Reinforcing informed medication prescription for low back pain in the emergency department (RIME): a controlled interrupted time series implementation study protocol.

INTRODUCTION: Management guidelines for low back pain (LBP) recommend exclusion of serious pathology, followed by simple analgesics, superficial heat therapy, early mobilisation and patient education. An audit in a large metropolitan hospital emergency department (ED) revealed high rates of non-recommended medication prescription for LBP (65% of patients prescribed opioids, 17% prescribed benzodiazepines), high inpatient admission rates (20% of ED LBP patients), delayed patient mobilisation (on average 6 hours) and inadequate patient education (48% of patients). This study aims to improve medication prescription for LBP in this ED by implementing an intervention shown previously to improve guideline-based management of LBP in other Australian EDs. METHODS AND ANALYSIS: A controlled interrupted time series study will evaluate the intervention in the ED before (24 weeks; 20 March 2023-3 September 2023) and after (24 weeks; 27 November 2024-12 May 2024) implementation (12 weeks; 4 September 2023-26 November 2023), additionally comparing findings with another ED in the same health service. The multicomponent implementation strategy uses a formalised clinical flow chart to support clinical decision-making and aims to change clinician behaviour, through clinician education, provision of alternative treatments, educational resources, audit and feedback, supported by implementation champions. The primary outcome is the percentage of LBP patients prescribed non-recommended medications (opioids, benzodiazepines and/or gabapentinoids), assessed via routinely collected ED data. Anticipated sample size is 2000 patients (n=1000 intervention, n=1000 control) based on average monthly admissions of LBP presentations in the EDs. Secondary outcomes include inpatient admission rate, time to mobilisation, provision of patient education, imaging requests, representation to the ED within 6 months and healthcare costs. In nested qualitative research, we will study ED clinicians' perceptions of the implementation and identify how benefits can be sustained over time. ETHICS AND DISSEMINATION: This study received ethical approval from the Metro North Human Research Ethics Committee (HREC/2022/MNHA/87995). Study findings will be published in peer-reviewed journals and presented at international conferences and educational workshops. TRIAL REGISTRATION NUMBER: ACTRN12622001536752.

Is chest imaging needed as part of pT1a renal cell carcinoma surveillance after surgical resection?

INTRODUCTION: Following surgical excision of pT1a renal cell carcinoma (RCC), 2% to 5% will recur, with 50% to 60% being lung metastases. The ideal surveillance strategy to identify recurrences is unclear. Guidelines are mixed, with NCCN and AUA recommending surveillance via chest x-ray (CXR) at least annually for 5 years, while EAU guidelines do not specifically recommend the use of CXR. In an effort to clarify the utility of surveillance CXR, we retrospectively evaluated pT1a patients following surgical treatment at a single institution. METHODS: We performed retrospective analysis of unique patients who underwent surgical excision of pT1 RCC between January 2000 and January 2020. In addition to demographic information, we collected RCC pathology, recurrence details, and most recent chest imaging. We excluded non-RCC pathology, and patients with pulmonary nodules on baseline imaging. RESULTS: We identified 463 unique patients (mean age 58.3 years, range 23-87) that underwent surgical excision of pT1a RCC with mean follow-up of 47.6 months (range 1-201). On the most recent pulmonary surveillance imaging, 72.4% (335/463) had CXR while 27.6% (128/463) had chest CT performed. Regardless of modality, pulmonary recurrence was not detected on any surveillance imaging (0/463). CONCLUSION: In patients without baseline preoperative lung pathology, we found that there is questionable clinical value in surveillance for pulmonary recurrence after resection of pT1a RCC.

Multi-Site Concordance of Diffusion-Weighted Imaging Quantification for Assessing Prostate Cancer Aggressiveness.

