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Background and Objective: Active surveillance (AS) of prostate cancer (PCa) is the standard of care for low-grade disease, but there is limited guidance on tailoring protocols for stable patients. We investigated long-term outcomes for patients without initial progression and risk factors for upgrade., Methods: Men on AS with Gleason grade group (GG) 1 PCa on three serial biopsies, ≥5 yr without progression, and ≥10 yr of follow-up were included. Outcomes were upgrade (GG ≥2), major upgrade (GG ≥3), progression to treatment, metastasis, PCa-specific survival, and overall survival. Cox proportional hazards regression models were used to estimate the associations between patient characteristics and risk of upgrade., Key Findings and Limitations: A total of 774 men met the inclusion criteria. At 10, 12, and 15 yr, upgrade-free survival rates were 56%, 45%, and 21%; major upgrade-free survival rates were 88%, 83%, and 61%; treatment-free survival rates were 86%, 83%, and 73%; metastasis-free survival rates were 99%, 99%, and 98%; and overall survival rates were 98%, 96%, and 95%, respectively. PCa-specific survival was 100% at 15 yr. On a multivariable analysis, year of diagnosis, age, body mass index (BMI), and biopsy core positivity were associated with upgrade (all p < 0.01), whereas age and prostate-specific antigen (PSA) density were associated with major upgrade., Conclusions and Clinical Implications: Patients without progression for 5 yr on AS had modest rates of upgrade and low rates of metastasis, and mortality at 15 yr of follow-up. Year of diagnosis, older age, increased BMI, and increased biopsy core positivity were associated with upgrade, whereas older age and greater PSA density were associated with an increased risk of major upgrade. A subset of these patients may benefit from deintensification of AS protocols., Patient Summary: There are little reported data or clinical guidelines for patients with PCa who are stable for many years on active surveillance (AS). We show, in a large cohort, that PCa patients without progression for 5 yr on AS have modest rates of upgrade and very low rates of metastasis, and mortality rates at 15 yr of follow-up, and that older age, increased body mass index, and increased PCa volume are associated with an increased likelihood of future upgrade. This study supports continued AS in this patient population and deintensification in select patients., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Active surveillance (AS) of prostate cancer (PCa) involves regular monitoring for disease progression. The aim is to avoid unnecessary treatment while ensuring appropriate and timely treatment for those whose disease progresses. AS has emerged as the standard of care for low-grade (Gleason grade 1, GG 1) PCa. Opponents are concerned that initial undersampling and delay of definitive management for patients with GG 2 disease may lead to adverse outcomes. We sought to determine whether the timing for definitive management of GG 2 PCa, either upfront or after initial AS, affects recurrence outcomes after radical prostatectomy (RP)., Methods: Participants were diagnosed with cT1-2N0/xM0/x, prostate-specific antigen (PSA) <20 ng/ml, and GG 1-2 PCa between 2000 and 2020 and underwent immediate RP for GG 2 or AS followed by delayed RP on upgrading to GG 2. The outcome was recurrence-free survival (RFS) after surgery, with recurrence defined as either biochemical failure (2 PSA measurements ≥0.2 ng/ml) or a second treatment. Multivariable Cox proportional-hazards regression models were used to calculate associations between the timing for definitive RP and the risk of recurrence, adjusted for age at diagnosis, percentage of positive biopsy cores (PPC), PSA density, PSA before RP, year of diagnosis, surgical margins, genomic risk score, and prostate MRI findings., Key Findings: Of the 1259 men who met the inclusion criteria, 979 underwent immediate RP after diagnosis of GG 2, 190 underwent RP within 12 mo of upgrading to GG 2 on AS, and 90 men underwent RP >12 mo after upgrading to GG 2. The 5-yr RFS rates were 81% for the immediate RP group, 80% for the delayed RP ≤12 mo, and 70% for the delayed RP >12 mo group (univariate log-rank p = 0.03). Cox multivariable regression demonstrated no difference in RFS outcomes between immediate RP for GG 2 disease and delayed RP after upgrading on AS. PPC (hazard ratio [HR] per 10% increment 1.08, 95% confidence interval [CI] 1.02-1.15; p = 0.01) and PSA before RP (HR 1.06, 95% CI 1.03-1.09; p < 0.01) were significantly associated with the risk of recurrence., Conclusions and Clinical Implications: PPC and PSA before RP, but not the timing of definitive surgery after upgrade to GG 2, were associated with the risk of PCa recurrence after RP on multivariable analysis. These findings support the safety of AS and delayed definitive therapy for a subset of patients with GG 2 disease., Patient Summary: In a large group of 1259 patients with low-grade prostate cancer, we found that delaying surgical treatment after an initial period of active surveillance resulted in no differences in prostate cancer recurrence. Our results support the safety of active surveillance for low-grade prostate cancer., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: The absence of predictive markers for kidney stone recurrence poses a challenge for the clinical management of stone disease. The unpredictability of stone events is also a significant limitation for clinical trials, where many patients must be enrolled to obtain sufficient stone events for analysis. In this study, we sought to use machine learning methods to identify a novel algorithm to predict stone recurrence. Subjects/Patients and Methods: Patients enrolled in the Registry for Stones of the Kidney and Ureter (ReSKU), a registry of nephrolithiasis patients collected between 2015-2020, with at least one prospectively collected 24-hour urine test (Litholink 24-hour urine test; Labcorp) were included in the training set. A validation set was obtained from chart review of stone patients not enrolled in ReSKU with 24-hour urine data. Stone events were defined as either an office visit where a patient reports symptomatic passage of stones or a surgical procedure for stone removal. Seven prediction classification methods were evaluated. Predictive analyses and receiver operator characteristics (ROC) curve generation were performed in R. Results: A training set of 423 kidney stone patients with stone event data and 24-hour urine samples were trained using the prediction classification methods. The highest performing prediction model was a Logistic Regression with ElasticNet machine learning model (area under curve [AUC] = 0.65). Restricting analysis to high confidence predictions significantly improved model accuracy (AUC = 0.82). The prediction model was validated on a validation set of 172 stone patients with stone event data and 24-hour urine samples. Prediction accuracy in the validation set demonstrated moderate discriminative ability (AUC = 0.64). Repeat modeling was performed with four of the highest scoring features, and ROC analyses demonstrated minimal loss in accuracy (AUC = 0.63). Conclusion: Machine-learning models based on 24-hour urine data can predict stone recurrences with a moderate degree of accuracy.

