Intermediate-term oncological and functional outcomes of salvage cryotherapy for the management of prostate cancer recurrence after primary brachytherapy versus primary cryotherapy: A propensity score-matched analysis.

BACKGROUND: Salvage cryotherapy (SCT) is widely used to treat prostate cancer (PCa) recurrence after radiotherapy (RT). We studied the intermediate oncological and functional outcomes of patients who underwent SCT following cryotherapy (CRYO-SCT) recurrence and compare it to recurrence after brachytherapy (BT-SCT). METHODS: An IRB-approved retrospective cohort study utilizing patient data from the Cryo On-Line Data Registry and the Duke PCa database between 1992 and 2016. Biochemical recurrence (BCR) using Phoenix criteria was the primary endpoint assessed at 2- and 5-years post-SCT. Secondary endpoints assessed functional outcomes including urinary continence, erectile function, and recto-urethral fistula. Association between treatment and biochemical progression-free survival was assessed using inverse probability weighted (IPTW) Cox proportional hazards regression. The differences in the secondary functional outcomes were assessed by Pearson's χ2 test or Fisher's exact test, corrected for IPTW. RESULTS: A total of 194 patients met inclusion criteria. The BCR rate for BT-SCT and CRYO-SCT was 23 (20.4%) and 17 (21%) at 2 years and 30 (26.5%) and 22 (27.2%) at 5 years according to Phoenix criteria. There was no statistical difference in 2 years (hazard ratio [HR] 0.9; 95% confidence interval [CI], 0.5-1.7, p = 0.7) or 5-year BCR (HR: 0.86; 95% CI, 0.5-1.5, p = 0.6) between the groups. The functional outcomes like urinary continence (p = 0.4), erectile function (p = 0.1), and recto-urethral fistula (p = 0.3) were not statistically different. CONCLUSION: CRYO-SCT appears to be well tolerated, with comparable oncological and functional outcomes to patients failing primary BT. The findings also demonstrated that SCT can render a significant number of patients biochemically free of disease after initial CRYO with minimal morbidity. SCT is a viable treatment option to salvage local PCa recurrence following either BT or cryoablation failure.

Force control during submaximal isometric contractions is associated with walking performance in persons with multiple sclerosis.

Individuals with multiple sclerosis (MS) experience progressive declines in movement capabilities, especially walking performance. The purpose of our study was to compare the amount of variance in walking performance that could be explained by the functional capabilities of lower leg muscles in persons with MS and a sex- and age-matched control group. Participants performed two walking tests (6-min walk and 25-ft walk), strength tests for the plantar flexor and dorsiflexor muscles, and steady submaximal (10% and 20% maximum) isometric contractions. High-density electromyography (EMG) was recorded during the steady contractions, and the signals were decomposed to identify the discharge times of concurrently active motor units. There were significant differences between the two groups in the force fluctuations during the steady contractions (force steadiness), the strength of the plantar flexor and dorsiflexor muscles, and the discharge characteristics during the steady contractions. Performance on the two walking tests by the MS group was moderately associated with force steadiness of the plantar flexor and dorsiflexor muscles; worse force steadiness was associated with poorer walking performance. In contrast, the performance of the control group was associated with muscle strength (25-ft test) and force steadiness of the dorsiflexors and variance in common input of motor units to the plantar flexors (6-min test). These findings indicate that a reduction in the ability to maintain a steady force during submaximal isometric contractions is moderately associated with walking performance of persons with MS.NEW & NOTEWORTHY The variance in walking endurance and walking speed was associated with force control of the lower leg muscles during submaximal isometric contractions in individuals with multiple sclerosis (MS). In contrast, the fast walking speed of a sex- and age-matched control group was associated with the strength of lower leg muscles. These findings indicate that moderate declines in the walking performance of persons with MS are more associated with impairments in force control rather than decreases in muscle strength.

The Absence of a Validated English-Language Survey to Assess Prosthesis Satisfaction: A Prospective Cohort Using the Sexual Quality of Life After Penile Prosthesis.