BACKGROUND: Diffusion-weighted imaging (DWI) is commonly used to detect prostate cancer, and a major clinical challenge is differentiating aggressive from indolent disease. PURPOSE: To compare 14 site-specific parametric fitting implementations applied to the same dataset of whole-mount pathologically validated DWI to test the hypothesis that cancer differentiation varies with different fitting algorithms. STUDY TYPE: Prospective. POPULATION: Thirty-three patients prospectively imaged prior to prostatectomy. FIELD STRENGTH/SEQUENCE: 3 T, field-of-view optimized and constrained undistorted single-shot DWI sequence. ASSESSMENT: Datasets, including a noise-free digital reference object (DRO), were distributed to the 14 teams, where locally implemented DWI parameter maps were calculated, including mono-exponential apparent diffusion coefficient (MEADC), kurtosis (K), diffusion kurtosis (DK), bi-exponential diffusion (BID), pseudo-diffusion (BID*), and perfusion fraction (F). The resulting parametric maps were centrally analyzed, where differentiation of benign from cancerous tissue was compared between DWI parameters and the fitting algorithms with a receiver operating characteristic area under the curve (ROC AUC). STATISTICAL TEST: Levene's test, P < 0.05 corrected for multiple comparisons was considered statistically significant. RESULTS: The DRO results indicated minimal discordance between sites. Comparison across sites indicated that K, DK, and MEADC had significantly higher prostate cancer detection capability (AUC range = 0.72-0.76, 0.76-0.81, and 0.76-0.80 respectively) as compared to bi-exponential parameters (BID, BID*, F) which had lower AUC and greater between site variation (AUC range = 0.53-0.80, 0.51-0.81, and 0.52-0.80 respectively). Post-processing parameters also affected the resulting AUC, moving from, for example, 0.75 to 0.87 for MEADC varying cluster size. DATA CONCLUSION: We found that conventional diffusion models had consistent performance at differentiating prostate cancer from benign tissue. Our results also indicated that post-processing decisions on DWI data can affect sensitivity and specificity when applied to radiological-pathological studies in prostate cancer. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

The prognostic value of digital rectal exam for the existence of advanced pathologic features after prostatectomy.

BACKGROUND: Accurate staging at the time of prostate cancer diagnosis is fundamental to risk stratification and management counseling. Digital rectal exam (DRE) is foundational in clinical staging of prostate cancer, even with a known limited interexaminer agreement and poor sensitivity for detecting extraprostatic disease. We sought to evaluate the prognostic value of DRE for the presence of advanced pathologic features (APFs) following radical prostatectomy (RP). METHODS: All patients undergoing RP as primary treatment for clinically localized prostate cancer in the National Cancer Database between 2008 and 2014 were identified. Patients with additional malignancies, prior treatment with radiation or systemic therapy, incongruent clinical staging and DRE findings or without fully evaluable clinical staging were excluded. The primary outcome was the presence of postsurgical APFs, defined as positive surgical margins, nodal disease, or pathologic stage T3 or greater. Multivariable logistic regression analysis was performed to account for prostate-specific antigen (PSA), biopsy grade group, percent of positive biopsy cores, and clinical stage. RESULTS: In total, 91,525 patients consisting of 69,182 cT1, 20,641 cT2, and 1702 cT3-T4 were included. The average age was 61.1 ± 7.0 years, and the average PSA was 8.6 ± 10.3 ng/ml. On multivariable analysis, cT3 and T4 were associated with the presence of APFs (odds ratio [OR] 11.12, p < .01 and 5.28, p = .04), however, cT2 was only slightly associated with the presence of APFs when compared with cT1 (OR 1.15, p < .01). Furthermore, cT2 was associated with more node-positive disease (OR 1.63, p < .01), positive margins (OR 1.06, p < .01), and more than or equal to pT3 disease (OR 1.22, p < .01). CONCLUSIONS: Overall, advanced clinical stage as assessed by DRE was independently associated with an increasing risk of APFs. For individual APFs, the greatest effect is noticed between clinical stage and nodal positivity and less so between clinical stage and positive margins. DRE continues to hold value, particularly for patients with locally advanced disease and potential lymph node disease.

Long-Term Outcomes of Dose-Escalated Pelvic Lymph Node Intensity-Modulated Radiation Therapy (IMRT) With a Simultaneous Hypofractionated Boost to the Prostate for Very High-Risk Adenocarcinoma of the Prostate: A Prospective Phase II Clinical Trial.