Background: Prostate cancers featuring an expansile cribriform (EC) pattern are associated with worse clinical outcomes following radical prostatectomy (RP). However, studies of the genomic characteristics of Gleason pattern 4 subtypes are limited., Objective: To explore transcriptomic characteristics and heterogeneity within Gleason pattern 4 subtypes (fused/poorly formed, glomeruloid, small cribriform, EC/intraductal carcinoma [IDC]) and the association with biochemical recurrence (BCR)-free survival., Design, Setting, and Participants: This was a retrospective cohort study including 165 men with grade group 2-4 prostate cancer who underwent RP at a single academic institution (2016-2020) and Decipher testing of the RP specimen. Patients with Gleason pattern 5 were excluded. IDC and EC patterns were grouped. Median follow-up was 2.5 yr after RP for patients without BCR., Outcomes Measurements and Statistical Analysis: Prompted by heterogeneity within pattern 4 subtypes identified via exploratory analyses, we investigated transcriptomic consensus clusters using partitioning around medoids and hallmark gene set scores. The primary clinical outcome was BCR, defined as two consecutive prostate-specific antigen measurements >0.2 ng/ml at least 8 wk after RP, or any additional treatment. Multivariable Cox proportional-hazards models were used to determine factors associated with BCR-free survival., Results and Limitations: In this cohort, 99/165 patients (60%) had EC and 67 experienced BCR. Exploratory analyses and clustering demonstrated transcriptomic heterogeneity within each Gleason pattern 4 subtype. In the multivariable model controlled for pattern 4 subtype, margin status, Cancer of the Prostate Risk Assessment Post-Surgical score, and Decipher score, a newly identified steroid hormone-driven cluster (hazard ratio 2.35 95% confidence interval 1.01-5.47) was associated with worse BCR-free survival. The study is limited by intermediate follow-up, no validation cohort, and lack of accounting for intratumoral and intraprostatic heterogeneity., Conclusions: Transcriptomic heterogeneity was present within and across each Gleason pattern 4 subtype, demonstrating there is additional biologic diversity not captured by histologic subtypes. This heterogeneity can be used to develop novel signatures and to classify transcriptomic subtypes, which may help in refining risk stratification following RP to further guide decision-making on adjuvant and salvage treatments., Patient Summary: We studied prostatectomy specimens and found that tumors with similar microscopic appearance can have genetic differences that may help to predict outcomes after prostatectomy for prostate cancer. Our results demonstrate that further gene expression analysis of prostate cancer subtypes may improve risk stratification after prostatectomy. Future studies are needed to develop novel gene expression signatures and validate these findings in independent sets of patients., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Although official T-staging criteria for prostate cancer are based on digital rectal examination findings, providers increasingly rely on transrectal US and MRI to define pragmatic clinical stage to guide management. We assessed the impact of incorporating imaging findings into T-staging on performance of a well-validated prognostic instrument., Materials and Methods: Patients who underwent radical prostatectomy for prostate cancer diagnosed between 2000 and 2019 with stage ≤cT3a on both digital rectal examination and imaging (transrectal US/MRI) were included. The University of California, San Francisco CAPRA (Cancer of the Prostate Risk Assessment) score was computed 2 ways: (1) incorporating digital rectal examination-based T stage and (2) incorporating imaging-based T stage. We assessed for risk changes across the 2 methods and associations of CAPRA (by both methods) with biochemical recurrence, using unadjusted and adjusted Cox proportional hazards models. Model discrimination and net benefit were assessed with time-dependent area under the curve and decision curve analysis, respectively., Results: Of 2,222 men included, 377 (17%) increased in CAPRA score with imaging-based staging ( P < .01). Digital rectal examination-based (HR 1.54; 95% CI 1.48-1.61) and imaging-based (HR 1.52; 95% CI 1.46-1.58) CAPRA scores were comparably accurate for predicting recurrence with similar discrimination and decision curve analyses. On multivariable Cox regression, positive digital rectal examination at diagnosis (HR 1.29; 95% CI 1.09-1.53) and imaging-based clinical T3/4 disease (HR 1.72; 95% CI 1.43-2.07) were independently associated with biochemical recurrence., Conclusions: The CAPRA score remains accurate whether determined using imaging-based staging or digital rectal examination-based staging, with relatively minor discrepancies and similar associations with biochemical recurrence. Staging information from either modality can be used in the CAPRA score calculation and still reliably predict risk of biochemical recurrence.

