patients undergoing circumcision where the foreskin was sent for histopathological review was 63.6%. In those with LS, the prevalence of urethral stricture disease was 22.1%.

Robot-Assisted Prostate-Specific Membrane Antigen-Radioguided Surgery in Primary Diagnosed Prostate Cancer.

The objective of this study was to evaluate the safety and feasibility of 99mTc-based prostate-specific membrane antigen (PSMA) robot-assisted-radioguided surgery to aid or improve the intraoperative detection of lymph node metastases during primary robot-assisted radical prostatectomy (RARP) for prostate cancer (PCa). Methods: Men with primary high-risk PCa (≥ cT3a, International Society of Urological Pathology (ISUP) grade group ≥ 3 or prostate-specific antigen of ≥ 15 ng/mL) with potential lymph node metastasis (Briganti nomogram risk > 10% or on preoperative imaging) were enrolled in the study. Patients underwent staging 68Ga-PSMA PET/CT scanning. Preoperatively, a 99mTc-labeled PSMA ligand (99mTc PSMA I&S; 500 MBq) was administered followed by SPECT/CT. A RARP including extended pelvic lymph node dissection was performed, with intraoperative tracing of PSMA-avid tissues using a prototype DROP-IN γ-probe. Resected specimens were also measured ex vivo. Histopathologic concordance with probe findings was evaluated. A radiotracer count of ≥ 1.5 times the background reference (in vivo), and ≥ 10 (absolute count) in the ex vivo setting, was considered positive. Results: Twelve patients were included (median age, 68 y, and prostate-specific antigen, 9.15 ng/mL). Most of the patients harbored ISUP 5 PCa (75%) and had avid lymph nodes on preoperative PSMA PET (64%). The DROP-IN probe aided resection of PSMA-avid (out-of-template) lymph nodes and residual disease at the prostate bed. Eleven metastatic lymph nodes were identified by the probe that were not observed on preoperative 68Ga-PSMA PET/CT. Of the 74 extraprostatic tissue specimens that were resected, 22 (29.7%) contained PCa. The sensitivity, specificity, positive predictive value, and negative predictive value of inpatient use of the γ-probe were 76% (95% CI, 53%-92%), 69% (95% CI, 55%-81%), 50%, and 88%, respectively. Ex vivo, the diagnostic accuracy was superior: 76% (95% CI, 53%-92%), 96% (95% CI, 87%-99%), 89%, and 91%, respectively, for sensitivity, specificity, positive predictive value, and negative predictive value. Of the missed lymph nodes in vivo (n = 5) and ex vivo (n = 5), 90% were micrometastasis (≤3 mm). No complications greater than Clavien-Dindo Grade I occurred. Conclusion: Robot-assisted 99mTc-based PSMA-radioguided surgery is feasible and safe in the primary setting, optimizing the detection of nodal metastases at the time of RARP and extended pelvic lymph node dissection. Further improvement of the detector technology may optimize the capabilities of robot-assisted 99mTc-based PSMA-radioguided surgery.

External Validation and Addition of Prostate-specific Membrane Antigen Positron Emission Tomography to the Most Frequently Used Nomograms for the Prediction of Pelvic Lymph-node Metastases: an International Multicenter Study.

