Conformation-driven strategy for resilient and functional protein materials.

The exceptional elastic resilience of some protein materials underlies essential biomechanical functions with broad interest in biomedical fields. However, molecular design of elastic resilience is restricted to amino acid sequences of a handful of naturally occurring resilient proteins such as resilin and elastin. Here, we exploit non-resilin/elastin sequences that adopt kinetically stabilized, random coil-dominated conformations to achieve near-perfect resilience comparable with that of resilin and elastin. We also show a direct correlation between resilience and Raman-characterized protein conformations. Furthermore, we demonstrate that metastable conformation of proteins enables the construction of mechanically graded protein materials that exhibit spatially controlled conformations and resilience. These results offer insights into molecular mechanisms of protein elastomers and outline a general conformation-driven strategy for developing resilient and functional protein materials.

Off-clamp vs on-clamp robot-assisted partial nephrectomy: a systematic review and meta-analysis.

OBJECTIVE: To compare intra- and postoperative outcomes between off-clamp and on-clamp robot-assisted partial nephrectomy (RAPN), using data from randomised controlled trials (RCTs) or covariate-matched studies (propensity score-matched or matched-pair analysis). METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant literature review was conducted on PubMed, EMBASE, Scopus and CENTRAL for relevant studies comparing off-clamp to on-clamp RAPN. Primary outcomes were estimated blood loss, postoperative percentage decrease in estimated glomerular filtration rate (eGFR), and margin positive rate. Secondary outcomes were operative time, postoperative eGFR, length of stay, all postoperative complications, major complications, and need for transfusion. Random-effects meta-analyses were performed to generate mean differences (MDs) or odds ratios (ORs). RESULTS: A total of 10 studies (2307 patients) were shortlisted for analysis. There was no significant difference in estimated operative blood loss between off-clamp and on-clamp RAPN (MD 21.9 mL, 95% confidence interval [CI] -0.9 to 44.7 mL; P = 0.06, I2 = 58%). Off-clamp RAPN yielded a smaller postoperative eGFR deterioration (MD 3.10%, 95% CI 1.05-5.16%; P = 0.008, I2 = 13%) and lower odds of margin positivity (OR 0.62, 95% CI 0.40-0.94; P = 0.03, I2 = 0%). No significant differences were found for all secondary outcomes. CONCLUSIONS: Off-clamp and on-clamp RAPN are similarly effective approaches for selected renal masses. Within the classic trifecta of PN outcomes, off-clamp RAPN yields similar rates of perioperative complications and may possibly offer better preservation of renal function and reduced margin-positive rates.

Patient-reported functional outcomes and oncological control after primary focal cryotherapy for clinically significant prostate cancer: A Phase II mandatory biopsy-monitored study.

INTRODUCTION: We report herein the impact of focal therapy (FT) on multi-domain functional outcomes in a Phase II prospective clinical trial (NCT04138914) in focal cryotherapy for clinically significant prostate cancer (csPCa). METHODS: The primary outcome was the detection of a ≥5 point deterioration in any of the four main expanded prostate index composite (EPIC) functional domains. Pretreatment multiparametric magnetic resonance imaging (mpMRI) and transperineal targeted and systematic saturation biopsy were used to select patients with prostate-specific antigen (PSA)≤20 ng/mL, Gleason grade group (GG) ≤4, mpMRI lesion volume ≤ 3 mL (for a single lesion) or ≤1.5 mL (where two lesions were present). Focal cryotherapy was performed with a minimum 5 mm margin around each target lesion. EPIC scores were obtained at baseline and posttreatment at 1, 3, 6, and 12 months. Mandatory repeat mpMRI and prostate biopsy were performed at 12 months to determine the infield and outfield recurrence. RESULTS: Twenty-eight patients were recruited. The mean age was 68 years, with PSA of 7.3 ng/mL and PSA density of 0.19 ng/mL2 . No Clavien-Dindo ≥3 complications occurred. Transient worsening of EPIC urinary (mean diff 16.0, p < 0.001, 95% confidence interval [CI]: 8.8-23.6) and sexual function scores (mean diff 11.0, p:0.005, 95% CI: 4.0-17.7) were observed at 1-month posttreatment, with recovery by Month 3. A subgroup who had ablation extending to the neurovascular bundle had a trend to delayed recovery of sexual function to Month 6. At 12-month repeat mpMRI and biopsy, 22 patients (78.6%) had no detectable csPCa. Of the six patients (21.4%) who had csPCa recurrences, four were GG2, one GG3, and one GG4. Four patients underwent repeat FT, one underwent radical prostatectomy, while the remaining one patient with low-volume GG2 cancer opted for active surveillance. CONCLUSION: FT using cryotherapy was associated with a transient deterioration of urinary and sexual function with resolution at 3 months posttreatment and with reasonable early efficacy in well-selected csPCa patients.