Although the American Urological Association recently dropped the very low-risk (VLR) subcategory for low-risk prostate cancer (PCa) and the European Association of Urology does not substratify low-risk PCa, the National Comprehensive Cancer Network (NCCN) guidelines still maintain this stratum, which is based on the number of positive biopsy cores, tumor extent in each core, and prostate-specific antigen density. This subdivision may be less applicable in the modern era in which imaging-targeted prostate biopsies are common practice. In our large institutional active surveillance cohort of patients diagnosed from 2000 to 2020 (n = 1276), the number of patients meeting NCCN VLR criteria decreased significantly in recent years, with no patient meeting VLR criteria after 2018. By contrast, the multivariable Cancer of the Prostate Risk Assessment (CAPRA) score effectively substratified patients over the same period and was predictive of upgrading on repeat biopsy to Gleason grade group ≥2 on multivariable Cox proportional-hazards regression modeling (hazard ratio 1.21, 95% confidence interval 1.05-1.39; p < 0.01), independent of age, genomic test results, and magnetic resonance imaging findings. These findings suggest that the NCCN VLR criteria are less applicable in the targeted biopsy era, and that the CAPRA score or similar instruments are better contemporary risk stratification tools for men on active surveillance. PATIENT SUMMARY: We investigated whether the National Comprehensive Cancer Network classification of very low risk (VLR) for prostate cancer is relevant in the modern era. We found that in a large group of patients on active surveillance, no man diagnosed after 2018 satisfied the VLR criteria. However, the Cancer of the Prostate Risk Assessment (CAPRA) score discriminated patients by cancer risk at diagnosis and was predictive of outcomes on active surveillance, and thus may be a more relevant classification scheme in the modern era., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Residual fragments (RFs) after percutaneous nephrolithotomy (PCNL) have a significant impact on patients' quality of life and clinical course. There is a paucity of studies that evaluate the natural history of RFs after PCNL. The objective of this study is to compare rates of reintervention, complications, stone growth, and passage in patients with RFs >4, ≤4, and ≤2 mm after PCNL. Methods: Sites from the Endourologic Disease Group for Excellence (EDGE) research consortium examined data of PCNL patients from 2015 to 2019 with at least 1-year follow-up. RF passage, regrowth, reintervention, and complications were recorded and RFs were stratified into >4 and ≤4 mm groups, as well as >2 and ≤2 mm groups. Potential predictors for stone-related events after PCNL were determined using multivariable logistic regression analysis. It was hypothesized that larger RF thresholds would result in lower passage rates, faster regrowth, and greater clinically significant events (complications and reinterventions) than smaller RF thresholds. Results: A total of 439 patients with RFs >1 mm on CT postoperative day 1 were included in this study. For RFs >4 mm, rates of reintervention were found to be significantly higher and Kaplan-Meier curve analysis showed significantly higher rates of stone-related events. Passage and RF regrowth were not found to be significantly different compared with RFs ≤4 mm. However, RFs ≤2 mm had significantly higher rates of passage, and significantly lower rates of fragment regrowth (>1 mm), complications, and reintervention compared with RFs >2 mm. On multivariable analysis, older age, body mass index, and RF size were found to be predictive of stone-related events. Conclusions: With the largest cohort to date, this study by the EDGE research consortium further confirms that clinically insignificant residual fragment is problematic for patients after PCNL, particularly in older more obese patients with larger RFs. Our study underscores the importance of complete stone clearance post-PCNL and challenges the use of Clinically insignificant residual fragment (CIFR).

Background: Urologic guidelines universally recommend increasing fluid intake for kidney stone prevention. Increased voided volume is thought to help reduce stone recurrence and severity, but supporting evidence is limited., Patients and Methods: Nephrolithiasis outcomes and 24-h urine data for patients from the Registry for Stones of the Kidney and Ureter (ReSKU), a registry of nephrolithiasis patients collected between 2015 and 2020, were retrospectively analysed. Outcome was stone events, either an office visit where a patient reports symptomatic passage of stones or surgery for stone removal., Results: We identified 450 stone patients with 24-h urine and kidney stone outcome data. There was no significant difference in 24-h voided volume between patients with one stone event and patients with two or more stone events. On multivariable logistic regression, after controlling for age, gender, BMI, and 24-h sodium and creatinine per kilogram, no significant associations were found between voided volume and stone events. There was a statistically significant negative correlation noted between voided volume and stone events in calcium oxalate dihydrate stone formers (Spearman R  = -0.42, p  = 0.04), but not others., Conclusions: Twenty-four-hour voided volume was not associated with stone events in a large institutional cohort, and subset analysis reveals that some stone formers may benefit more from increased voided volume than others; identifying such patients represents a novel precision medicine opportunity., Competing Interests: All authors declare that they have no conflict of interest regarding the material presented in this manuscript. All authors declare that they approve submission of the final article., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Purpose: Clinical guidelines suggest that for low-grade, clinically localized prostate cancer, patients with higher volume of disease at diagnosis may benefit from definitive therapy, although the data remain unclear. Our objective was to determine associations between low-grade prostate cancer volume and outcomes in men managed with primary radical prostatectomy., Materials and Methods: Men with cT1-2N0/xM0/x prostate cancer, prostate specific antigen at diagnosis <10 ng/mL, and Gleason grade group 1 pathology on diagnostic biopsy managed with primary radical prostatectomy were included. Outcomes were pathological upgrade at radical prostatectomy (≥Gleason grade group 2), University of California, San Francisco adverse pathology at radical prostatectomy (≥Gleason grade group 3, pT3/4, or pN1), alternate adverse pathology at radical prostatectomy (≥Gleason grade group 3, ≥pT3b, or pN1), and recurrence (biochemical failure with 2 prostate specific antigen ≥0.2 ng/mL or salvage treatment). Multivariable logistic regression models were used to estimate associations between percentage of positive cores and risk of upgrade and adverse pathology at radical prostatectomy. Multivariable Cox proportional hazards regression models were used to estimate associations between percentage of positive cores and hazard of recurrence after radical prostatectomy., Results: A total of 1,029 men met inclusion criteria. Multivariable logistic regression models demonstrated significant associations between percentage of positive cores and pathological upgrade (OR 1.31, 95% CI 1.1-1.57, P < . 01), but not University of California, San Francisco adverse pathology at radical prostatectomy ( P = . 84); percentage of positive cores was negatively associated with alternate adverse pathology (OR 0.67, 95% CI 0.48-0.93, P = . 02). Multivariable Cox regression models demonstrated no association between percentage of positive cores and hazard of recurrence after radical prostatectomy ( P = . 11)., Conclusions: In men with Gleason grade group 1 prostate cancer, tumor volume may be associated with upgrading at radical prostatectomy, but not more clinically significant outcomes of adverse pathology or recurrence.

In order to proliferate in unfavourable conditions, cancer cells can take advantage of the naturally occurring endoplasmic reticulum-associated unfolded protein response (UPR) via three highly conserved signalling arms: IRE1α, PERK and ATF6. All three arms of the UPR have key roles in every step of tumour progression: from cancer initiation to tumour growth, invasion, metastasis and resistance to therapy. At present, no cure for metastatic prostate cancer exists, as targeting the androgen receptor eventually results in treatment resistance. New research has uncovered an important role for the UPR in prostate cancer tumorigenesis and crosstalk between the UPR and androgen receptor signalling pathways. With an improved understanding of the mechanisms by which cancer cells exploit the endoplasmic reticulum stress response, targetable points of vulnerability can be uncovered., (© 2022. Springer Nature Limited.)