BACKGROUND: Prior assessments of sexual quality of life (SQoL) after penile prosthesis implantation have been performed without validated implant-specific tools. The Quality of Life and Sexuality with Penile Prosthesis (QoLSPP) questionnaire was designed and validated in Italian to specifically evaluate SQoL after a penile prosthesis is placed. AIM: We aim to better characterize prosthesis-specific SQoL after inflatable penile prosthesis placement using the English translation of the QoLSPP questionnaire. METHODS: A total of 395 consecutive patients received an inflatable penile prosthesis between January 1, 2009 and November 27, 2017, and 270 had functional emails to whom the QoLSPP questionnaire was sent. 90 surveys were completed by 75 first-time implantees and 15 patients who underwent removal/replacement surgery. Responses were considered positive if ≥ 3. Among first-time implantees, subpopulation analysis was carried out by age at survey completion (<55 years, 55-65 years, and ≥66 years), age of penile prosthesis at survey completion (<1 year, 1-5 years, and >5 years), device model (Coloplast Titan, AMS 700 CX, and AMS LGX), history of a psychiatric diagnosis, etiology of erectile dysfunction, total device length > or ≤ 21 cm, diabetes status, and body mass index < /≥ 30. Responses were analyzed in R using t-tests for continuous variables and Chi-squared tests (Fisher's for small counts) for categorical variables. OUTCOMES: The main outcome measure of this study was sexual quality of life assessed by QoLSPP. RESULTS: Patients completed the survey on average 3.15 years from their most recent prosthesis placement. 84% of first-time implantees had positive responses. Among them, there were no significant differences in the proportion of positive responses by device type, age, history of a psychiatric diagnosis, total implanted device length, etiology of erectile dysfunction, diabetes, or body mass index statuses (all P > .05). There was no difference in SQoL between first-time implantees and those who underwent removal/replacement surgery (P = 1.0). CLINICAL IMPLICATIONS: Patients experience a positive impact on their SQoL following implantation of a penile prosthesis. STRENGTHS & LIMITATIONS: Our study is the first to apply the English language QoLSPP which demonstrates high prosthesis specific SQoL but is limited by size and a lack of a validated English language tool. CONCLUSIONS: The positive impact on patients' SQoL with penile prosthesis is 84% when assessed by the English QoLSPP questionnaire. While these results mirror those reported from Italy, the English-speaking patient population is plagued with a lack of a validated tool to assess satisfaction, a void the academic and prosthetic community must fill to better understand the impact prostheses have on their patients. Carlos EC, Nosé BD, Barton GJ, et al. The Absence of a Validated English-Language Survey to Assess Prosthesis Satisfaction: A Prospective Cohort Using the Sexual Quality of Life After Penile Prosthesis. J Sex Med 2020;17:2307-2310.

Differences in postural sway among healthy adults are associated with the ability to perform steady contractions with leg muscles.

Upright standing involves small displacements of the center of mass about the base of support. These displacements are often quantified by measuring various kinematic features of the center-of-pressure trajectory. The plantar flexors have often been identified as the key muscles for the control of these displacements; however, studies have suggested that the hip abductor and adductors may also be important. The purpose of our study was to determine the association between the force capabilities of selected leg muscles and sway-area rate across four balance conditions in young (25 ± 4 years; 12/19 women) and older adults (71 ± 5 years; 5/19 women). Due to the marked overlap in sway-area rate between the two age groups, the data were collapsed, and individuals were assigned to groups of low- and high-sway area rates based on a k-medoid cluster analysis. The number of participants assigned to each group varied across balance conditions and a subset of older adults was always included in the low-sway group for each balance condition. The most consistent explanatory variable for the variance in sway-area rate was force control of the hip abductors and ankle dorsiflexors as indicated by the magnitude of the normalized force fluctuations (force steadiness) during a submaximal isometric contraction. The explanatory power of the regression models varied across conditions, thereby identifying specific balance conditions that should be examined further in future studies of postural control.

Bone scan positivity in non-metastatic, castrate-resistant prostate cancer: external validation study.

INTRODUCTION: Tables predicting the probability of a positive bone scan in men with non-metastatic, castrate-resistant prostate cancer have recently been reported. We performed an external validation study of these bone scan positivity tables. MATERIALS AND METHODS: We performed a retrospective cohort study of patients seen at a tertiary care medical center (1996-2012) to select patients with non-metastatic, castrate-resistant prostate cancer. Abstracted data included demographic, anthropometric, and disease-specific data such as patient race, BMI, PSA kinetics, and primary treatment. Primary outcome was metastasis on bone scan. Multivariable logistic regression was performed using generalized estimating equations to adjust for repeated measures. Risk table performance was assessed using ROC curves. RESULTS: We identified 6.509 patients with prostate cancer who had received hormonal therapy with a post-hormonal therapy PSA ≥2ng/mL, 363 of whom had non-metastatic, castrate-resistant prostate cancer. Of these, 187 patients (356 bone scans) had calculable PSA kinetics and ≥1 bone scan. Median follow-up after castrate-resistant prostate cancer diagnosis was 32 months (IQR: 19-48). There were 227 (64%) negative and 129 (36%) positive bone scans. On multivariable analysis, higher PSA at castrate-resistant prostate cancer (4.67 vs. 4.4ng/mL, OR=0.57, P=0.02), shorter time from castrate-resistant prostate cancer to scan (7.9 vs. 14.6 months, OR=0.97, P=0.006) and higher PSA at scan (OR=2.91, P<0.0001) were significantly predictive of bone scan positivity. The AUC of the previously published risk tables for predicting scan positivity was 0.72. CONCLUSION: Previously published risk tables predicted bone scan positivity in men with non-metastatic, castrate-resistant prostate cancer with reasonable accuracy.