Intensive sampling of the umbra and penumbra improves clinically significant prostate cancer detection and reduces risk of grade group upgrading at radical prostatectomy.

PURPOSE: Our objective is to evaluate the clinically significant prostate cancer detection rate of overlapping and perilesional systematic biopsy cores and its impact on grade group (GG) concordance at prostatectomy. MATERIALS AND METHODS: Biopsy maps of those undergoing MRI-targeted (TB) and systematic biopsy (SB) were reviewed to reclassify systematic cores. Perilesional (PL) cores were defined as adjacent cores within 10 mm of the target lesion ("penumbra") whilst overlap (OL) cores were defined as cores within the ROI itself ("umbra"). All other cores were designated as distant cores (DC). The incremental csPCa detection rate (GG ≥ 2) and the rate of GG upgrading on prostatectomy as OL, PL and DC sequentially added to TB were determined. RESULTS: Out of the 398 patients included, the median number of OL and PL cores was 5 (IQR 4-7) and 5 (IQR 3-6) respectively. OL cores detected more csPCa than PL cores (31 vs 16%, p < 0.001). OL and PL cores improved the csPCa detection rate of TB from 34 to 39% (p < 0.001) and 37% (p = 0.001) respectively. TB+OL+PL had greater csPCa detection compared to just TB+OL (41 vs 39%, p = 0.016) and TB+PL (41 vs 37%, p < 0.001). Of the 104 patients who underwent prostatectomy, GG upgrading rate for TB+OL+PL was lower compared to TB (21 vs 36%, p < 0.001) and was not significantly different compared to TB+OL+PL+DC (21 vs 19%, p = 0.500). CONCLUSION: A biopsy strategy incorporating both intensive sampling of the umbra and penumbra improved csPCa detection and reduced risk of GG upgrading at prostatectomy.

The associations between spiritual well-being, hope and psychological symptoms in Chinese childhood cancer patients: A path analysis.

AIMS: We aimed to test a model in which hope and spiritual well-being acted as protective factors against anxiety and depressive symptoms in childhood cancer patients (CCPs). We hypothesized that hope and spiritual well-being were mutually reinforcing factors that would both reduce anxiety and depressive symptoms. METHODS: Using path analysis, the hypothetical model was tested on a cross-sectional sample of 412 Chinese CCPs aged 8-17 years. Self-reported measures were used to obtain data on participants' social and clinical characteristics, spiritual well-being, hope, anxiety and depressive symptoms. RESULTS: The hypothetical model was supported. Results suggested that sex, treatment type and diagnosis predicted spiritual well-being; diagnosis and time since diagnosis predicted hope. Spiritual well-being and hope were mutually predictive and mutually reinforcing, and were both negatively associated with anxiety and depressive symptoms. This model predicted 40% of the variance in spiritual well-being, 37% in hope, 39% in depressive symptoms, and 28% in anxiety. CONCLUSION: Spiritual well-being and hope were mutually reinforcing and served as protective factors against anxiety and depressive symptoms. These support the value for integrating spiritual and hope elements in developing interventions for CCPs to improve their spiritual and psychological well-being along the disease trajectory.

Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics.

MicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Their inherently pleiotropic nature makes miRNAs strong candidates for the development of cancer therapeutics, yet despite their potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor-suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNAi function. To demonstrate the general applicability of this approach to other tumor-suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types, including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nanomolar range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.

Far from the truth: Real-world treatment patterns among newly diagnosed metastatic prostate cancer in the era of treatment intensification.

