Impact of operator expertise on transperineal free-hand mpMRI-fusion-targeted biopsies under local anaesthesia for prostate cancer diagnosis: a multicenter prospective learning curve.

PURPOSE: Transperineal mpMRI-targeted fusion prostate biopsies (TPFBx) are recommended for prostate cancer diagnosis, but little is known about their learning curve (LC), especially when performed under local anaesthesia (LA). We investigated how operators' and institutions' experience might affect biopsy results. METHODS: Baseline, procedure and pathology data of consecutive TPFBx under LA were prospectively collected at two academic Institutions, from Sep 2016 to May 2019. Main inclusion criterion was a positive MRI. Endpoints were biopsy duration, clinically significant prostate cancer detection rate on targeted cores (csCDR-T), complications, pain and urinary function. Data were analysed per-centre and per-operator (with ≥ 50 procedures), comparing groups of consecutive patient, and subsequently through regression and CUSUM analyses. Learning curves were plotted using an adjusted lowess smoothing function. RESULTS: We included 1014 patients, with 27.3% csCDR-T and a median duration was 15 min (IQR 12-18). A LC for biopsy duration was detected, with the steeper phase ending after around 50 procedures, in most operators. No reproducible evidence in favour of an impact of experience on csPCa detection was found at operator's level, whilst a possible gentle LC of limited clinical relevance emerged at Institutional level; complications, pain and IPSS variations were not related to operator experience. CONCLUSION: The implementation of TPFBx under LA was feasible, safe and efficient since early phases with a relatively short learning curve for procedure time.

Transperineal freehand multiparametric MRI fusion targeted biopsies under local anaesthesia for prostate cancer diagnosis: a multicentre prospective study of 1014 cases.

OBJECTIVE: To assess the outcomes of multiparametric magnetic resonance imaging (mpMRI) transperineal targeted fusion biopsy (TPFBx) under local anaesthesia. PATIENTS AND METHODS: We prospectively screened 1327 patients with a positive mpMRI undergoing TPFBx (targeted cores and systematic cores) under local anaesthesia, at two tertiary referral institutions, between September 2016 and May 2019, for inclusion in the present study. Primary outcomes were detection of clinically significant prostate cancer (csPCa) defined as (1) International Society of Urological Pathologists (ISUP) grade >1 or ISUP grade 1 with >50% involvement of prostate cancer (PCa) in a single core or in >2 cores (D1) and (2) ISUP grade >1 PCa (D2). Secondary outcomes were: assessment of peri-procedural pain (numerical rating scale [NRS]) and procedure timings; erectile (International Index of Erectile Function) and urinary (International Prostate Symptom Score) function changes; and complications. We also investigated the value of systematic sampling and concordance with radical prostatectomy (RP). RESULTS: A total of 1014 patients were included, of whom csPCa was diagnosed in 39.4% (n = 400). The procedure was tolerable (NRS pain score 3.1 ± 2.3), with no impact on erectile (P = 0.45) or urinary (P = 0.58) function, and a low rate of complications (Clavien-Dindo grades 1 or 2, n = 8; grade >2, n = 0). No post-biopsy sepsis was recorded. Twenty-two men (95% confidence interval [CI] 17-29) needed to undergo additional systematic biopsy to diagnose one csPCa missed by targeted biopsies (D1). ISUP grade concordance of biopsies with RP was as follows: k = 0.40 (95% CI 0.31-0.49) for targeted cores alone and k = 0.65 (95% CI 0.57-0.72; P < 0.05) overall. CONCLUSIONS: The use of TPFBx under local anaesthesia yielded good csPCa detection and was feasible, quick, well tolerated and safe. Infectious risk was negligible. Addition of systematic to targeted cores may not be needed in all men, although it improves csPCa detection and concordance with RP.

Pain in Men Undergoing Transperineal Free-Hand Multiparametric Magnetic Resonance Imaging Fusion Targeted Biopsies under Local Anesthesia: Outcomes and Predictors from a Multicenter Study of 1,008 Patients.