Evaluation of the Fluorescence In Situ Hybridization Test to Predict Recurrence and/or Progression of Disease after bacillus Calmette-Guérin for Primary High Grade Nonmuscle Invasive Bladder Cancer: Results from a Prospective Multicenter Trial.

PURPOSE: Single center studies have shown that positive UroVysion® fluorescence in situ hybridization results were associated with recurrence of nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin. Our goal was to validate these findings. MATERIALS AND METHODS: We performed a prospective, multicenter diagnostic trial to determine whether the fluorescence in situ hybridization test could predict recurrence or progression in patients with primary high grade nonmuscle invasive bladder cancer who were scheduled to receive bacillus Calmette-Guérin. Fluorescence in situ hybridization testing was performed prior to the first bacillus Calmette-Guérin instillation, prior to the sixth instillation and at 3-month cystoscopy. The performance of fluorescence in situ hybridization was evaluated. RESULTS: A total of 150 patients were enrolled in analysis, including 68 with Ta disease, 41 with T1 disease, 26 with carcinoma in situ alone and 15 with papillary carcinoma plus carcinoma in situ. At 9 months of followup there were 46 events, including 37 recurrences and 9 progressions. For events with positive fluorescence in situ hybridization findings the HR was 2.59 (95% CI 1.42-4.73) for the baseline test, 1.94 (95% CI 1.04-3.59) for the 6-week test and 3.22 (95% CI 1.65-6.27) at 3 months. Patients with positive results at baseline, 6 weeks and 3 months had events 55% of the time and patients with negative results at each time point had no event 76% of the time. CONCLUSIONS: The study validated that a positive UroVysion fluorescence in situ hybridization test was associated with a 3.3-fold increased risk of recurrence. The test may be useful to risk stratify patients entering clinical trials in whom induction therapy fails. However, using the test to change management decisions is limited due to the discordance between results and outcomes as well as the variance of tests results with time.

Psychiatric Diagnoses and Other Factors Associated with Emergency Department Return within 30 Days of Ureteroscopy.

PURPOSE: Emergency department visits after ureteroscopy are costly and inconvenient. To better understand those at risk we aimed to identify patient demographic, medical and surgical factors associated with 30-day emergency department presentation following ureteroscopy for urolithiasis with particular attention to those with a history of a psychiatric diagnosis. MATERIALS AND METHODS: We retrospectively reviewed 1,576 cases (1,395 adults) who underwent stone related ureteroscopy during 3 years at a total of 2 hospitals. We collected patient demographics, medical history and operative details. The primary outcome was return to the emergency department within 30 days of ureteroscopy. Logistic regression was performed to examine factors associated with emergency department presentation. RESULTS: Of the patients 613 (43.9%) had a history of psychiatric diagnosis. Of those with ureteroscopy encounters 12.6% returned to the emergency department within 30 days of ureteroscopy, including 58.8% with a history of psychiatric diagnosis. On multivariable analysis variables associated with emergency department return included a history of psychiatric diagnosis (OR 1.57, p = 0.012), uninsured status (OR 2.46, p = 0.001) and a stone only in the kidney (OR 1.76, p = 0.022). Patients who returned to the emergency department had had more emergency department visits in the year prior to surgery (OR 1.40, p <0.001). On univariable analysis older patients and those with longer operative time were more frequently admitted from the emergency department (OR 1.03, p = 0.002 and OR 1.96, p = 0.03. respectively) while uninsured patients were admitted less frequently (OR 0.19, p = 0.013). No difference was noted in admissions between those with a psychiatric diagnosis and all others (60.7% vs 55.8%, p = 0.48). CONCLUSIONS: We identified factors associated with emergency department return after ureteroscopy, including a history of psychiatric diagnosis, uninsured status and emergency department visits in the year before surgery. These patients may benefit from targeted interventions to help avoid unnecessary emergency department visits.

Nomenclature of Subchondral Nonneoplastic Bone Lesions.