OBJECTIVES: Real-world uptake of treatment intensification (TI) with novel hormonal agents (NHA) or chemotherapy as treatment of metastatic prostate cancer remains low outside of trial settings. We aim to report the prescription patterns and treatment outcomes of de novo metastatic hormone-sensitive prostate cancer (mHSPC) in a tertiary institution. METHODS: This is a retrospective cohort study using real-world data from a prospectively maintained prostate cancer registry. We selected patients newly diagnosed with mHSPC from January 2016 to December 2020. Clinicopathological parameters were recorded to determine their impact on prescription patterns. RESULTS: In total, 585 patients with metastatic prostate cancer were identified. Prescription of NHA increased from 10.5% (2016) to 50.4% (2020), but that of chemotherapy declined. Factors associated with TI were (1) baseline health status: Charlson Comorbidity Index 0-2, ECOG 0-1, age ≤ 65, (2) disease burden: PSA (>400, CHAARTED high volume disease, p = 0.004), development of systemic complications and (3) physician factor: primary physician being uro-oncologist and medical oncologist versus general urologist. Patients with TI had a longer mean time to castration-resistant prostate cancer (45.0 vs. 32.5 months, HR 0.567, 95% CI: 0.441-0.730, p < 0.001) and overall survival (55.3 vs. 46.8 months, HR 0.612, 95% CI, 0.447-0.837, p = 0.001). CONCLUSION: This study demonstrated the trend of treatment prescription of mHSPC and factors contributing to the use of TI. TI improved mean time to CRPC and OS.

Family caregivers' lived experience of caring for hospitalised patients with cancer during the COVID-19 lockdown: A descriptive phenomenological study.

AIMS: This study aimed to capture and explore family caregivers' lived experience of caring for hospitalised patients with cancer during the lockdown. BACKGROUND: The unprecedented lockdown episodes due to COVID-19 have brought significant changes in the hospital visiting policies and caregiving practices. As part of the precautionary measures for hospital visits, the bedside companion was restricted to one caregiver for patients with cancer in Shanghai hospitals. DESIGN: This study adopted a descriptive phenomenological approach. METHODS: Data were collected among 20 family caregivers recruited from the Oncology department of a tertiary hospital in Shanghai in May 2022, using purposive sampling method and followed by unstructured, open-ended interviews. Colaizzi's seven-step data analysis method was used to analyse the data to reveal the emergent themes and subthemes of the phenomenon. RESULTS: Four themes were generated on family caregivers' lived experience of caring for hospitalised patients with cancer during the lockdown, including (1) Feeling scared for the patient; (2) Living a life feeling trapped under COVID-19 surveillance; (3) Feeling neglected and unseen; (4) Growing resilience and appreciation. CONCLUSIONS: The lockdown exacerbated the burden of family caregivers when they cared for the hospitalised patients with cancer during the lockdown period. However, positive reframing of the lived experience facilitated their coping with the challenging situation. RELEVANCE TO CLINICAL PRACTICE: Findings from this study highlighted the potential proactive roles the healthcare providers could play in improving family caregivers' health and supporting them during and beyond the COVID-19 pandemic. REPORTING METHOD: The study adhered to relevant EQUATOR guidelines; the study was reported according to the COREQ checklist. PATIENT OR PUBLIC CONTRIBUTION: Family caregivers of patients with cancer were involved in data collection and member-checking of the transcripts and interpretations of their experiences.

Incorporating artificial intelligence in urology: Supervised machine learning algorithms demonstrate comparative advantage over nomograms in predicting biochemical recurrence after prostatectomy.