PURPOSE: There remains limited data as to the feasibility, safety, and efficacy of higher doses of elective radiation therapy to the pelvic lymph nodes in men with high-risk prostate cancer. We conducted a phase II study to evaluate moderate dose escalation to the pelvic lymph nodes using a simultaneous integrated boost to the prostate. METHODS AND MATERIALS: Patients were eligible with biopsy-proven adenocarcinoma of the prostate, a calculated lymph node risk of at least 25%, Karnofsky performance scale ≥70, and no evidence of M1 disease. Acute and late toxicity were prospectively collected at each follow-up using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). The pelvic lymph nodes were treated to a dose of 56 Gy over 28 fractions with a simultaneous integrated boost to the prostate to a total dose of 70 Gy over 28 fractions using intensity-modulated radiation therapy. RESULTS: Thirty patients were prospectively enrolled from October 2010 to August 2014. Median patient age was 70 years (57-83), pretreatment prostate-specific antigen was 11.5 ng/mL (3.23-111.5), T stage was T2c (T1c-T3b), and Gleason score was 9 (6-9). CTCAE v4.0 rate of any grade 1 or 2 genitourinary and gastrointestinal toxicity were 55% and 44%, respectively, and there was 1 reported acute grade 3 genitourinary and gastrointestinal toxicity, both unrelated to protocol therapy. With a median follow-up of 6.4 years, the biochemical failure free survival rate was 80.2%, and mean biochemical progression free survival was 8.3 years (95% confidence interval [CI], 7.2-9.4). The prostate cancer specific survival was 95.2%, and mean prostate cancer specific survival was 8.7 years (95% CI, 8.0-9.4). Five-year distant metastases free survival was 96%. Medians were not reached. CONCLUSIONS: In this single arm, small, prospective feasibility study, nodal radiation therapy dose escalation was safe, feasible, and seemingly well tolerated. Rates of progression free survival are highly encouraging in this population of predominately National Comprehensive Cancer Network very high-risk patients.

Accurate segmentation of prostate cancer histomorphometric features using a weakly supervised convolutional neural network.

Purpose: Prostate cancer primarily arises from the glandular epithelium. Histomophometric techniques have been used to assess the glandular epithelium in automated detection and classification pipelines; however, they are often rigid in their implementation, and their performance suffers on large datasets where variation in staining, imaging, and preparation is difficult to control. The purpose of this study is to quantify performance of a pixelwise segmentation algorithm that was trained using different combinations of weak and strong stroma, epithelium, and lumen labels in a prostate histology dataset. Approach: We have combined weakly labeled datasets generated using simple morphometric techniques and high-quality labeled datasets from human observers in prostate biopsy cores to train a convolutional neural network for use in whole mount prostate labeling pipelines. With trained networks, we characterize pixelwise segmentation of stromal, epithelium, and lumen (SEL) regions on both biopsy core and whole-mount H&E-stained tissue. Results: We provide evidence that by simply training a deep learning algorithm on weakly labeled data generated from rigid morphometric methods, we can improve the robustness of classification over the morphometric methods used to train the classifier. Conclusions: We show that not only does our approach of combining weak and strong labels for training the CNN improve qualitative SEL labeling within tissue but also the deep learning generated labels are superior for cancer classification in a higher-order algorithm over the morphometrically derived labels it was trained on.

Enzalutamide-Induced Feed-Forward Signaling Loop Promotes Therapy-Resistant Prostate Cancer Growth Providing an Exploitable Molecular Target for Jak2 Inhibitors.

The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate cancer (CRPC) and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of prostate cancer growth. Here, we investigated the significance of Jak2-Stat5 signaling in resistance of prostate cancer to enzalutamide. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in prostate cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate cancer to pharmacologic inhibitors of Jak2-Stat5 signaling was assessed in vivo in mice bearing prostate cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to Stat5 blockade as second-line treatment after enzalutamide ex vivo in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2-Stat5 phosphorylation in prostate cancer leading to the formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, enzalutamide-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted prostate cancer growth during enzalutamide treatment. Jak2-Stat5 inhibition induced death of prostate cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2-Stat5 signaling in enzalutamide-resistant prostate cancer, which is readily targetable by Jak2 inhibitors in clinical development.

Pathogen-Boosted Adoptive Cell Transfer Therapy Induces Endogenous Antitumor Immunity through Antigen Spreading.