BACKGROUND: Different nomograms exist for the preoperative prediction of pelvic lymph-node metastatic disease in individual patients with prostate cancer (PCa). These nomograms do not incorporate modern imaging techniques such as prostate-specific membrane antigen (PSMA) positron emission tomography (PET). OBJECTIVE: To determine the predictive performance of the Briganti 2017, Memorial Sloan Kettering Cancer Center (MSKCC), and Briganti 2019 nomograms with the addition of PSMA-PET in an international, multicenter, present-day cohort of patients undergoing robot-assisted radical prostatectomy (RARP) and extended pelvic lymph-node dissection (ePLND) for localized PCa. DESIGN, SETTING, AND PARTICIPANTS: All 757 eligible patients who underwent a PSMA-PET prior to RARP and ePLND in three reference centers for PCa surgery between January 2016 and November 2020 were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Performance of the three nomograms was assessed using the receiver operating characteristic curve-derived area under the curve (AUC), calibration plots, and decision curve analyses. Subsequently, recalibration and addition of PSMA-PET to the nomograms were performed. RESULTS AND LIMITATIONS: Overall, 186/757 patients (25%) had pelvic lymph-node metastatic (pN1) disease on histopathological examination. AUCs of the Briganti 2017, MSKCC, and Briganti 2019 nomograms were 0.70 (95% confidence interval [95% CI]: 0.64-0.77), 0.71 (95% CI: 0.65-0.77), and 0.76 (95% CI: 0.71-0.82), respectively. PSMA-PET findings showed a significant association with pN1 disease when added to the nomograms (p < 0.001). Addition of PSMA-PET substantially improved the discriminative ability of the models yielding cross-validated AUCs of 0.76 (95% CI: 0.70-0.82), 0.77 (95% CI: 0.72-0.83), and 0.82 (95% CI: 0.76-0.87), respectively. In decision curve analyses, the addition of PSMA-PET to the three nomograms resulted in increased net benefits. CONCLUSIONS: The addition of PSMA-PET to the previously developed nomograms showed substantially improved predictive performance, which suggests that PSMA-PET is a likely future candidate for a modern predictive nomogram. PATIENT SUMMARY: Different tools have been developed to individualize the prediction of prostate cancer spread to lymph nodes before surgery. We found that the inclusion of modern imaging (prostate-specific membrane antigen positron emission tomography) improved substantially the overall performance of these prediction tools.

Sarcomatoid urothelial carcinoma of the ureter with heterologous elements of chondrosarcoma and osteosarcoma, and concurrent divergent squamous differentiation: A rare case report.

Primary sarcomatoid urothelial carcinoma of the ureter with heterologous elements is rare and carries a poor prognosis. Although there is some literature on primary bladder sarcomatoid urothelial carcinoma, ureteric involvement has been reported infrequently, and this case report describes this unusual histological finding with concurrent divergent squamous differentiation. Despite laparoscopic radical nephroureterectomy, our patient died within six months of diagnosis with local recurrence and metastatic spread. A more thorough understanding of this disease process and consideration of standardised guidelines for treatment are needed to improve patient outcomes.

Diagnostic accuracy of 68 Ga-prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) and multiparametric (mp)MRI to detect intermediate-grade intra-prostatic prostate cancer using whole-mount pathology: impact of the addition of 68 Ga-PSMA PET to mpMRI.

OBJECTIVE: To evaluate the ability of prostate-specific membrane antigen (PSMA)-positron-emission tomography (PET)/computed tomography (CT) to detect intermediate-grade intra-prostatic prostate cancer (PCa), and to determine if PSMA-PET improves the diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: A total of 56 consecutive patients with International Society of Urological Pathology (ISUP) grade 2-3 PCa after radical prostatectomy, who underwent both mpMRI and PSMA-PET CT (hereafter PSMA-PET) preoperatively, were enrolled in this study. The accuracy of PSMA-PET, mpMRI alone, and the two procedures in combination was analysed for identifying ISUP grades 1-3 within a 12-segment model. The accuracy of a combined predictive model (PSMA-PET and mpMRI) was determined. Receiver-operating characteristic curve analysis to determine the optimal standardized uptake value (SUVmax ) for PSMA-PET in discriminating between ISUP grades 1 and ≥2 was performed. RESULTS: On a per-patient basis, the sensitivities for PSMA-PET and mpMRI in identifying ISUP grades 2-3 PCa were 100% and 97%, respectively. Assessing ISUP grade ≥2 PCa using a 12-segment analysis, PSMA-PET demonstrated greater diagnostic accuracy (area under the curve), sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV), with values of 0.91, 88%, 93%, 95% and 85%, respectively, than did mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] 3-5), at 0.79, 68%, 91%, 87%, and 75%, respectively. When used in combination (PSMA-PET and mpMRI PIRADS 4-5), sensitivity, specificity, NPV and PPV were 92%, 90%, 96% and 81%, respectively. The sensitivity for both techniques reduced markedly when assessing ISUP grade 1 PCa (18% for PSMA-PET, 10% for mpMRI). An SUVmax value of 3.95 resulted in 94% sensitivity and 100% specificity. CONCLUSION: PSMA-PET is accurate in detecting segments containing intermediate-grade intra-prostatic PCa (ISUP grade ≥ 2), compared with and complementary to mpMRI. By contrast the detection rate for ISUP grade 1 disease for both PSMA-PET and mpMRI was low.