OBJECTIVE: After radical prostatectomy (RP), one-third of patients will experience biochemical recurrence (BCR), which is associated with subsequent metastasis and cancer-specific mortality. We employed machine learning (ML) algorithms to predict BCR after RP, and compare them with traditional regression models and nomograms. METHODS: Utilizing a prospective Uro-oncology registry, 18 clinicopathological parameters of 1130 consecutive patients who underwent RP (2009-2018) were recorded, yielding over 20,000 data points for analysis. The data set was split into a 70:30 ratio for training and validation. Three ML models: Naïve Bayes (NB), random forest (RF), and support vector machine (SVM) were studied, and compared with traditional regression models and nomograms (Kattan, CAPSURE, John Hopkins [JHH]) to predict BCR at 1, 3, and 5 years. RESULTS: Over a median follow-up of 70.0 months, 176 (15.6%) developed BCR, at a median time of 16.0 months (interquartile range [IQR]: 11.0-26.0). Multivariate analyses demonstrated strongest association of BCR with prostate-specific antigen (PSA) (p: 0.015), positive surgical margins (p < 0.001), extraprostatic extension (p: 0.002), seminal vesicle invasion (p: 0.004), and grade group (p < 0.001). The 3 ML models demonstrated good prediction of BCR at 1, 3, and 5 years, with the area under curves (AUC) of NB at 0.894, 0.876, and 0.894, RF at 0.846, 0.875, and 0.888, and SVM at 0.835, 0.850, and 0.855, respectively. All models demonstrated (1) robust accuracy (>0.82), (2) good calibration with minimal overfitting, (3) longitudinal consistency across the three time points, and (4) inter-model validity. The ML models were comparable to traditional regression analyses (AUC: 0.797, 0.848, and 0.862) and outperformed the three nomograms: Kattan (AUC: 0.815, 0.798, and 0.799), JHH (AUC: 0.820, 0.757, and 0.750) and CAPSURE nomograms (AUC: 0.706, 0.720, and 0.749) (p < 0.001). CONCLUSION: Supervised ML algorithms can deliver accurate performances and outperform nomograms in predicting BCR after RP. This may facilitate tailored care provisions by identifying high-risk patients who will benefit from multimodal therapy.

The role of surgery for loco-regional and advanced urological cancers.

PURPOSE OF REVIEW: There is a general misconception that surgery is the antithesis of palliation. However, symptom mitigation, the basic tenet of palliative interventions, can be achieved by invasive procedures. Surgical care, thus, plays an important role in palliative oncology, alongside radiation and systemic therapy. There is global movement to improve palliation in oncology, and thus it is timely to evaluate the role of surgical interventions can play in this setting. RECENT FINDINGS: Many of the surgical interventions done with palliative intent were first established as curative options. Most studies looked at interventions for local control of primary tumour including extirpative surgeries, while some studies studied pain relief for bone metastases. Results show that patients have an acceptable survival outcome and complication rate comparable to those done in the curative setting. However, not all studies report functional outcomes and symptom-relief consistently, highlighting an unmet need. SUMMARY: More studies are needed to further define the role of surgery in palliative care. Randomized controlled trials studying surgical intervention in the palliative setting will be challenging because of lack of equipoise, inherent bias in patient and disease characteristics in those who undergo surgery. Nonetheless, studies should endeavour to study symptom-free survival and PROMs as meaningful endpoints of interventions performed in a palliative setting rather than solely focus on hard oncological endpoints of survival.

Prostatic ductal adenocarcinoma variant predicts worse pathological and oncological outcomes: Insight from over 1000 consecutive patients from a large prospective uro-oncology registry.

OBJECTIVE: To evaluate if prostatic ductal adenocarcinoma (PDA) independently predicts poorer pathological and oncological outcomes after radical prostatectomy (RP). METHODS AND MATERIALS: Utilizing a large prospective uro-oncology registry, clinicopathological parameters of 1027 consecutive patients who underwent RP (2008-2017) were recorded. Oncological outcomes were determined by failure to achieve unrecordable PSA postoperatively and biochemical failure (BCF). RESULTS: PDA was present in 79 (7.7%) patients, whereas 948 (92.3%) patients had conventional prostatic acinar adenocarcinoma (PAA). Patients with PDA were older (mean 64.4 vs. 62.8-years old; p = .045), had higher PSA at diagnosis (mean 12.53 vs. 10.80 ng/ml; p = .034), and a higher percentage of positive biopsy cores (mean 39.34 vs. 30.53%; p = .006). Compared to PAA, PDA exhibited a more aggressive tumor biology: (1) Grade groups 4 or 5 (26.6 vs. 9.4%, p < .001), (2) tumor multifocality (89.9 vs. 83.6%; p = .049), and (3) tumor size (mean 2.97 vs. 2.00 cm; p < .001). On multivariate analysis, PDA was independently associated with locally advanced disease (p = .002, hazard ratio [HR]: 2.786, 95% confidence interval [CI]: 1.473-5.263), with a trend towards positive surgical margins (p = .055) and nodal involvement (p = .061). Translating the poorer pathological features to oncological outcomes, presence of PDA independently predicted less likelihood of achieving unrecordable PSA (p = .019, HR: 2.368, 95% CI: 1.152-4.868, and higher BCF (p = .028, HR: 1.918, 95% CI: 1.074-3.423). Subgroup analysis demonstrated that a higher ductal component greater than 15% proportionally predicted worse oncological outcomes, with a shorter time to BCF of 14.3 months compared to 19.8 months in patients with ductal component lesser than 15% (p = .040, HR: 2.660, 95% CI: 1.046-6.757). CONCLUSION: PDA is independently associated with adverse pathological and oncological outcomes after RP. A higher proportion of PDA supports a higher BCF rate with a shorter time interval. An aggressive extirpative approach with close monitoring of postoperative serum PSA levels is warranted for these patients.