Loss of target antigens in tumor cells has become one of the major hurdles limiting the efficacy of adoptive cell therapy (ACT)-based immunotherapies. The optimal approach to overcome this challenge includes broadening the immune response from the initially targeted tumor-associated antigen (TAA) to other TAAs expressed in the tumor. To induce a more broadly targeted antitumor response, we utilized our previously developed Re-energized ACT (ReACT), which capitalizes on the synergistic effect of pathogen-based immunotherapy and ACT. In this study, we showed that ReACT induced a sufficient endogenous CD8+ T-cell response beyond the initial target to prevent the outgrowth of antigen loss variants in a B16-F10 melanoma model. Sequentially, selective depletion experiments revealed that Batf3-driven cDC1s were essential for the activation of endogenous tumor-specific CD8+ T cells. In ReACT-treated mice that eradicated tumors, we observed that endogenous CD8+ T cells differentiated into memory cells and facilitated the rejection of local and distal tumor rechallenge. By targeting one TAA with ReACT, we provided broader TAA coverage to counter antigen escape and generate a durable memory response against local relapse and metastasis.See related Spotlight on p. 2.

Factors Influencing Patient Selection of Urologists.

OBJECTIVE: To describe the factors affecting patients' selection of a urologist, and the utilization of the Internet and social media. MATERIALS AND METHODS: All new patients presenting to a single-institution for evaluation were invited to complete an anonymous 26-item questionnaire between April 2018 and October 2018, including demographic information, use of Internet and social media resources, and relative importance of factors when selecting a urologist. Descriptive statistics were reported, and a stratified analysis was performed for age, gender, and education. RESULTS: A total of 238 patients responded. More than half (53%) of patients searched their medical condition prior to presentation. When stratified by age, younger patients were 3 times as likely to utilize Internet resources (Group 1 vs Group 2; OR 3.3, 95%CI 1.5-7.2, P <.01). Few patients utilized Facebook (7%) or Twitter (1%). The 3 most important surveyed urologist selection factors included hospital reputation (4.3 ± 1.0), in-network providers (4.0 ± 1.3), and appointment availability (3.9 ± 1.0). The 3 least important included medical school attended (2.7 ± 1.3), urologist on social media (1.9 ± 1.2), and TV, radio, and/or billboard advertisements (1.7 ± 1.3). CONCLUSION: This study suggests a significant proportion of patients search the Internet regarding their medical condition prior to presenting to clinic. Further, younger patients utilize this methodology significantly more than the senior population. Important factors when selecting a urologist may be driven by a hospital's reputation, in addition to scheduling convenience.

Digital Rectal Examination Remains a Key Prognostic Tool for Prostate Cancer: A National Cancer Database Review.

BACKGROUND: Prostate cancer clinical stage T2 (cT2) subclassifications, as determined by digital rectal examination (DRE), are a historic method of staging prostate cancer. However, given the potential discomfort associated with prostate examination and the wide availability of other prognostic tests, the necessity of DRE is uncertain. This study sought to determine the prognostic value of the prostate cancer cT2 subclassifications in a contemporary cohort of patients. METHODS: The National Cancer Database was used to identify a cohort of men with high-risk clinical T2N0M0 prostate cancer treated with external-beam radiotherapy and androgen deprivation therapies ± surgery from 2004 to 2010. We assessed overall survival from a landmark time of 10 months using Kaplan-Meier and log-rank test analysis. A multivariate proportional hazards model was used to estimate the simultaneous effects of multiple factors, including cT2 subclassification and other well-established prognostic indicators of overall survival in prostate cancer. RESULTS: A total of 5,291 men were included in the final analysis, with a median follow-up of 5.4 years. The cT2a, cT2b, and cT2c subclassifications demonstrated increasing hazard ratios of 1.00 (reference), 1.25 (95% CI, 1.07-1.45; P=.0046), and 1.43 (95% CI, 1.25-1.63; P<.0001), respectively, reflecting a higher probability of death with each incremental increase in cT2 subclassification. This finding was independent of other known prognostic variables on multivariate analysis. CONCLUSIONS: Results show that cT2 subclassifications had independent prognostic value in a large and contemporary cohort of men. cT2 classification remains an important, low-cost prognostic tool for men with prostatic adenocarcinoma. The clinical relevance of this test should be appreciated and accounted for by providers treating prostate adenocarcinoma.

Evolving Trends for Selected Treatments of T1a Renal Cell Carcinoma.