Preliminary Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging to Detect Residual Prostate Cancer Following Focal Therapy with Irreversible Electroporation.

BACKGROUND: It is recommended to perform multiparametric magnetic resonance imaging (mpMRI) in the follow-up following focal therapy of prostate cancer (PCa). OBJECTIVE: To determine the diagnostic accuracy of mpMRI to detect residual PCa following focal therapy with irreversible electroporation. DESIGN, SETTING, AND PARTICIPANTS: Seventy-six patients with biopsy-proven localized PCa consented for primary irreversible electroporation between February 2013 and March 2016. Final analysis was performed on 50 patients that received follow-up mpMRI at 6 mo, serial prostate-specific antigen (PSA) testing, and transperineal template-mapping biopsies at 12 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outfield regions of interest (ROI) were reported using PI-RADS version 2. A binary outcome (suspicious vs nonsuspicious) was given for the infield ablation zone. Sensitivity, specificity, positive predictive values, and negative predictive values were calculated for different definitions of significant PCa: (1) Gleason ≥4+3 or Gleason ≥3+3 with a maximum cancer core length ≥6mm, (2) Gleason ≥3+4 or Gleason ≥3+3 with a maximum cancer core length ≥4mm, for outfield and infield ROI. Multivariate linear regression analyses evaluated the additional value of nadir PSA. RESULTS AND LIMITATIONS: Sensitivity, specificity, positive predictive values, and negative predictive values of infield ROI was 43%, 86%, 33%, and 90% for definition 1 and 38%, 86%, 33%, and 88% for definition 2, respectively. For outfield ROI this was 33%, 82%, 20%, and 90% for definition 1 and 38%, 86%, 50%, and 80% for definition 2. PSA had no additional value in predicting residual significant PCa. Limitations include retrospective design, single reader, and low incidence of residual PCa. CONCLUSIONS: Our preliminary data suggest that mpMRI can rule out high-volume residual PCa. However, follow-up biopsies should still be performed to determine oncological control. PATIENT SUMMARY: Multiparametric magnetic resonance imaging is able to detect high-volume significant prostate cancer following focal therapy. Prostate biopsies are still required in the follow-up of focal therapy as (low-volume) significant prostate cancer is being missed by multiparametric magnetic resonance imaging.

Impact on genitourinary function and quality of life following focal irreversible electroporation of different prostate segments.

PURPOSE: We aimed to evaluate the genitourinary function and quality of life (QoL) following the ablation of different prostate segments with irreversible electroporation (IRE) for localized prostate cancer (PCa). METHODS: Sixty patients who received primary focal IRE for organ-confined PCa were recruited for this study. Patients were evaluated for genitourinary function and QoL per prostate segment treated (anterior vs. posterior, apex vs. base vs. apex-to-base, unilateral vs. bilateral). IRE system settings and patient characteristics were compared between patients with preserved vs. those with impaired erectile function and urinary continence. Data were prospectively collected at baseline, 3, 6, and 12 months using the expanded prostate cancer index composite, American Urological Association symptom score, SF-12 physical and mental component summary surveys. Difference over time within segments per questionnaire was evaluated using the Wilcoxon's signed rank test. Outcome differences between segments were assessed using covariance models. Baseline measurements included questionnaire scores, age, and prostate volume. RESULTS: There were no statistically significant changes over time for overall urinary (P = 0.07-0.89), bowel (P = 0.06-0.79), physical (P = 0.18-0.71) and mental (P = 0.45-0.94) QoL scores within each segment. Deterioration of sexual function scores was observed at 6 months within each segment (P = 0.001-0.16). There were no statistically significant differences in QoL scores between prostate segments (P = 0.08-0.97). Older patients or those with poor baseline sexual function at time of treatment were associated with a greater risk of developing erectile dysfunction. CONCLUSION: IRE is a feasible modality for all prostate segments without any significantly different effect on the QoL outcomes. Older patients and those with poor sexual function need to be counseled regarding the risk of erectile dysfunction.