Defining prostate cancer size and treatment margin for focal therapy: does intralesional heterogeneity impact the performance of multiparametric MRI?

OBJECTIVES: To evaluate the impact of intralesional heterogeneity on the performance of multiparametric magnetic resonance imaging (mpMRI) in determining cancer extent and treatment margins for focal therapy (FT) of prostate cancer. PATIENTS AND METHODS: We identified men who underwent primary radical prostatectomy for organ- confined prostate cancer over a 3-year period. Cancer foci on whole-mount histology were marked out, coding low-grade (LG; Gleason 3) and high-grade (HG; Gleason 4-5) components separately. Measurements of entire tumours were grouped according to intralesional proportion of HG cancer: 0%, <50% and ≥50%; the readings were corrected for specimen shrinkage and correlated with matching lesions on mpMRI. Separate measurements were also taken of HG cancer components only, and correlated against entire lesions on mpMRI. Size discrepancies were used to derive the optimal tumour size and treatment margins for FT. RESULTS: There were 122 MRI-detected cancer lesions in 70 men. The mean linear specimen shrinkage was 8.4%. The overall correlation between histology and MRI dimensions was r = 0.79 (P < 0.001). Size correlation was superior for tumours with high burden (≥50%) compared to low burden (<50%) of HG cancer (r = 0.84 vs r = 0.63; P = 0.007). Size underestimation by mpMRI was more likely for larger tumours (51% for >12 mm vs 26% for ≤12 mm) and those containing HG cancer (44%, vs 20% for LG only). Size discrepancy analysis suggests an optimal tumour size of ≤12 mm and treatment margins of 5-6 mm for FT. For tumours ≤12 mm in diameter, applying 5- and 6-mm treatment margins would achieve 98.6% and 100% complete tumour ablation, respectively. For tumours of all sizes, using the same margins would ablate >95% of the HG cancer components. CONCLUSIONS: Multiparametric MRI performance in estimating prostate cancer size, and consequently the treatment margin for FT, is impacted by tumour size and the intralesional heterogeneity of cancer grades.

Ambulatory robot-assisted laparoscopic radical prostatectomy with extended recovery by total extraperitoneal approach.

OBJECTIVE: To evaluate the feasibility of performing robot-assisted laparoscopic radical prostatectomy in an ambulatory with extended recovery setting by using a total extraperitoneal approach. METHODS: Patients with low- to intermediate-risk, prostate cancer were prospectively recruited in the ambulatory robot-assisted laparoscopic radical prostatectomy with extended recovery by total extraperitoneal approach group (n = 30), and a matched-pair inpatient surgery control group by total extraperitoneal approach (n = 20). Objective discharge criteria were based on the postanesthesia discharge scoring system. All patients underwent preoperative counseling on preoperative preparation and postoperative care. RESULTS: There were no statistically significant differences between the ambulatory with extended recovery-total extraperitoneal approach and inpatient-total extraperitoneal approach groups in patient factors (age, body mass index, American Society of Anesthesiologists score, Charlson Comorbidity Index), disease factors (prostate-specific antigen, clinical T stage, biopsy Gleason score, prostate volume) and peri-operative parameters (operative time, blood loss, Trendelenburg angle). All total extraperitoneal robot-assisted laparoscopic radical prostatectomy patients (ambulatory with extended recovery and inpatient surgery groups) met the postanesthesia discharge scoring system discharge criteria ≤23 h from admission. The mean hospital stays for ambulatory with extended recovery-total extraperitoneal and inpatient-total extraperitoneal groups were 20.3 and 52.4 h, respectively (P < 0.001). A total of 29 of 30 patients (97%) in the ambulatory with extended recovery-total extraperitoneal group were discharged ≤23 h of admission. CONCLUSIONS: This is the first prospective evaluation of robot-assisted laparoscopic radical prostatectomy by the total extraperitoneal approach, showing that the short-stay ambulatory with extended recovery approach is safe, feasible and with a high success rate. Total extraperitoneal surgical approach is a critical factor for the success of the ambulatory with extended recovery protocol.

Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development.

Resistance to cancer treatment is one of the major challenges currently faced when treating gastrointestinal (GI) cancers. A major contributing factor to this resistance is the presence of cancer stem cells (CSCs) in GI cancers (e.g., colorectal, pancreatic, gastric, liver cancer). Non-coding RNAs, such as microRNAs (miRNAs), have been found to regulate several key targets that are responsible for cancer stemness, and function as oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs. As a result, several miRNAs have been found to alter, or be altered by, the expression of CSC-defining markers and their related pathways. These miRNAs can be utilized to affect stemness in multiple ways, including directly targeting CSCs and enhancing the efficacy of cancer therapeutics. This review highlights current studies regarding the roles of miRNAs in GI CSCs, and efforts towards the development of cancer therapeutics.

Multiparametric MRI-ultrasonography software fusion prostate biopsy: initial results using a stereotactic robotic-assisted transperineal prostate biopsy platform comparing systematic vs targeted biopsy.

OBJECTIVE: To compare the detection rates of prostate cancer between systematic biopsy and targeted biopsy using a stereotactic robot-assisted transperineal prostate platform. MATERIALS AND METHODS: We identified consecutive patients with suspicious lesion(s) on multiparametric magnetic resonance imaging (mpMRI), who underwent both systematic and MRI-transrectal ultrasonography (US) fusion targeted biopsy using our proprietary transperineal robot-assisted prostate biopsy platform between January 2015 and January 2019 at our institution, for retrospective analysis. Comparative analysis was performed between systematic and targeted biopsy using McNemar's test, and the cohort was further stratified by prior biopsy status and Prostate Imaging Reporting and Data System (PI-RADS) v2.0 score. International Society of Urological Pathology (ISUP) grade group (GG) ≥2 cancers (previously known as Gleason grade ≥7) were considered to be clinically significant. RESULTS: A total of 500 patients were included in our final analysis, of whom 67 (13%) were patients with low-risk cancer on active surveillance. Of the 433 patients without prior diagnosis of cancer, 288 (67%) were biopsy-naïve. A total of 248 (57%) were diagnosed with prostate cancer, with 199 (46%) having clinically significant prostate cancer (ISUP GG ≥2). There were no statistically significant differences in the overall prostate cancer and clinically significant prostate cancer detection rate between systematic and targeted biopsy (51% vs 49% and 40% vs 38% respectively; P = 0.306 and P = 0.609). Of the 248 prostate cancers detected, 75% (187/248) were detected on both systematic and targeted biopsy, 14% (35/248) were detected on systematic biopsy alone and 11% (26/248) were detected on targeted biopsy alone. Of the 199 clinically significant cancers detected, 69% (138/199) were detected on both systematic and targeted biopsy, 17% (33/199) on systematic biopsy alone and 14% (28/199) on targeted biopsy alone. There were no statistically significant differences in the detection rate between systematic and targeted biopsy for both overall and clinically significant prostate cancer, even when the cohort was stratified by prior biopsy status and PI-RADS score. Targeted biopsy has greater sampling efficiency compared to systematic biopsy for both overall and clinically significant prostate cancer (23.2% vs 9.8%, P < 0.001 and 14.8% vs 5.6%, P < 0.001). CONCLUSIONS: Using our robot-assisted transperineal prostate platform, combined MRI-US targeted biopsy with concurrent systematic prostate systematic biopsy probably represents the optimal method for the detection of clinically significant prostate cancer.

Prospects and challenges for cell-cultured fat as a novel food ingredient.