OBJECTIVE: To evaluate contemporary trends in the management of small renal masses and how patient age has impacted practice patterns. METHODS: Using the NCDB Participant User File (PUF) from 2002 to 2015, we identified patients with T1a renal masses. The initial treatment was categorized as radical nephrectomy (RN), partial nephrectomy (PN), ablation, or active surveillance (AS). A multinominal logistic regression model was used to identify significant factors impacting treatment. RESULTS: We identified 75,691 patients for analysis. RN, PN, and ablation accounted for 28%, 52%, and 12%, respectively, while 8% were managed with AS. In the past decade the likelihood of undergoing PN, ablation, or surveillance compared to RN has consistently increased, independent of age, sex, race, comorbidity, tumor size, or institution. As age increased, patients were independently less likely to undergo PN and more likely to be managed with ablation or AS. Compared to patients under 40 years of age, patients between 70 and 79 were far less likely to undergo PN (RR 0.58, P< .01), and far more likely to undergo either ablation (RR 5.53, P< .01) or AS (RR 3.7, P< .01). CONCLUSION: Trends in small renal mass management continue to evolve, with PN supplanting RN over the past decade as the predominant surgical treatment. Age significantly impacts treatment selection, particularly in older cohorts whom are much more likely to undergo ablation or AS. While the use of minimally invasive therapies has increased over the past decade, AS lags behind despite quality data supporting its use. When controlling for multiple clinical factors, PN, ablation and surveillance have consistently increased in utilization compared to RN.

Positive STAT5 Protein and Locus Amplification Status Predicts Recurrence after Radical Prostatectomy to Assist Clinical Precision Management of Prostate Cancer.

BACKGROUND: A significant fraction of prostate cancer patients experience post-radical prostatectomy (RP) biochemical recurrence (BCR). New predictive markers are needed for optimizing postoperative prostate cancer management. STAT5 is an oncogene in prostate cancer that undergoes amplification in 30% of prostate cancers during progression. METHODS: We evaluated the significance of a positive status for nuclear STAT5 protein expression versus STAT5 locus amplification versus combined positive status for both in predicting BCR after RP in 300 patients. RESULTS: Combined positive STAT5 status was associated with a 45% disadvantage in BCR in Kaplan-Meier survival analysis in all Gleason grade patients. Patients with Gleason grade group (GG) 2 and 3 prostate cancers and combined positive status for STAT5 had a more pronounced disadvantage of 55% to 60% at 7 years after RP in univariate analysis. In multivariate analysis, including the Cancer of the Prostate Risk Assessment Postsurgical nomogram (CAPRA-S) variables, combined positive STAT5 status was independently associated with a shorter BCR-free survival in all Gleason GG patients (HR, 2.34; P = 0.014) and in intermediate Gleason GG 2 or 3 patients (HR, 3.62; P = 0.021). The combined positive STAT5 status improved the predictive value of the CAPRA-S nomogram in both ROC-AUC analysis and in decision curve analysis for BCR. CONCLUSIONS: Combined positive status for STAT5 was independently associated with shorter disease-free survival in univariate analysis and was an independent predictor for BCR in multivariate analysis using the CAPRA-S variables in prostate cancer. IMPACT: Our results highlight potential for a novel precision medicine concept based on a pivotal role of STAT5 status in improving selection of prostate cancer patients who are candidates for early adjuvant interventions to reduce the risk of recurrence.

Gleason Probability Maps: A Radiomics Tool for Mapping Prostate Cancer Likelihood in MRI Space.

Prostate cancer is the most common noncutaneous cancer in men in the United States. The current paradigm for screening and diagnosis is imperfect, with relatively low specificity, high cost, and high morbidity. This study aims to generate new image contrasts by learning a distribution of unique image signatures associated with prostate cancer. In total, 48 patients were prospectively recruited for this institutional review board-approved study. Patients underwent multiparametric magnetic resonance imaging 2 weeks before surgery. Postsurgical tissues were annotated by a pathologist and aligned to the in vivo imaging. Radiomic profiles were generated by linearly combining 4 image contrasts (T2, apparent diffusion coefficient [ADC] 0-1000, ADC 50-2000, and dynamic contrast-enhanced) segmented using global thresholds. The distribution of radiomic profiles in high-grade cancer, low-grade cancer, and normal tissues was recorded, and the generated probability values were applied to a naive test set. The resulting Gleason probability maps were stable regardless of training cohort, functioned independent of prostate zone, and outperformed conventional clinical imaging (area under the curve [AUC] = 0.79). Extensive overlap was seen in the most common image signatures associated with high- and low-grade cancer, indicating that low- and high-grade tumors present similarly on conventional imaging.