Objective: The utilization of video telemedicine has dramatically increased due to the COVID-19 pandemic. However, significant social and technological barriers have led to disparities in access. We aimed to identify factors associated with patient inability to successfully initiate a video visit across a high-volume urologic practice., Materials and Methods: Video visit completion rates and patient characteristics were extracted from the electronic medical record and linked with census-level socioeconomic data. Associations between video visit failure were identified using multivariate regression modeling and random forest ensemble classification modeling., Results: Six thousand eighty six patients and their first video visits were analyzed. On multivariate logistic regression analysis, Hispanic or Latino patients (OR 0.52, 95%CI 0.31-0.89), patients insured by Medicare (OR 0.46, 95%CI 0.26-0.79) or Medicaid (OR 0.50, 95%CI 0.29-0.87), patients of low socioeconomic status (OR 0.98, 95%CI 0.98-0.99), patients with an un-activated MyChart patient portal (OR 0.43, 95%CI 0.29-0.62), and patients unconfirmed at appointment reminder (OR 0.68, 95%CI 0.48-0.96) were significantly associated with video visit failure. Patients with primary diagnosis category of men's health (OR 47.96, 95%CI 10.24-856.35), and lower urinary tract syndromes (OR 2.69, 95%CI 1.66-4.51) were significantly associated with video visit success. Random forest analyses identified insurance status and socioeconomic status as the top predictors of video visit failure., Conclusion: An analysis of a urology video telemedicine cohort reveals clinical and demographic disparities in video visit completion and priorities for future interventions to ensure equity of access. Our study further suggests that specific urologic indications may play a role in success or failure of video visits., (Published by Elsevier Inc.)

Objective: To rank percentages of underrepresented residents in surgical subspecialties and understand the experience of mentees and mentors who participated in the inaugural University of California, San Francisco Urology UnderRepresented Trainees Entering Residency (UReTER) Mentorship Program for Black, Indigenous, and/or LatinX medical students applying into urology., Methods: Medical student mentees across the country were recruited via social media and email listservs. Demographic information and photos of mentors were presented on the UReTER website. Medical students could choose a mentor, and once matched, both parties were notified. A survey was emailed to all participants on Urology Match Day 2021., Result: The 2018 -2019 ACGME Databook showed underrepresented minority residents made up 7.6% of urology residents, lagging behind neurosurgery, vascular surgery, general surgery, and obstetrics and gynecology. 71 mentees and 101 mentors volunteered for the UReTER Mentorship Program (71 mentor-mentee couplets). Overall response rate was 51% [33 mentors and 32 mentees]. Of mentees who completed the survey, 16 (47%) participated in the 2021 Urology Match; 15 (94%) matched and 6 (38%) felt that UReTER helped them match., Conclusion: Feedback on this pilot program was very positive including a high match rate among those who participated. Future changes to the program include expanded student outreach, increased structure, broadened mentor network. The implementation of a low-cost program to increase underrepresented applicants into Urology has great potential to increase representation and improve the field. This program can and should be replicated in all subspecialties., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Enzalutamide is an antiandrogen used to treat both metastatic and nonmetastatic prostate cancer. Here we present results from a phase 2 trial designed to determine the safety, tolerability, and efficacy of adding enzalutamide to standard androgen deprivation therapy with radiation therapy in high-risk localized or regional, nonmetastatic patients with prostate cancer., Methods and Materials: Enrollment criteria included at least 2 of the following: stage cT3a/b, prostate specific antigen (PSA) ≥20 ng/mL, Gleason grade 8 to 10, ≥33% core involvement on biopsy, or pelvic lymph node involvement on computed tomography or magnetic resonance imaging. Patients with metastatic disease were excluded. All patients received 24 months of leuprolide and enzalutamide, and 5 weeks of intensity modulated radiation therapy followed by a brachytherapy boost. Adverse events (AE), PSA, testosterone, and basic laboratory tests were then followed for up to 36 months. Primary outcomes were safety and tolerability and PSA complete response rate (PSA-CR, defined as PSA ≤0.3). Secondary outcomes included time to biochemical recurrence (BCR; nadir + 2 ng/mL)., Results: Sixteen patients were enrolled; 2 were ineligible and 3 withdrew before starting treatment. Median age at enrollment was 69.0 years (interquartile range [IQR] 11.5). Median treatment duration was 24.0 months (IQR 11.9). Median follow-up time was 35.5 months (IQR 11.2), and 9 of 11 (81.8%) patients completed the 36 months of follow-up. One of 11 (9%) patients had grade 4 AE (seizure), and no grade 5 AE were reported. Four of 11 (36.4%) patients had grade 3 AE, such as erectile dysfunction and hot flashes. All patients achieved PSA-CR, and median time to PSA-CR was 4.2 months (IQR 1.4). At 24 months follow-up, 0 of 11 (0%) patients had a biochemical recurrence. At 36 months, 1 of 9 (11.1%) patient had a biochemical recurrence. Of note, this patient did not complete the full 24 months of enzalutamide and leuprolide due to AEs., Conclusions: Enzalutamide in combination with standard androgen deprivation therapy and radiation therapy was well-tolerated and effective warranting further study in a randomized controlled trial., (© 2022 The Author(s).)

Primary hyperoxalurias are a devastating family of diseases leading to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease. Traditional treatment paradigms are limited to conservative management, dialysis and combined transplantation of the kidney and liver, of which the liver is the primary source of oxalate production. However, transplantation is associated with many potential complications, including operative risks, graft rejection, post-transplant organ failure, as well as lifelong immunosuppressive medications and their adverse effects. New therapeutics being developed for primary hyperoxalurias take advantage of biochemical knowledge about oxalate synthesis and metabolism, and seek to specifically target these pathways with the goal of decreasing the accumulation and deposition of oxalate in the body., (© 2021. Springer Nature Limited.)