OBJECTIVE. The purpose of this article is to summarize the nomenclature of nonneoplastic conditions affecting subchondral bone through a review of the medical literature and expert opinion of the Society of Skeletal Radiology Subchondral Bone Nomenclature Committee. CONCLUSION. This consensus statement summarizes current understanding of the pathophysiologic characteristics and imaging findings of subchondral nonneoplastic bone lesions and proposes nomenclature to improve effective communication across clinical specialties and help avoid diagnostic errors that could affect patient care.

Anterior gland focal cryoablation: proof-of-concept primary prostate cancer treatment in select men with localized anterior cancers detected by multi-parametric magnetic resonance imaging.

BACKGROUND: Due to their location away from the nerve bundles, anterior prostate cancers (APC) represent a rational target for image-guided cryoablation. This report describes the feasibility and short-term outcomes of anterior focal cryosurgery. METHODS: A retrospective review between 2012 and 2016 of patients with clinically localized APC treated with anterior gland cryoablation was performed. Descriptive statistics were used to report: age, PSA, prostate volume, prostate cancer grade group (PGG), median time to follow-up, and changes in functional status measured with the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF-5) score. RESULTS: A total of 17 patients underwent anterior focal cryoablation with a median follow-up of 15 months. Median age and PSA at diagnosis were 67 years and 8.7 ng/mL. Pre-operative PGG1 was identified in 12 (71%) men and PGG2 in 5 (29%) men. Median (IQR) lesion volume was 2 mL(0.86, 3.1). Preoperative median IIEF-5 and IPSS scores were 19.5 and 5, and decreased to 19 and 4, post-operatively. All patients remained continent with no change in sexual function. All post-procedure targeted biopsies of the treated cancers were negative. CONCLUSION: Our pilot study demonstrates the feasibility of treating APCs with image-guided targeted focal cryoablation as a good balance between short-term oncologic control and near complete preservation of genitourinary function. Further follow-up is necessary to examine the potential benefits long-term.

A rare case of type 2 entrapment of the median nerve after posterior elbow dislocation with MRI and ultrasound correlation.

A 9-year-old boy sustained an ulnohumeral dislocation with a medial epicondyle fracture and experienced incomplete post-traumatic median nerve palsy in addition to post-traumatic stiffness following closed reduction and cast immobilization. When his motor palsy and stiffness did not improve, MRI and ultrasound were obtained, which demonstrated entrapment of the median nerve in an osseous tunnel at the fracture site, compatible with type 2 median nerve entrapment. Subsequently, the patient underwent surgery to mobilize the medial epicondyle and free the median nerve, resulting in improved range of motion, near complete restoration of motor function, and complete restoration of sensory function in the median nerve distribution within 6 months of surgery. Median nerve entrapment, particularly intraosseous, is a rare complication of posterior elbow dislocation and medial epicondyle fracture that may result in significant, sometimes irreversible, nerve damage if there is a delay in diagnosis and treatment. A high degree of clinical suspicion with early imaging is indicated in patients with persistent stiffness or nerve deficits following reduction of an elbow dislocation. Intra-articular entrapment diagnosed on ultrasound has been reported and intraosseous entrapment diagnosed clinically and on MR neurography have been reported; however, to our knowledge, this is the first reported case of intraosseous (type 2) median nerve entrapment clearly visualized and diagnosed on traditional MRI and ultrasound. The use of ultrasound for diagnosing median nerve entrapment is an accurate, accessible, and non-invasive imaging option for patients presenting with suspected nerve entrapment following elbow dislocation.

Electrical nerve stimulation modulates motor unit activity in contralateral biceps brachii during steady isometric contractions.

The purpose of our study was to compare the influence of five types of electrical nerve stimulation delivered through electrodes placed over the right biceps brachii on motor unit activity in the left biceps brachii during an ongoing steady isometric contraction. The electrical stimulation protocols comprised different combinations of pulse duration (0.2 and 1.0 ms), stimulus frequency (50 and 90 Hz), and stimulus current (greater or less than motor threshold). The electrical nerve stimulation protocols were applied over the muscle of the right elbow flexors of 13 participants (26 ± 3 yr) while they performed voluntary contractions with the left elbow flexors to match a target force set at 10% of maximum. All five types of electrical nerve stimulation increased the absolute amplitude of the electromyographic (EMG) signal recorded from the left biceps brachii with high-density electrodes. Moreover, one stimulation condition (1 ms, 90 Hz) had a consistent influence on the centroid location of the EMG amplitude distribution and the average force exerted by the left elbow flexors. Another stimulation condition (0.2 ms, 90 Hz) reduced the coefficient of variation for force during the voluntary contraction, and both low-frequency conditions (50 Hz) increased the duration of the mean interspike interval of motor unit action potentials after the stimulation had ended. The findings indicate that the contralateral effects of electrical nerve stimulation on the motor neuron pool innervating the homologous muscle can be influenced by both stimulus pulse duration and stimulus frequency. NEW & NOTEWORTHY Different types of electrical nerve stimulation delivered through electrodes placed over the right biceps brachii modulated the ongoing motor unit activity in the left biceps brachii. Although the effects varied with stimulus pulse duration, frequency, and current, all five types of electrical nerve stimulation increased the amplitude of the electromyographic activity in the left biceps brachii. Moreover, most of the effects in the left arm occurred after the electrical nerve stimulation of the right arm had been terminated.