The implications of fellowship expansion on future pediatric urologist surgical volumes.

INTRODUCTION: Over the past 25 years, Pediatric Urology fellowship programs accredited by the Accreditation Council for Graduate Medical Education (ACGME) have more than doubled. This increase may lead to a significant decrease in the number of operative cases per surgeon and therefore impact the current practice of pediatric urology. OBJECTIVE: The objective in conducting this study is to try and predict the effect of the current number of pediatric urology fellowship training positions on future case volume per surgeon using a mathematical model and to discuss future management of the pediatric urology workforce. DESIGN: The current study employed a mathematical model to predict the effect of the number of fellowship graduates on future "case volume per surgeon". We incorporated population growth rates, to calculate incidence rates of key procedures/conditions and the anticipated retirement rate of the current pool of pediatric urologists to help calculate this. RESULTS: There is a possibility to increase the number of practicing board-certified pediatric urologists in the next 30 years from approximately 325 to 900 (figure). There will be a twofold reduction in case volume per surgeon compared to the present in model 1. In model 2 the decrease in case volumes is less significant. The annual number of fellows needed to obtain a future-to-current ratio equal to 1 is 16 for model 1, and 26 for model 2. DISCUSSION: Our study demonstrates, by using two different models that the current number of pediatric urology fellowship training positions in the United States will ultimately lead to a significant decrease in the case volume per surgeons. Our model has limitations as it relies on multiple assumptions. We are assuming that all fellowship positions would be filled every year and that all fellows would graduate, establish their practices in the United States, and devote 100% of their assumed 30-year professional career to pediatric urology. We also made assumptions of disease occurrence and need for surgical correction. The final assumption we made was that the birth rate would stay static over the next 30 years even though it has been declining for many decades. CONCLUSION: This exercise, even with its inherent limitations, is still sufficient to demonstrate that fellowship expansion warrants thoughtful discussion.

Radio-pathomic Maps of Epithelium and Lumen Density Predict the Location of High-Grade Prostate Cancer.

PURPOSE: This study aims to combine multiparametric magnetic resonance imaging (MRI) and digitized pathology with machine learning to generate predictive maps of histologic features for prostate cancer localization. METHODS AND MATERIALS: Thirty-nine patients underwent MRI prior to prostatectomy. After surgery, tissue was sliced according to MRI orientation using patient-specific 3-dimensionally printed slicing jigs. Whole-mount sections were annotated by our pathologist and digitally contoured to differentiate the lumen and epithelium. Slides were co-registered to the T2-weighted MRI scan. A learning curve was generated to determine the number of patients required for a stable machine-learning model. Patients were randomly stratified into 2 training sets and 1 test set. Two partial least-squares regression models were trained, each capable of predicting lumen and epithelium density. Predicted density values were calculated for each patient in the test dataset, mapped into the MRI space, and compared between regions confirmed as high-grade prostate cancer. RESULTS: The learning-curve analysis showed that a stable fit was achieved with data from 10 patients. Maps indicated that regions of increased epithelium and decreased lumen density, generated from each independent model, corresponded with pathologist-annotated regions of high-grade cancer. CONCLUSIONS: We present a radio-pathomic approach to mapping prostate cancer. We find that the maps are useful for highlighting high-grade tumors. This technique may be relevant for dose-painting strategies in prostate radiation therapy.

STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair.

Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy.Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors.Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues.Conclusions: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2-Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917-31. ©2018 AACR.

Optimized b-value selection for the discrimination of prostate cancer grades, including the cribriform pattern, using diffusion weighted imaging.

Multiparametric magnetic resonance imaging (MP-MRI), including diffusion-weighted imaging, is commonly used to diagnose prostate cancer. This radiology-pathology study correlates prostate cancer grade and morphology with common b-value combinations for calculating apparent diffusion coefficient (ADC). Thirty-nine patients undergoing radical prostatectomy were recruited for MP-MRI prior to surgery. Diffusion imaging was collected with seven b-values, and ADC was calculated. Excised prostates were sliced in the same orientation as the MRI using 3-D printed slicing jigs. Whole-mount slides were digitized and annotated by a pathologist. Annotated samples were aligned to the MRI, and ADC values were extracted from annotated peripheral zone (PZ) regions. A receiver operating characteristic (ROC) analysis was performed to determine accuracy of tissue type discrimination and optimal ADC b-value combination. ADC significantly discriminates Gleason (G) G4-5 cancer from G3 and other prostate tissue types. The optimal b-values for discriminating high from low-grade and noncancerous tissue in the PZ are 50 and 2000, followed closely by 100 to 2000 and 0 to 2000. Optimal ADC cut-offs are presented for dichotomized discrimination of tissue types according to each b-value combination. Selection of b-values affects the sensitivity and specificity of ADC for discrimination of prostate cancer.