Primary hyperoxaluria 1 (PH1) is a devastating condition involving recurrent urolithiasis, early end-stage renal disease and multisystemic deposition of calcium oxalate crystals. Treatment options for PH1 are limited, inevitably requiring transplantation, usually combined kidney and liver transplant. Here we report successful compassionate use of Nedosiran, an RNA interference targeting lactate dehydrogenase, in an index patient. Monthly Nedosiran injections led to dramatically decreased plasma oxalate levels, decreased frequency of weekly hemodialysis sessions from 6 to 3, and deferral of combined kidney and liver transplant. Nedosiran represents a novel and impactful potential therapeutic for PH1 patients with end-stage renal disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To determine if older men with Gleason grade group (GG) 1 prostate cancer have a higher risk of having adverse pathology at radical prostatectomy after initially being managed with active surveillance (AS)., Methods: A total of 365 patients with GG1 prostate cancer initially managed with AS followed by delayed radical prostatectomy were identified. The primary outcome was adverse pathology after delayed radical prostatectomy in the men that were <65 years vs. men ≥65 years at the initiation of AS. Adverse pathology was defined as GG ≥3 or pT3 or pN1. Multivariable Cox proportional hazards regression models were used to calculate risk of adverse pathological findings at radical prostatectomy by age group., Results: At diagnosis, there were no significant differences in median prostate specific antigen density, percent positive biopsy cores, multiparametric magnetic resonance imaging (mpMRI) results or composite genomic classifier scores (derived from three commercially available genomic tests) between the two age groups. Men ≥65 years had more adverse pathology at radical prostatectomy (59.2% vs. 44.1%, P <0.01) and lower rates of biopsy upgrade-free survival and adverse pathology-free survival (log-rank P <0.01). On multivariable analysis age ≥65 years (Hazard Ratio (HR) 2.21, 95% Confidence Interval (CI) 1.57, 3.12) was associated with adverse pathology at radical prostatectomy. In separate multivariable analyses done for each age group, mpMRI (HR 3.33, 95% CI 1.01, 10.95) was predictor of adverse pathology in the group ≥65 years., Conclusion: Older patients might require closer monitoring on AS and additional testing such as mpMRI might improve their risk stratification., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Patients and providers often lack clinical decision tools to enable effective shared decision making. This is especially true in the rapidly changing therapeutic landscape of metastatic kidney cancer. Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria, a validated risk prediction tool for patients with metastatic renal cell carcinoma, we created and user-tested a novel interactive visualization for clinical use., Methods: An interactive visualization depicting IMDC criteria was created, with the final version including data for more than 4,500 patients. Usability testing was performed with nonmedical lay-users and medical oncology fellow physicians. Subjects used the tool to calculate median survival times based on IMDC criteria. User confidence was surveyed. An iterative user feedback implementation cycle was completed and informed revision of the tool., Results: The tool is available at CloViz-IMDC. Initially, 400 lay-users and 15 physicians completed clinical scenarios and surveys. Cumulative accuracy across scenarios was higher for physicians than lay-users (84% v 74%; P = .03). Eighty-three percent of lay-users and 87% of physicians thought the tool became intuitive with use. Sixty-eight percent of lay-users wanted to use the tool clinically compared with 87% of physicians. After revisions, the updated tool was user-tested with 100 lay-users and 15 physicians. Physicians, but not lay-users, showed significant improvement in accuracy in the updated version of the tool (90% v 67%; P = .008). Seventy-two percent of lay-users and 93% of physicians wanted to use the updated tool in a clinical setting., Conclusion: A graphical method of interacting with a validated nomogram provides prognosis results that can be used by nonmedical lay-users and physicians, and has the potential for expanded use across many clinical conditions.

Lessons Learned: Fulvestrant is a selective estrogen receptor (ER)-downregulating antiestrogen that blocks ER transcriptional activity and is approved for ER-positive breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models., Background: Fulvestrant is a selective estrogen receptor (ER)-downregulating antiestrogen that blocks ER transcriptional activity and is approved for ER-positive (+) breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models., Methods: This is a single-center phase Ib study with a 3+3 design of fulvestrant and the proteasome inhibitor ixazomib (MLN9708) in patients with advanced ER+ breast cancer that was progressing on fulvestrant. A dose-escalation design allowed establishment of the ixazomib maximum tolerated dose (MTD). Secondary objectives included progression-free survival, pharmacokinetics, and tumor molecular analyses., Results: Among nine evaluable subjects, treatment was well-tolerated without dose-limiting toxicities The MTD of ixazomib was 4 mg in combination with fulvestrant. Plasma concentrations of the active form of ixazomib (MLN2238) in the 4-mg dose cohort had a median (range) maximal concentration (C max ) of 155 (122-171) ng/mL, time of maximal concentration (T max ) of 1 (1-1.5) hour, terminal elimination half-life of 66.6 (57.3-102.6) hour after initial dose, and area under the curve (AUC) of 5,025 (4,160-5,345) ng*h/mL. One partial response was observed, and median progression-free survival was 51 days (range, 47-137)., Conclusion: This drug combination has a favorable safety profile and antitumor activity in patients with fulvestrant-resistant advanced ER+ breast cancer that justifies future testing., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Abstract: Preliminary data suggest that opioid-related overdose deaths have increased subsequent to COVID-19. Despite national support for expanding the role of physician assistants (PAs) and NPs in serving patients with opioid use disorder, these clinicians are held to complex and stringent regulatory barriers. COVID-19 triggered significant changes from regulatory and federal agencies, yet disparate policies and regulations persist between physicians and PAs and NPs. The dual epidemics of COVID-19 and opioid use disorder highlight the inadequate infrastructure required to support patients, communities, and clinicians, and may serve as the catalyst for eliminating barriers to care., (Copyright © 2021 American Academy of Physician Assistants.)

Purpose: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME)., Experimental Design: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1-high (PD-1 HI ) CD8 + peripheral T cells and examination of a cytolytic gene signature in whole blood., Results: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden., Conclusions: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence., (©2020 American Association for Cancer Research.)

Purpose: Circulating tumor DNA in plasma may present a minimally invasive opportunity to identify tumor-derived mutations to inform selection of targeted therapies for individual patients, particularly in cases of oligometastatic disease where biopsy of multiple tumors is impractical. To assess the utility of plasma DNA as a "liquid biopsy" for precision oncology, we tested whether sequencing of plasma DNA is a reliable surrogate for sequencing of tumor DNA to identify targetable genetic alterations., Methods: Blood and biopsies of 1-3 tumors were obtained from 4 evaluable patients with advanced breast cancer. One patient provided samples from an additional 7 tumors post-mortem. DNA extracted from plasma, tumor tissues, and buffy coat of blood were used for probe-directed capture of all exons in 149 cancer-related genes and massively parallel sequencing. Somatic mutations in DNA from plasma and tumors were identified by comparison to buffy coat DNA., Results: Sequencing of plasma DNA identified 27.94 ± 11.81% (mean ± SD) of mutations detected in a tumor(s) from the same patient; such mutations tended to be present at high allelic frequency. The majority of mutations found in plasma DNA were not found in tumor samples. Mutations were also found in plasma that matched clinically undetectable tumors found post-mortem., Conclusions: The incomplete overlap of genetic alteration profiles of plasma and tumors warrants caution in the sole reliance of plasma DNA to identify therapeutically targetable alterations in patients and indicates that analysis of plasma DNA complements, but does not replace, tumor DNA profiling., Trial Registration: Subjects were prospectively enrolled in trial NCT01836640 (registered April 22, 2013).