Evidence for Regulation of Hemoglobin Metabolism and Intracellular Ionic Flux by the Plasmodium falciparum Chloroquine Resistance Transporter.

Plasmodium falciparum multidrug resistance constitutes a major obstacle to the global malaria elimination campaign. Specific mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) mediate resistance to the 4-aminoquinoline drug chloroquine and impact parasite susceptibility to several partner agents used in current artemisinin-based combination therapies, including amodiaquine. By examining gene-edited parasites, we report that the ability of the wide-spread Dd2 PfCRT isoform to mediate chloroquine and amodiaquine resistance is substantially reduced by the addition of the PfCRT L272F mutation, which arose under blasticidin selection. We also provide evidence that L272F confers a significant fitness cost to asexual blood stage parasites. Studies with amino acid-restricted media identify this mutant as a methionine auxotroph. Metabolomic analysis also reveals an accumulation of short, hemoglobin-derived peptides in the Dd2 + L272F and Dd2 isoforms, compared with parasites expressing wild-type PfCRT. Physiologic studies with the ionophores monensin and nigericin support an impact of PfCRT isoforms on Ca2+ release, with substantially reduced Ca2+ levels observed in Dd2 + L272F parasites. Our data reveal a central role for PfCRT in regulating hemoglobin catabolism, amino acid availability, and ionic balance in P. falciparum, in addition to its role in determining parasite susceptibility to heme-binding 4-aminoquinoline drugs.

Pair-matched patient-reported quality of life and early oncological control following focal irreversible electroporation versus robot-assisted radical prostatectomy.

PURPOSE: The design, conduct and completion of randomized trials for curative prostate cancer (PCa) treatments are challenging. To evaluate the effect of robot-assisted radical prostatectomy (RARP) versus focal irreversible electroporation (IRE) on patient-reported quality of life (QoL) and early oncological control using propensity-scored matching. METHODS: Patients with T1c-cT2b significant PCa (high-volume ISUP 1 or any 2/3) who received unifocal IRE were pair-matched to patients who received nerve-sparing RARP. Patient-reported outcomes were prospectively assessed using the Expanded Prostate Cancer Index Composite (EPIC), AUA symptom score and Short Form of Health Survey (SF-12) physical and mental components. Oncological failure was defined as biochemical recurrence (RARP) or positive follow-up biopsies (IRE). Generalized mixed-effect models were used to compare IRE and RARP. RESULTS: 50 IRE patients were matched to 50 RARP patients by propensity score. IRE was significantly superior to RARP in preserving pad-free continence (UC) and erections sufficient for intercourse (ESI). The absolute differences were 44, 21, 13, 14% for UC and 32, 46, 27, 22% for ESI at 1.5, 3, 6, and 12 months, respectively. The EPIC summary scores showed no statistically significant differences. Urinary symptoms were reduced for IRE and RARP patients at 12 months, although IRE patient initially had more complaints. IRE patients experienced more early oncological failure than RARP patients. CONCLUSIONS: These data demonstrated the superior preservation of UC and ESI with IRE compared to RARP up to 12 months after treatment. Long-term oncological data are warranted to provide ultimate proof for or against focal therapy.

Focal irreversible electroporation as primary treatment for localized prostate cancer.