PURPOSE: Several transperineal biopsy series have proven feasibility under local anesthesia. However, there is a lack of large analyses detailing pain outcomes and factors influencing pain. MATERIALS AND METHODS: From 2016 to 2019 we performed a multicenter prospective study in men undergoing multiparametric magnetic resonance imaging-transperineal fusion biopsies (target+systematic cores) under local anesthesia. Primary outcomes were 1) pain scores (assessed through a 0 to 10-point numeric rating scale) and 2) identification of factors associated with severe pain. The secondary outcome was to evaluate pain influence on clinically significant prostate cancer target cores detection. RESULTS: We included 1,008 men undergoing transperineal fusion biopsies under local anesthesia. Mean±SD numeric rating scale pain scores were 3.9±2.1 at local anesthesia administration and 3.1±2.3 when performing biopsies. Pain was not associated with lower clinically significant prostate cancer detection on targeted cores (p=0.23 and p=0.47 depending on clinically significant prostate cancer definition). On multivariate analysis age (OR 0.96, 95% CI 0.94-0.99) and severe anxiety (OR 2.99, 95% CI 1.83-4.89) were a protective and risk factor, respectively, for severe biopsy pain. Procedural time was also associated with an increased risk of experiencing severe biopsy pain (OR 1.04, 95% CI 1.00-1.08). If aiming to test the possible effects of anxiety preventive measures on pain, an anxiety cutoff greater than 6 on a numeric rating scale would decrease to 13% the number of patients being treated while identifying 56% of those experiencing severe pain. CONCLUSIONS: Transperineal fusion biopsies under local anesthesia result in moderate pain. Pain does not influence clinically significant prostate cancer target detection. Patient anxiety predicts pain. A numeric rating scale based anxiety assessment may be used to identify those at higher risk for experiencing severe pain in men undergoing transperineal fusion biopsies.

Clinico-radiological characteristic-based machine learning in reducing unnecessary prostate biopsies of PI-RADS 3 lesions with dual validation.

OBJECTIVE: To evaluate machine learning-based classifiers in detecting clinically significant prostate cancer (PCa) with Prostate Imaging Reporting and Data System (PI-RADS) score 3 lesions. METHODS: We retrospectively enrolled 346 patients with PI-RADS 3 lesions at two institutions. All patients underwent prostate multiparameter MRI (mpMRI) and transperineal MRI-ultrasonography (MRI-US)-targeted biopsy. We collected data on age, pre-biopsy serum prostate-specific antigen (PSA) level, prostate volume (PV), PSA density (PSAD), the location of suspicious PI-RADS 3 lesions, and histopathology results. Four machine learning-based classifiers-logistic regression, support vector machine, eXtreme Gradient Boosting (XGBoost), and random forest-were trained using datasets from Nanjing Drum Tower Hospital. External validation was carried out using datasets from Molinette Hospital. RESULTS: Among 287 PI-RADS 3 patients, prostate cancer was proven pathologically in 59 (20.6%), and 228 (79.4%) had benign lesions. For 380 PI-RADS 3 lesions, 81 (21.3%) were proven to be PCa and 299 (78.7%) benign. Among four classifiers, the random forest classifier had the best performance in both patient-based and lesion-based datasets, with overall accuracy of 0.713 and 0.860, sensitivity of 0.857 and 0.613, and area under curve (AUC) of 0.771 and 0.832, respectively. In external validation, our best classifiers had an AUC of 0.688 with the best sensitivity (0.870) and specificity (0.500) in the 59 PI-RADS 3 patients in Molinette Hospital dataset. CONCLUSIONS: The machine learning-based random forest classifier provided a reliable probability if a PI-RADS 3 patient was benign. KEY POINTS: • Machine learning-based classifiers could combine the clinical characteristics with accessible information on image report of PI-RADS 3 patient to generate a probability of malignancy. • This probability could assist surgeons to make diagnostic decisions with more confidence and higher efficiency.

Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism.

Recent investigations into heterochronic parabiosis have unveiled robust rejuvenating effects of young blood on aged tissues. However, the specific rejuvenating mechanisms remain incompletely elucidated. Here we demonstrate that small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels. Intravenous injection of young sEVs into aged mice extends their lifespan, mitigates senescent phenotypes and ameliorates age-associated functional declines in multiple tissues. Quantitative proteomic analyses identified substantial alterations in the proteomes of aged tissues after young sEV treatment, and these changes are closely associated with metabolic processes. Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their miRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.