Purpose: Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies., Experimental Design: Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER + breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy., Results: Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the antidiabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival., Conclusions: AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER + breast cancer., (©2020 American Association for Cancer Research.)

Introduction: Recent molecular characterization of gliomas has uncovered somatic gene variation and DNA methylation changes that are associated with etiology, prognosis, and therapeutic response. Here we describe genomic profiling of gliomas assessed for associations between genetic mutations and patient outcomes, including overall survival (OS) and recurrence-free survival (RFS)., Methods: Mutations in a 50-gene cancer panel, 1p19q co-deletion, and MGMT promoter methylation (MGMT methylation) status were obtained from tumor tissue of 293 glioma patients. Multivariable regression models for overall survival (OS) and recurrence-free survival (RFS) were constructed for MGMT methylation, 1p19q co-deletion, and gene mutations controlling for age, treatment status, and WHO grade., Results: Mutational profiles of gliomas significantly differed based on WHO Grade, such as high prevalence of BRAF V600E, IDH1, and PTEN mutations in WHO Grade I, II/III, and IV tumors, respectively. In multivariate regression analysis, MGMT methylation and IDH1 mutations were significantly associated with improved OS (HR = 0.44, p = 0.0004 and HR = 0.21, p = 0.007, respectively), while FLT3 and TP53 mutations were significantly associated with poorer OS (HR = 19.46, p < 0.0001 and HR = 1.67, p = 0.014, respectively). MGMT methylation and IDH1 mutations were the only significant alterations associated with improved RFS in the model (HR = 0.42, p < 0.0001 and HR = 0.37, p = 0.002, respectively). These factors were then included in a combined model, which significantly exceeded the predictive value of the base model alone (age, surgery, radiation, chemo, grade) (likelihood ratio test OS p = 1.64 × 10 -8 and RFS p = 3.80 × 10 -7 )., Conclusions: This study highlights the genomic landscape of gliomas in a single-institution cohort and identifies a novel association between FLT3 mutation and OS in gliomas.

Robotic surgical skill development is central to training in urology as well as other surgical disciplines. Vesicourethral anastomosis (VUA) in robotic prostatectomy is a challenging task for novices due to delicate tissue and difficult suturing angles. Commercially available, realistic training models are limited. Here, we describe the development and validation of a 3D-printed model of the VUA for ex vivo training using the da Vinci Surgical System. Models of the bladder and urethra were created using 3D-printing technology based on estimations of average in vivo anatomy. 10 surgical residents without prior robotics training were enrolled in the study: 5 residents received structured virtual reality (VR) training on the da Vinci Skills Simulator ("trained"), while the other 5 did not ("untrained"). 4 faculty robotic surgeons trained in robotic urologic oncology ("experts") were also enrolled. Mean (range) completion percentage was 20% (10-30%), 54% (40-70%), and 96% (85-100%) by the untrained, trained, and expert groups, respectively. Anastomosis integrity was rated as excellent (as opposed to moderate or poor) in 40%, 60%, and 100% of untrained, trained, and expert groups, respectively. Face validity (realism) was rated as 8 of 10 on average by the expert surgeons, each of whom rated the model as a superior training tool to digital VR trainers. Content validity (usefulness) was rated as 10 of 10 by all participants. This is the first reported 3D-printed ex vivo trainer for VUA in robotic prostatectomy validated for use in robotic simulation. The addition of 3D-printed ex vivo training to existing digital simulation technologies may augment and improve robotic surgical education in the future.

Background: Among patients diagnosed with non-muscle invasive bladder cancer (NMIBC), 30% to 70% experience recurrences within 6 to 12 years of diagnosis. The need to screen for these events every 3 to 6 months and ultimately annually by cystoscopy makes bladder cancer one of the most expensive malignancies to manage., Objective: The purpose of this study was to identify reproducible prognostic microRNAs in resected non-muscle invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype as potential biomarkers and molecular therapeutic targets., Methods: Two independent cohorts of NMIBC patients were analyzed using a biomarker discovery and validation approach, respectively., Results: miRNA Let-7f-5p showed the strongest association with recurrence across both cohorts. Let-7f-5p levels in urine and plasma were both found to be significantly correlated with levels in tumor tissue. We assessed the therapeutic potential of targeting Lin28, a negative regulator of Let-7f-5p, with small-molecule inhibitor C1632. Lin28 inhibition significantly increased levels of Let-7f-5p expression and led to significant inhibition of viability and migration of HTB-2 cells., Conclusions: We have identified Let-7f-5p as a miRNA biomarker of recurrence in NMIBC tumors. We further demonstrate that targeting Lin28, a negative regulator of Let-7f-5p, represents a novel potential therapeutic opportunity in NMIBC.

Purpose: We hypothesized that integrated analysis of cancer types from different lineages would reveal novel molecularly defined subgroups with unique therapeutic vulnerabilities. On the basis of the molecular similarities between subgroups of breast and ovarian cancers, we analyzed these cancers as a single cohort to test our hypothesis., Experimental Design: Identification of transcriptional subgroups of cancers and drug sensitivity analyses were performed using mined data. Cell line sensitivity to Hsp90 inhibitors (Hsp90i) was tested in vitro . The ability of a transcriptional signature to predict Hsp90i sensitivity was validated using cell lines, and cell line- and patient-derived xenograft (PDX) models. Mechanisms of Hsp90i sensitivity were uncovered using immunoblot and RNAi., Results: Transcriptomic analyses of breast and ovarian cancer cell lines uncovered two mixed subgroups comprised primarily of triple-negative breast and multiple ovarian cancer subtypes. Drug sensitivity analyses revealed that cells of one mixed subgroup are significantly more sensitive to Hsp90i compared with cells from all other cancer lineages evaluated. A gene expression classifier was generated that predicted Hsp90i sensitivity in vitro , and in cell line- and PDXs. Cells from the Hsp90i-sensitive subgroup underwent apoptosis mediated by Hsp90i-induced upregulation of the proapoptotic proteins Bim and PUMA., Conclusions: Our findings identify Hsp90i as a potential therapeutic strategy for a transcriptionally defined subgroup of ovarian and breast cancers. This study demonstrates that gene expression profiles may be useful to identify therapeutic vulnerabilities in tumor types with limited targetable genetic alterations, and to identify molecularly definable cancer subgroups that transcend lineage., (©2019 American Association for Cancer Research.)