Ten-Year Review of Perioperative Complications After Transurethral Resection of Bladder Tumors: Analysis of Monopolar and Plasmakinetic Bipolar Cases.

OBJECTIVES: To evaluate the rate of perioperative complications after plasmakinetic bipolar and monopolar transurethral resection of bladder tumor (BTURB and MTURB). In addition, the study identifies patient and procedure characteristics associated with early complications. PATIENTS AND METHODS: Retrospective review was conducted on patients undergoing transurethral resection of bladder tumor procedures at a single institution from 2003 to 2013 to assess the 30-day complication rates associated with BTURB and MTURB. RESULTS: Four hundred twenty-seven patients met inclusion criteria and underwent 586 procedures (379 BTURB and 207 MTURB). Baseline patient demographics, tumor stage, and tumor grade were similar in BTURB and MTURB cohorts. The overall complication rate was 34.3% for MTURB and 26.7% for BTURB. The most frequent complications were acute urinary retention (AUR) 11%, hematuria 8%, and urinary tract infection (UTI) 7%. There was no statistical difference in rates of AUR, hematuria, UTI, or readmission for continuous bladder irrigation or hemostasis procedures between BTURB and MTURB cohorts. There was a trend toward lower perforation rate during BTURB (2.6% vs 5.8%). In multivariate logistic regression analysis, MTURB, male gender, and large resections were predictive of overall complications. Male gender was associated with hematuria and AUR. Large bladder tumor resection size was also associated with increased risk of overall complications and AUR. CONCLUSION: BTURB was associated with a lower risk of overall complications, but there was no difference in the rate of hematuria in the two cohorts. Male gender and large tumor size are associated with higher risk of early complications.

Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles.

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms.

Toward Quantitative Whole Organ Thermoacoustics With a Clinical Array Plus One Very Low-Frequency Channel Applied to Prostate Cancer Imaging.

Thermoacoustics has the potential to provide quantitative images of intrinsic tissue properties, most notably electrical conductivity in Siemens/meter, much as shear wave elastography provides tissue stiffness in kilopascal. Although thermoacoustic imaging with optical excitation has been commercialized for small animals, it has not yet made the transition to clinic for whole organ imaging in humans. The purpose of this work was to develop and validate specifications for a clinical ultrasound array for quantitative whole organ thermoacoustic imaging. Imaging a large organ requires exciting thermoacoustic pulses throughout the volume and broadband detection of those pulses because tomographic image reconstruction preserves frequency content. Applying the half-wavelength limit to a [Formula: see text] inclusion inside a 7.5-cm diameter organ requires measurement sensitivity to frequencies ranging from 4 MHz to 10 kHz, respectively. A dual-transducer system utilizing a P4-1 array connected to a Verasonics V1 system as well as a focused single-element transducer sensitive to lower frequencies was developed. Very high-frequency (VHF) irradiation generated thermoacoustic pulses throughout a [Formula: see text] volume. In the VHF regime, electrical conductivity drives thermoacoustic signal production. Simultaneous acquisition of thermoacoustic pulses by both transducers enabled comparison of transducer performance. Data from the clinical array generated a stack of 96 images with a separation of 0.3 mm, whereas the single-element transducer imaged only in a single plane. In-plane resolution and quantitative accuracy were quantified at isocenter. The array provided volumetric imaging capability with superior resolution whereas the single-element transducer provided superior quantitative accuracy in axial images. Combining axial images from both transducers preserved resolution of the P4-1 array and improved image contrast. Neither transducer was sensitive to frequencies below 50 kHz, resulting in a dc offset and low-frequency shading over fields of view exceeding 15 mm. Fresh human prostates were imaged ex vivo and volumetric reconstructions reveal structures rarely seen in diagnostic images. In conclusion, quantitative whole-organ thermoacoustic tomography will be feasible by sparsely interspersing transducer elements sensitive to the low end of the ultrasonic range.