OBJECTIVES: To determine the safety, quality of life (QoL) and short-term oncological outcomes of primary focal irreversible electroporation (IRE) for the treatment of localized prostate cancer (PCa), and to identify potential risk factors for oncological failure. PATIENTS AND METHODS: Patients who met the consensus guidelines on patient criteria and selection methods for primary focal therapy were eligible for analysis. Focal IRE was performed for organ-confined clinically significant PCa, defined as high-volume disease with Gleason sum score 6 (International Society of Urological Pathology [ISUP] grade 1) or any Gleason sum score of 7 (ISUP grades 2-3). Oncological, adverse event (AE) and QoL outcome data, with a minimum of 6 months' follow-up, were analysed. Patient characteristics and peri-operative treatment variables were compared between patients with and without oncological failure on follow-up biopsy. Wilcoxon's signed rank test, Wilcoxon's rank sum test and the chi-squared test were used to assess statistically significant differences in paired continuous, unpaired continuous and categorical variables respectively. RESULTS: A total of 63 patients met all eligibility criteria and were included in the final analysis. No high-grade AEs occurred. QoL questionnaire analysis demonstrated no significant change from baseline in physical (P = 0.81), mental (P = 0.48), bowel (P = 0.25) or urinary QoL domains (P = 0.41 and P = 0.25), but there was a mild decrease in the sexual QoL domain (median score 66 at baseline vs 54 at 6 months; P < 0.001). Compared with baseline, a decline of 70% in prostate-specific antigen level (1.8 ng/mL, interquartile range 0.96-4.8 ng/mL) was seen at 6-12 months. A narrow safety margin (P = 0.047) and system errors (P = 0.010) were identified as potential early risk factors for in-field oncological failure. In-field and whole-gland oncological control on follow-up biopsies was 84% (38/45 patients) and 76% (34/45 patients); this increased to 97% (38/39 patients) and 87% (34/39 patients) when patients treated with a narrow safety margin and system errors were excluded. CONCLUSION: Our data support the safety and feasibility of focal IRE as a primary treatment for localized PCa with effective short-term oncological control in carefully selected men.

Superior Biochemical Recurrence and Long-term Quality-of-life Outcomes Are Achievable with Robotic Radical Prostatectomy After a Long Learning Curve-Updated Analysis of a Prospective Single-surgeon Cohort of 2206 Consecutive Cases.

BACKGROUND: Our earlier analysis suggested that robot-assisted radical prostatectomy (RARP) achieved superiority over open radical prostatectomy (ORP) in terms of positive surgical margin (PSM) rates and functional outcomes. OBJECTIVE: With larger sample size and longer follow-up, the objective of this study update is to assess whether our previous findings are upheld and whether the improved PSM rates for RARP after an initial learning curve compared with ORP-as observed in our earlier analysis-ultimately resulted in improved biochemical control. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study comparing two surgical techniques; 2271 consecutive men underwent RARP (1520) or ORP (751) at a single centre from 2006 to 2016. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Demographic and clinicopathological data were prospectively collected. The EPIC-QOL questionnaire was administered at baseline and 1.5, 3, 6, 12, and 24 mo. Multivariate linear regression modelled the difference in quality of life (QOL) domains against case number; logistic and Cox regression modelled the differences in PSM and biochemical recurrence (BCR) hazard ratios (HR), respectively. RESULTS AND LIMITATIONS: A total of 2206 men were included in BCR/PSM analysis and 1045 consented for QOL analysis. Superior pT2 surgical margins, early and late sexual outcomes, and early urinary outcomes were upheld and became more robust (narrowing of 95% confidence intervals [CIs]). The risk of BCR was initially higher for RARP, improved after 191 RARPs, and was 35% lower (hazard ratio [HR] 0.65, 95% CI 0.47-0.90) at final RARP, plateauing after 226 RARPs. Improved late (12-24 mo) urinary bother scores (adjusted mean difference [AMD]=4.7, 95% CI 1.3-8.0) and irritative-obstructive scores (AMD=3.8, 95% CI 0.9-5.6) at final RARP were demonstrated. Limitations include observational single surgeon data, possible residual confounding, and short follow-up. CONCLUSIONS: The results from this updated analysis demonstrate that RARP can be beneficial for patients of high-volume surgeons, although more randomised studies and studies with survival outcomes are needed. PATIENT SUMMARY: Robot-assisted radical prostatectomy was able to improve functional and oncological outcomes in this single surgeon's learning curve.