Background: Precision oncology seeks to integrate multiple layers of data from a patient's cancer to effectively tailor therapy. Conventional chemotherapies are sometimes effective but accompanied by adverse events, warranting the identification of a biomarker of chemosensitivity., Objective: Identify an mRNA biomarker that predicts chemosensitivity across solid tumor subtypes., Methods: We performed a pan-solid tumor analysis integrating gene expression and drug sensitivity profiles from 3 cancer cell line datasets to identify transcripts correlated with sensitivity to a panel of chemotherapeutics. We then tested the ability of an mRNA biomarker to predictive clinical outcomes in cohorts of patients with breast, lung, or ovarian cancer., Results: Expression levels of several mRNA transcripts were significantly correlated with sensitivity or resistance chemotherapeutics in cancer cell line datasets. The only mRNA transcript significantly correlated with sensitization to multiple classes of DNA-damaging chemotherapeutics in all 3 cell line datasets was encoded by Schlafen Family Member 11 (SLFN11). Analyses of multiple breast, lung, and ovarian cancer patient cohorts treated with chemotherapy confirmed SLFN11 mRNA expression as a predictive biomarker of longer overall survival and improved tumor response., Conclusions: Tumor SLFN11 mRNA expression is a biomarker of sensitivity to an array of DNA-damaging chemotherapeutics across solid tumor subtypes., Competing Interests: The authors have declared that no competing interests exist.

The patient is a 72-year-old female who presents with new onset jaundice. The patient has a past medical history significant for right-sided estrogen receptor (ER)-positive and left-sided ER-negative breast cancers in 2005 and 2009, respectively, and recent 1-year history of ER-positive right-sided breast cancer with bone and brain metastases. CT scan and endoscopic ultrasound (EUS) revealed a new 2 cm mass in the head of the pancreas, leading to EUS-guided fine-needle aspiration of the lesion. Pathologic workup revealed adenocarcinoma with signet-ring cells, representing either metastatic breast or primary pancreatic cancer. Immunohistochemistry and molecular diagnostic workup identified positive GATA-binding protein 3 (GATA3) immunoreactivity and a mutation in Erb-B2 receptor tyrosine kinase 2 (ERBB2), also known as human epidermal growth factor receptor 2 (HER2). Here, we review the diagnostic markers commonly used to differentiate metastatic breast vs primary pancreatic adenocarcinoma, and discuss the challenges of utilizing GATA3 immunoreactivity and ERBB2 mutations for diagnosis., (© 2019 Wiley Periodicals, Inc.)

Estrogens have been shown to elicit anticancer effects against estrogen receptor α (ER)-positive breast cancer. We sought to determine the mechanism underlying the therapeutic response. Response to 17β-estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient-derived xenografts, C7-2-HI and C4-HI murine mammary adenocarcinomas, and long-term estrogen-deprived MCF-7 cells. As another means to reactivate ER, the anti-estrogen fulvestrant was withdrawn from fulvestrant-resistant MCF-7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17β-estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17β-estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anticancer effects were most pronounced in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long-term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17β-estradiol treatment and anti-estrogen withdrawal hyperactivate ER, which drives an unfolded protein response and subsequent growth inhibition and apoptosis. 17β-estradiol treatment should be considered as a therapeutic option for anti-estrogen-resistant disease, particularly in patients with tumors harboring ESR1 amplification or ER overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may increase the therapeutic effects of ER reactivation., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Pancreatic cancer has a 5-year survival rate below 10% and the treatment options are limited. Signal transducer and activator of transcription (STAT3) is a constitutively expressed protein in human pancreatic cancers and is associated with their poor prognosis. Targeting of STAT3 signaling using novel therapeutic agents is a potential strategy for pancreatic cancer treatment. Diarylidenylpiperidone (DAP) compounds, such as H-4073 and HO-3867, have been shown to be STAT3 inhibitors in several human ovarian cancers. Particularly, HO-3867 is an N-hydroxypyrroline derivative of DAP that has targeted cytotoxicity toward cancer cells without affecting healthy cells. In the present study, we evaluated the anticancer efficacy of H-4073 and HO-3867 in a human pancreatic cell line (AsPC-1). We found that both the compounds exhibited potential cytotoxicity to AsPC-1 cells by inducing G2/M cell-cycle arrest, apoptosis, and cell death, by mitochondrial damage and inhibition of STAT3 phosphorylation. In summary, H-4073 and HO-3867 are cytotoxic to AsPC-1 cells and seem to act through similar mechanisms, including STAT3 inhibition, cell-cycle arrest, and apoptosis.