Machine Learning-Based Prediction of Pathological Upgrade From Combined Transperineal Systematic and MRI-Targeted Prostate Biopsy to Final Pathology: A Multicenter Retrospective Study.

Objective: This study aimed to evaluate the pathological concordance from combined systematic and MRI-targeted prostate biopsy to final pathology and to verify the effectiveness of a machine learning-based model with targeted biopsy (TB) features in predicting pathological upgrade. Materials and Methods: All patients in this study underwent prostate multiparametric MRI (mpMRI), transperineal systematic plus transperineal targeted prostate biopsy under local anesthesia, and robot-assisted laparoscopic radical prostatectomy (RARP) for prostate cancer (PCa) sequentially from October 2016 to February 2020 in two referral centers. For cores with cancer, grade group (GG) and Gleason score were determined by using the 2014 International Society of Urological Pathology (ISUP) guidelines. Four supervised machine learning methods were employed, including two base classifiers and two ensemble learning-based classifiers. In all classifiers, the training set was 395 of 565 (70%) patients, and the test set was the remaining 170 patients. The prediction performance of each model was evaluated by area under the receiver operating characteristic curve (AUC). The Gini index was used to evaluate the importance of all features and to figure out the most contributed features. A nomogram was established to visually predict the risk of upgrading. Predicted probability was a prevalence rate calculated by a proposed nomogram. Results: A total of 515 patients were included in our cohort. The combined biopsy had a better concordance of postoperative histopathology than a systematic biopsy (SB) only (48.15% vs. 40.19%, p = 0.012). The combined biopsy could significantly reduce the upgrading rate of postoperative pathology, in comparison to SB only (23.30% vs. 39.61%, p < 0.0001) or TB only (23.30% vs. 40.19%, p < 0.0001). The most common pathological upgrade occurred in ISUP GG1 and GG2, accounting for 53.28% and 20.42%, respectively. All machine learning methods had satisfactory predictive efficacy. The overall accuracy was 0.703, 0.768, 0.794, and 0.761 for logistic regression, random forest, eXtreme Gradient Boosting, and support vector machine, respectively. TB-related features were among the most contributed features of a prediction model for upgrade prediction. Conclusion: The combined effect of SB plus TB led to a better pathological concordance rate and less upgrading from biopsy to RP. Machine learning models with features of TB to predict PCa GG upgrading have a satisfactory predictive efficacy.

Cancer-associated fibroblasts promote the stemness and progression of renal cell carcinoma via exosomal miR-181d-5p.

The mechanisms underlying the effects of cancer-associated fibroblasts (CAFs) on cancer stemness and tumor progression in renal cell carcinoma (RCC) have not been elucidated yet. In the present study, we found that the enrichment of CAFs was positively associated with tumor progression and cancer stemness in RCC. Further investigation revealed that CAFs could enhance cancer stemness through delivering exosomes to RCC cells, and miR-181d-5p was identified as the critical exosomal miRNA in CAF-secreted exosomes by small RNA sequencing and subsequent screening assays. Mechanistically, exosomal miR-181d-5p transferred from CAFs to RCC cells directly suppressed the expression of ring finger protein 43 (RNF43) and activated Wnt/ß-catenin signaling pathway, thus promoted cancer stemness and tumor progression. Overexpression of RNF43 strongly suppressed stemness properties and the effects could be reverted by miR-181d-5p. Overall, our findings revealed a crucial mechanism by which CAF-secreted exosomal miRNAs to enhance cancer stemness and thus promote RCC progression, suggesting a new avenue based on CAF-secreted miRNAs for more effective targeted therapies.

Local anesthesia for percutaneous US/CT-guided bipolar radiofrequency ablation of small renal masses: A safe and feasible alternative.