Feasibility and safety of focal irreversible electroporation as salvage treatment for localized radio-recurrent prostate cancer.

OBJECTIVES: To evaluate the feasibility, safety, early quality-of-life (QoL) and oncological outcomes of salvage focal irreversible electroporation (IRE) for radio-recurrent prostate cancer (PCa). PATIENTS AND METHODS: Patients with localized, radio-recurrent PCa without evidence of metastatic or nodal disease were offered focal IRE according to the consensus guidelines. Patients with a minimum follow-up of 6 months were eligible for analysis. Adverse events were monitored using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Patient-reported QoL data were collected at baseline, 6 weeks, 3, 6 and 12 months using the Expanded Prostate Cancer Index Composite (EPIC), the American Urological Association (AUA) symptom score and the 12-item short-from health survey (SF-12) physical and mental component summary questionnaires. Oncological control was evaluated according to serial prostate-specific antigen (PSA), 6-month multiparametric magnetic resonance imaging (mpMRI) and 12-month prostate biopsy. Wilcoxon's signed rank test was used to assess QoL differences over time in paired continuous variables. RESULTS: A total of 18 patients were included in the analysis. The median follow-up was 21 months. No high-grade adverse events (CTCAE >2) or recto-urethral fistulae occurred. No statistically significant declines were observed in QoL outcomes (n = 11) on the EPIC bowel domain (P = 0.29), AUA symptom score (P = 0.77), or the SF-12 physical (P = 0.17) or SF-12 mental component summary (P = 0.77) questionnaires. At 6 months, patients who had undergone salvage therapy experienced a decline in EPIC sexual domain score (median of 38-24; P = 0.028) and urinary domain (median of 96-92; P = 0.074). Pad-free continence and erections sufficient for intercourse were preserved in 8/11 patients and 2/6 patients at 6 months, respectively. The mpMRI was clear in 11/13 patients, with two single out-field lesions (true-positive and false-positive, respectively). The median (interquartile range) nadir PSA was 0.39 (0.04-0.43) µg/L. Three and four patients experienced biochemical failure using the Phoenix and Stuttgart definitions of biochemical failure, respectively. Eight out of 10 of the patients were clear of any PCa on follow-up biopsy, whereas two patients had significant PCa on follow-up biopsy (International Society of Urological Pathology grade 5). CONCLUSION: Our short-term safety, QoL and oncological control data show that focal IRE is a feasible salvage option for localized radio-recurrent PCa. A prospective multicentre study (FIRE trial) has been initiated that will provide further insight into the ability of focal IRE to obtain oncological control of radio-recurrent PCa with acceptable patient morbidity.

Initial multicentre experience of 68 gallium-PSMA PET/CT guided robot-assisted salvage lymphadenectomy: acceptable safety profile but oncological benefit appears limited.