BACKGROUND: In vitro meat production has been proposed as a solution to environmental and animal welfare issues associated with animal agriculture. While most academic work on cell-cultured meat has focused on innovations for scalable muscle tissue culture, fat production is an important and often neglected component of this technology. Developing suitable biomanufacturing strategies for adipose tissue from agriculturally relevant animal species may be particularly beneficial due to the potential use of cell-cultured fat as a novel food ingredient. SCOPE AND APPROACH: Here we review the relevant studies from areas of meat science, cell biology, tissue engineering, and bioprocess engineering to provide a foundation for the development of in vitro fat production systems. We provide an overview of adipose tissue biology and functionality with respect to meat products, then explore cell lines, bioreactors, and tissue engineering strategies of potential utility for in vitro adipose tissue production for food. Regulation and consumer acceptance are also discussed. KEY FINDINGS AND CONCLUSIONS: Existing strategies and paradigms are insufficient to meet the full set of unique needs for a cell-cultured fat manufacturing platform, as tradeoffs are often present between simplicity, scalability, stability, and projected cost. Identification and validation of appropriate cell lines, bioprocess strategies, and tissue engineering techniques must therefore be an iterative process as a deeper understanding of the needs and opportunities for cell-cultured fat develops.

Effect of Stepwise Voltage Escalation on Treatment Outcomes following Extracorporeal Shock Wave Lithotripsy of Renal Calculi: A Prospective Randomized Study.

PURPOSE: In this study we assessed the effects of a ramping protocol in patients undergoing extracorporeal shock wave lithotripsy of renal stones. MATERIALS AND METHODS: In this prospective study patients with renal stones were randomized to receive shock wave lithotripsy delivered using a ramping protocol in group 1 (first 1,000 shocks at energy level 5 followed by 1,000 shocks at energy level 6 and 1,000 final shocks at energy level 7) and a fixed voltage protocol in group 2 (all 3,000 shocks at energy level 7). Treatment was administered using a Modulith® SLX-F2. The primary outcome was treatment success 12 weeks after a single shock wave lithotripsy session, defined as lack of a stone or a less than 4 mm stone fragment on computerized tomography. Other outcomes included the stone-free rate and the perinephric hematoma incidence. RESULTS: A total of 300 patients (150 per group) were recruited between February 2016 and June 2018. The 2 groups did not differ in baseline parameters. Group 1 received 14.8% lower energy than group 2, which was significant (p <0.001). The treatment success rate in groups 1 and 2 was 67.8% and 73.6%, respectively, which did not statistically differ (group 1 crude OR 0.753, 95% CI 0.456-1.244, p=0.268). The stone-free rate in groups 1 and 2 was 36.6% and 41.9%, respectively, which did not differ statistically between the groups. However, in groups 1 and 2 perinephric hematoma developed in 23.8% and 43.8% of patients, respectively, which was a statistically significant difference (p <0.001). CONCLUSIONS: The fixed voltage shock wave lithotripsy and ramping protocols provided similar treatment success rates for renal stones. However, the ramping protocol reduced the incidence of perinephric hematoma after shock wave lithotripsy.

Evolving trends in the surgical management of renal masses over the past two decades: A contemporary picture from a large prospectively-maintained database.

OBJECTIVES: To investigate the trends in the presentation and surgical management of renal tumors at Singapore General Hospital, Singapore. METHODS: We accessed our uro-oncological registry to extract the clinicopathological data of patients with renal tumors who underwent nephrectomy from 2000 to 2015. Binary logistic regression was used to identify predictors of nephron-sparing surgery utilization, Clavien-Dindo grade ≥III complications and progression to stage ≥3 chronic kidney disease. Cox regression models were created to evaluate the proportional hazards of the risk factors for overall survival and cancer-specific survival. RESULTS: A total of 1208 cases of nephrectomy were carried out between 2000 and 2015. The proportion of cT1a tumors increased from 2000-2004 to 2010-2015, which was accompanied by the doubling of utilization rates of nephron-sparing surgery and minimally invasive surgery. Charlson Comorbidity Index score <2, asymptomatic presentation, clinical T1a tumors and having an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 were all independent predictors of nephron-sparing surgery utilization. Age, symptomatic presentation and nephron-sparing surgery utilization were all significantly associated with greater odds of having Clavien-Dindo grade ≥III complications, whereas minimally invasive surgery was associated with decreased risk. The utilization of partial nephrectomy and minimally invasive surgery was significantly associated with a decreased risk of developing postoperative stage ≥3 chronic kidney disease. Both overall survival and cancer-specific survival were not significantly affected by whether nephron-sparing surgery was utilized. CONCLUSIONS: There has been an increasing proportion of small renal masses diagnosed incidentally with a shift towards nephron-sparing surgery for clinically localized tumors. With the adoption of nephron-sparing surgery, progression to stage 3 chronic kidney disease has decreased, without any compromise in oncological and survival outcomes.