PURPOSE: This study is to evaluate the safety and feasibility of local anesthesia (LA) for percutaneous ultrasound/computed tomography (US/CT)-guided bipolar radiofrequency ablation (RFA) for small renal masses (SRMs) by comparing the LA with general anesthesia. MATERIALS AND METHODS: A retrospective review was carried out between January 2018 to June 2020, 102 patients with SRMs were treated with US/CT-guided bipolar RFA. General anesthesia (GA) was performed in 42 and LA was performed in 60 patients. Demographics, tumor characteristics, peri-procedural data, pathologic and follow-up outcomes were analyzed. The factors associated with pain were also identified. RESULTS: There was no significant difference in demographics and tumor characteristics between the LA and GA group. A statistically significant difference was observed in terms of procedural time (P = 0.010) and hospital stays (P < 0.001). The maximum perceived pain in LA group comprised 60.0% (36 of 60) mild, 40.0% (24 of 60) moderate. The anxiety in LA group comprised 65.0% (39 of 60) mild, 33.3% (20 of 60) moderate, 1.7% (1 of 60) severe. On multivariate analysis, tumor diameter was a significant predictor for pain in RFA procedure (OR 1.560, 95% CI 1.233-1.974, P < 0.001). All patients were followed up for a median (range) of 12 (2-24) months. Local recurrence occurred in 8.3% (5 of 60) of the LA group and in 7.1% (3 of 42) in GA group (P = 1.000). CONCLUSION: Percutaneous bipolar RFA of SRMs using CT and ultrasound guidance under LA can be an effective and tolerable method for patients who are unfit for surgery and provide satisfactory oncologic control.

Phenylenediamine-Based Carbon Nanodots Alleviate Acute Kidney Injury via Preferential Renal Accumulation and Antioxidant Capacity.

As a reactive oxygen species (ROS)-promoted disease, acute kidney injury (AKI) is associated with high mortality and morbidity, but no effective pharmacological treatment is available. Kidney-targeted and ROS-reactive antioxidants are in urgent demand for AKI treatment. A promising nanotechnology-based strategy for targeting renal tubules offers new perspectives for AKI treatment but remains challenging because of the glomerular filtration barrier, which requires ultrasmall-sized therapeutics for penetration and filtration. Here, we fabricated four potential antioxidative carbon nanodots (CNDs) with ultrasmall size. After balancing the antioxidant properties and biocompatibility, m-phenylenediamine-based CNDs (PDA-CNDs) were chosen for further research. PDA-CNDs demonstrated remarkable antioxidant properties for scavenging multiple toxic free radicals, enabling efficient protection of cells under various oxidative stresses in vitro. Moreover, fluorescence imaging revealed that PDA-CNDs preferentially accumulated in the injured kidney of mice with ischemia-reperfusion (IR)-induced AKI. Blood renal function tests and kidney tissue staining revealed the therapeutic efficacy of PDA-CNDs for AKI in both the murine IR-induced AKI model and cisplatin-induced AKI model. Collectively, this is the first study revealing that specific rationally designed CNDs could be a promising pharmacological treatment for AKI induced by ROS.

Systematic gene microarray analysis of the lncRNA expression profiles in human uterine cervix carcinoma.

The human uterine cervix carcinoma is one of the most well-known malignancy reproductive system cancers, which threatens women health globally. However, the mechanisms of the oncogenesis and development process of cervix carcinoma are not yet fully understood. Long non-coding RNAs (lncRNAs) have been proved to play key roles in various biological processes, especially development of cancer. The function and mechanism of lncRNAs on cervix carcinoma is still rarely reported. We selected 3 cervix cancer and normal cervix tissues separately, then performed lncRNA microarray to detect the differentially expressed lncRNAs. Subsequently, we explored the potential function of these dysregulated lncRNAs through online bioinformatics databases. Finally, quantity real-time PCR was carried out to confirm the expression levels of these dysregulated lncRNAs in cervix cancer and normal tissues. We uncovered the profiles of differentially expressed lncRNAs between normal and cervix carcinoma tissues by using the microarray techniques, and found 1622 upregulated and 3026 downregulated lncRNAs (fold-change>2.0) in cervix carcinoma compared to the normal cervical tissue. Furthermore, we found HOXA11-AS might participate in cervix carcinogenesis by regulating HOXA11, which is involved in regulating biological processes of cervix cancer. This study afforded expression profiles of lncRNAs between cervix carcinoma tissue and normal cervical tissue, which could provide database for further research about the function and mechanism of key-lncRNAs in cervix carcinoma, and might be helpful to explore potential diagnosis factors and therapeutic targets for cervix carcinoma.