Historically, ductal carcinoma in situ (DCIS) of the breast has been managed aggressively with surgery and radiotherapy because of a risk of progression to invasive ductal carcinoma. However, this treatment paradigm has been challenged by overtreatment concerns and evidence that suggests that DCIS can be stratified according to risk of recurrence or risk of progression to invasive disease. Traditional methods of risk stratification include histologic grade and hormone receptor status. Recent technological advancements have enabled an era of precision medicine, where DCIS can be molecularly analyzed by tools, such as next-generation DNA and RNA sequencing, to identify molecular biomarkers for risk stratification. These findings have led to the development of tools such as the Oncotype DX Breast DCIS Score, a gene expression-based assay with the potential to prevent overtreatment in low-risk disease., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine patterns of crowdsourcing on the social media platform Twitter among urologists., Methods: Urologists' public Twitter accounts were reviewed for original posts seeking clinical advice or feedback, and associated reply posts, before and after the 140-character-limit expansion in 2017. Predictors of responses to crowdsourcing requests were determined using multivariable regression. When patient data were posted, we noted whether consent was documented., Results: A total of 276 posts in 23 crowdsourcing requests prior to character-limit expansion were analyzed. Reasons for crowdsourcing included requesting solutions to a clinical dilemma (82 posts, 30%); advice seeking about a surgical plan (77 posts, 28%); surveying colleagues' experiences with a new product (64 posts, 23%); and soliciting feedback about a proposed course of action (53 posts, 19%). Recent completion of training (as a proxy for inexperience) did not appear to disproportionately motivate crowdsourcing; authors' median time in practice was 7 years, and authors practicing for ≤ 7 years initiated 57% of requests. 22 (96%) crowdsourcing requests received ≥ 1 reply. Of 15 requests about a specific patient, eight included imaging, but only one cited patient consent. A second analysis of 184 posts in 17 crowdsourcing requests initiated after character-limit expansion demonstrated significantly more authors replying per request (P = 0.01), but no change in the frequency of patient-specific crowdsourcing or citation of consent., Conclusions: Urologists are leveraging Twitter for crowdsourcing clinical guidance and experiential knowledge. Nearly all requests were answered, suggesting low barriers to entry for novice users. Even after character-limit expansion, dissemination of potentially identifiable patient data remains a concern.

Despite the success of approved systemic therapies for estrogen receptor α (ER)-positive breast cancer, drug resistance remains common. We hypothesized that secreted factors from the human tumor microenvironment could modulate drug resistance. We previously screened a library of 297 recombinant-secreted microenvironmental proteins for the ability to confer resistance to the anti-estrogen fulvestrant in 2 ER + breast cancer cell lines. Herein, we considered whether factors that enhanced drug sensitivity could be repurposed as therapeutics and provide leads for drug development. Screening data revealed bone morphogenic protein (BMP)4 as a factor that inhibited cell growth and synergized with approved anti-estrogens and cyclin-dependent kinase 4/6 inhibitors (CDK4/6 i ). BMP4-mediated growth inhibition was dependent on type I receptor activin receptor-like kinase (ALK)3-dependent phosphorylation (P) of mothers against decapentaplegic homolog (SMAD/P-SMAD)1 and 5, which could be reversed by BMP receptor inhibitors and ALK3 knockdown. The primary effect of BMP4 on cell fate was cell-cycle arrest, in which RNA sequencing, immunoblot analysis, and RNA interference revealed to be dependent on p21 WAF1/Cip1 upregulation. BMP4 also enhanced sensitivity to approved inhibitors of mammalian target of rapamycin complex 1 and CDK4/6 via ALK3-mediated P-SMAD1/5 and p21 upregulation in anti-estrogen-resistant cells. Patients bearing primary ER + breast tumors, exhibiting a transcriptomic signature of BMP4 signaling, had improved disease outcome following adjuvant treatment with anti-estrogen therapy, independently of age, tumor grade, and tumor stage. Furthermore, a transcriptomic signature of BMP4 signaling was predictive of an improved biologic response to the CDK4/6 i palbociclib, in combination with an aromatase inhibitor in primary tumors. These findings highlight BMP4 and its downstream pathway activation as a therapeutic opportunity in ER + breast cancer.-Shee, K., Jiang, A., Varn, F. S., Liu, S., Traphagen, N. A., Owens, P., Ma, C. X., Hoog, J., Cheng, C., Golub, T. R., Straussman, R., Miller, T. W. Cytokine sensitivity screening highlights BMP4 pathway signaling as a therapeutic opportunity in ER + breast cancer.

p53 is an important tumor-suppressor protein that is mutated in more than 50% of cancers. Strategies for restoring normal p53 function are complicated by the oncogenic properties of mutant p53 and have not met with clinical success. To counteract mutant p53 activity, a variety of drugs with the potential to reconvert mutant p53 to an active wildtype form have been developed. However, these drugs are associated with various negative effects such as cellular toxicity, nonspecific binding to other proteins, and inability to induce a wildtype p53 response in cancer tissue. Here, we report on the effects of a curcumin analog, HO-3867, on p53 activity in cancer cells from different origins. We found that HO-3867 covalently binds to mutant p53, initiates a wildtype p53-like anticancer genetic response, is exclusively cytotoxic toward cancer cells, and exhibits high anticancer efficacy in tumor models. In conclusion, HO-3867 is a p53 mutant-reactivating drug with high clinical anticancer potential., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Drug resistance to approved systemic therapies in estrogen receptor-positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance. FGF2-driven drug resistance in anti-estrogen-sensitive and -resistant models, including patient-derived xenografts, was reverted by neutralizing FGF2 or FGFRs. A transcriptomic signature of FGF2 signaling in primary tumors predicted shorter recurrence-free survival independently of age, grade, stage, and FGFR amplification status. These findings delineate FGF2 signaling as a ligand-based drug resistance mechanism and highlights an underdeveloped aspect of precision oncology: characterizing and treating patients according to their TME constitution., (© 2018 Shee et al.)

Hyperactivation of the PI3K pathway has been implicated in resistance to antiestrogen therapies in estrogen receptor α (ER)-positive breast cancer, prompting the development of therapeutic strategies to inhibit this pathway. Autophagy has tumor-promoting and -suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER + breast cancer cells. PI3K inhibition with GDC-0941 (pictilisib) induced autophagy. Inhibition of autophagy using CQ or RNA interference potentiated PI3K inhibitor-induced apoptosis. Combined inhibition of PI3K and autophagy effectively induced mitochondrial membrane depolarization, which required the BH3-only proapoptotic proteins Bim and PUMA. Treatment with GDC-0941, CQ, or the combination, significantly suppressed the growth of ER + breast cancer xenografts in mice. In an antiestrogen-resistant xenograft model, GDC-0941 synergized with CQ to provide partial, but durable, tumor regression. These findings warrant clinical evaluation of therapeutic strategies to target ER, PI3K, and autophagy for the treatment of ER + breast cancer.-Yang, W., Hosford, S. R., Traphagen, N. A., Shee, K., Demidenko, E., Liu, S., Miller, T. W. Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.

Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article.