Assessing quality of life using WHOQOL-BREF: a cross-sectional study on the association between quality of life and neighborhood environmental satisfaction, and the mediating effect of health-related behaviors.

BACKGROUND: Quality of life (QOL) is an important component in assessing people's health. Environmental quality can influence people's QOL in the physical health, psychological, social relationships and environment domains. QOL in the four domains, overall QOL and general heath of residents living in the Kowloon Peninsula of Hong Kong were assessed. The association between satisfaction with the neighborhood environment and QOL, and health-related behaviors which mediated the effect were investigated. METHODS: A sample of 317 residents completed a questionnaire which comprised the WHOQOL-BREF (Hong Kong version) to assess QOL, the International Physical Activity Questionnaire (IPAQ) to study physical activities, and questions on satisfaction with the neighborhood environment, health-related behaviors and socio-demographics. One-way ANOVA and linear regression were used to study the associations between environmental satisfaction and QOL in the four domains, overall QOL and general health, followed by assessing the relationships between environmental satisfaction and the potential health-related behavior mediators with regression tests. Mediation analysis was conducted using multiple linear regressions to study the effects of environmental satisfaction on QOL in the four domains, overall QOL and general health, as well as the potential mediating roles played by various health-related behaviors. A P-value of < 0.05 was considered as statistically significant. RESULTS: The residents had a relatively higher physical health mean score of 70.83 ± 12.69, and a lower environmental mean score of 61.98 ± 13.76. Moderate satisfaction with the neighborhood environment had a significant relationship with QOL in the psychological domain (ß = 0.170, P = 0.006), however, this effect was partially mediated by the non-smoking behavior of the residents (ß = 0.143, P = 0.022). CONCLUSIONS: Our residents had lower QOL in the physical health and psychological domains but similar QOL in the social relationships and environmental domains compared to other countries. Only QOL in the psychological domain could be predicted by the satisfaction with the neighborhood environment, and non-smoking status was a partial mediator of the effect of moderate environmental satisfaction on QOL in the psychological domain. Refrain from smoking seems to be able to lower the influence of neighborhood environment on people's QOL in the psychological domain to a certain extent.

Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a mini-chromosome essential for HBV replication, is supposed to be resistant to nucleos(t)ide analogue treatment. We investigated the effect of long-term nucleos(t)ide analogue treatment on cccDNA. METHODS: Among 129 patients who had been enrolled in previous international nucleos(t)ide analogue clinical trials and had liver biopsies at baseline and one year after treatment, we recruited 43 patients on long-term continuous treatment for 72 to 145months for a third liver biopsy. Serum HBV DNA, hepatitis B surface antigen (HBsAg) levels, total intrahepatic HBV DNA (ihHBV DNA), cccDNA, HBV pregenomic RNA (pgRNA) as well as histologic changes were examined. RESULTS: At the time of the third biopsy, serum HBV DNA levels were undetectable in all but one patient. The median levels of HBsAg, ihHBV DNA, and cccDNA were 2.88logIU/ml, 0.03copies/cell, and 0.01copies/cell, respectively. Compared to baseline levels, there was reduction of HBsAg levels by 0.54log (71.46%), ihHBV DNA levels by 2.81log (99.84%), and cccDNA levels by 2.94log (99.89%), with 49% having cccDNA levels below the detection limit. One patient had undetectable HBsAg. The median pgRNA level, measured only in the third biopsy, was 0.021copies/cell, with 40% of patients having undetectable pgRNA. CONCLUSIONS: Long-term nucleos(t)ide analogue treatment induced marked depletion of cccDNA in the majority of patients while serum HBsAg levels, though reduced, were detectable in all but one patient. Whether cccDNA depletion is sustained and associated with better patient outcome requires further study. LAY SUMMARY: It is generally presumed that a form of hepatitis B virus DNA, called covalently closed circular DNA (cccDNA), which hides inside the nuclei of liver cells of patients with chronic hepatitis B, cannot be reduced by antiviral treatment. The present study showed that with prolonged treatment (median period 126months), cccDNA can be markedly reduced, with 49% of liver biopsies having undetectable cccDNA. This suggests that viral replication capacity would be very low after prolonged antiviral treatment.