OBJECTIVES: To evaluate the safety and short-term oncological outcomes of 68 gallium-labelled prostate-specific membrane antigen (68 Ga-PSMA) positron-emission tomography (PET)/computed tomography (CT)-directed robot-assisted salvage node dissection (RASND) for prostate cancer oligometastatic nodal recurrence. MATERIALS AND METHODS: Between February 2014 and April 2016, 35 patients across two centres underwent RASND for 68 Ga-PSMA PET/CT-detected oligometastatic nodal recurrence. RASND was performed using targeted pelvic dissection, unilateral extended pelvic template or bilateral extended pelvic template dissection, depending on previous pelvic treatment and extent/location of nodal disease. Complications were reported using the Clavien-Dindo classification system. Definitions of prostate-specific antigen (PSA) treatment response to RASND were defined as 6-week PSA <0.2 ng/mL (broad definition) or PSA <0.05 ng/mL (strict definition) in those who had undergone primary prostatectomy, and 6-week PSA level < post-radiotherapy nadir in those who had undergone primary radiotherapy. Biochemical recurrence (BCR) after RASND was defined as a PSA >0.2 ng/mL or PSA > nadir, for those who had undergone primary prostatectomy and primary radiotherapy, respectively. Predictors of treatment response were analysed using univariate binary logistic regression. RESULTS: A total of 58 lesions suspicious for lymph node metastases (LNM) in 35 patients were detected on 68 Ga-PSMA imaging. A total of 32 patients (91%) had histopathologically proven LNM at RASND, with a total of 87 LNM and a median (interquartile range) of 2 (1-3) LNM per patient. In all, eight patients (23%) experienced complications, all Clavien-Dindo grade ≤2. Treatment response was seen in 15 (43%) and 11 patients (31%), using the broad and strict definitions, respectively. BCR-free survival and clinical recurrence-free survival at a median follow-up of 12 months were 23% and 66%, respectively, for the entire cohort. Bilateral template dissection was the only significant univariate predictor of treatment response in our cohort. CONCLUSIONS: Although RASND appears safe and feasible, less than half of our cohort had a treatment response, and less than a quarter experienced BCR-free survival at 12-month median follow-up. 68 Ga-PSMA imaging underestimates micro-metastatic disease, therefore RASND will rarely be curative. Strict patient selection and restricting RASND to clinical trials is recommended. Long-term follow-up from such trials is required to further assess potential quality of life and mortality benefits.

Evolution of Fitness Cost-Neutral Mutant PfCRT Conferring P. falciparum 4-Aminoquinoline Drug Resistance Is Accompanied by Altered Parasite Metabolism and Digestive Vacuole Physiology.

Southeast Asia is an epicenter of multidrug-resistant Plasmodium falciparum strains. Selective pressures on the subcontinent have recurrently produced several allelic variants of parasite drug resistance genes, including the P. falciparum chloroquine resistance transporter (pfcrt). Despite significant reductions in the deployment of the 4-aminoquinoline drug chloroquine (CQ), which selected for the mutant pfcrt alleles that halted CQ efficacy decades ago, the parasite pfcrt locus is continuously evolving. This is highlighted by the presence of a highly mutated allele, Cam734 pfcrt, which has acquired the singular ability to confer parasite CQ resistance without an associated fitness cost. Here, we used pfcrt-specific zinc-finger nucleases to genetically dissect this allele in the pathogenic setting of asexual blood-stage infection. Comparative analysis of drug resistance and growth profiles of recombinant parasites that express Cam734 or variants thereof, Dd2 (the most common Southeast Asian variant), or wild-type pfcrt, revealed previously unknown roles for PfCRT mutations in modulating parasite susceptibility to multiple antimalarial agents. These results were generated in the GC03 strain, used in multiple earlier pfcrt studies, and might differ in natural isolates harboring this allele. Results presented herein show that Cam734-mediated CQ resistance is dependent on the rare A144F mutation that has not been observed beyond Southeast Asia, and reveal distinct impacts of this and other Cam734-specific mutations on CQ resistance and parasite growth rates. Biochemical assays revealed a broad impact of mutant PfCRT isoforms on parasite metabolism, including nucleoside triphosphate levels, hemoglobin catabolism and disposition of heme, as well as digestive vacuole volume and pH. Results from our study provide new insights into the complex molecular basis and physiological impact of PfCRT-mediated antimalarial drug resistance, and inform ongoing efforts to characterize novel pfcrt alleles that can undermine the efficacy of first-line antimalarial drug regimens.

Predicting Low-Risk Prostate Cancer from Transperineal Saturation Biopsies.

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.

Leiomyoma in a Renal Allograft.

Leiomyomas are smooth muscle tumours that are rarely found in the kidney. There is one report of a leiomyoma in a kidney transplant in a paediatric recipient. Here, we report an adult renal transplant recipient who developed an Epstein-Barr virus-positive leiomyoma in his allograft 15 years after transplantation. The patient was converted to everolimus for posttransplant immunosuppression management and there was no sign of progression over a year.