Motor unit discharge characteristics and walking performance of individuals with multiple sclerosis.

Walking performance of persons with multiple sclerosis (MS) is strongly influenced by the activation signals received by lower leg muscles. We examined the associations between force steadiness and motor unit discharge characteristics of lower leg muscles during submaximal isometric contractions with tests of walking performance and disability status in individuals who self-reported walking difficulties due to MS. We expected that worse walking performance would be associated with weaker plantar flexor muscles, worse force steadiness, and slower motor unit discharge times. Twenty-three individuals with relapsing-remitting MS (56 ± 7 yr) participated in the study. Participants completed one to three evaluation sessions that involved two walking tests (25-ft walk and 6-min walk), a manual dexterity test (grooved pegboard), health-related questionnaires, and measurement of strength, force steadiness, and motor unit discharge characteristics of lower leg muscles. Multiple regression analyses were used to construct models to explain the variance in measures of walking performance. There were statistically significant differences (effect sizes: 0.21-0.60) between the three muscles in mean interspike interval (ISI) and ISI distributions during steady submaximal contractions with the plantar flexor and dorsiflexor muscles. The regression models explained 40% of the variance in 6-min walk distance and 47% of the variance in 25-ft walk time with two or three variables that included mean ISI for one of the plantar flexor muscles, dorsiflexor strength, and force steadiness. Walking speed and endurance in persons with relapsing-remitting MS were reduced in individuals with longer ISIs, weaker dorsiflexors, and worse plantar flexor force steadiness. NEW & NOTEWORTHY The walking endurance and gait speed of persons with relapsing-remitting multiple sclerosis (MS) were worse in individuals who had weaker dorsiflexor muscles and greater force fluctuations and longer times between action potentials discharged by motor units in plantar flexor muscles during steady isometric contractions. These findings indicate that the control of motor unit activity in lower leg muscles of individuals with MS is associated with their walking ability.

Over half of contemporary clinical Gleason 8 on prostate biopsy are downgraded at radical prostatectomy.

INTRODUCTION: Contemporary clinical guidelines utilize the highest Gleason sum (HGS) in any one core on prostate biopsy to determine prostate cancer treatment. Here, we present a large discrepancy between prostate cancer risk stratified as high risk on biopsy and their pathology after radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed 1424 men who underwent either open or robotic-assisted prostatectomy between 2004 and 2015. We analyzed 148 men who were diagnosed with HGS 8 on prostate biopsy. Biopsy and prostatectomy pathology were compared in aggregate and over 1 year time intervals. Chi-squared test, Fisher's exact test, Student's t-test, and Wilcoxon Rank-Sum test were used for statistical analysis. RESULTS: A total of 61.5% (91/148) of clinical HGS 8 diagnoses were downgraded on prostatectomy, with 58.8% (87/148) downgraded to Gleason 7 (Gleason 4 + 3 n = 59; Gleason 3 + 4 n = 28). Factors associated with downgrading include lower prostate-specific antigen (PSA) at biopsy (median 6.8 ng/mL versus 9.1 ng/mL, p < 0.001), number of Gleason 8 biopsy cores (median 1 versus 2, p < 0.02), presence of Gleason pattern 3 on biopsy cores (67.9% versus 44.8%, p < 0.03), pT2 staging (72.4% versus 55.1%, p < 0.04), positive margins (53.9% versus 69.1%, p < 0.04), extracapsular extension (53.4% versus 74.1%, p < 0.02), and smaller percent tumor (median 10% versus 15%, p < 0.004). CONCLUSION: The large percentage of pathology downgrading of biopsy-diagnosed HGS 8 suggests suboptimal risk-stratification that may lead to suboptimal treatment strategies and much patient distress. Our study adds great urgency to the efforts refining prostate cancer clinical assessment.

Private equity in radiology - Why aren't we more concerned?

There has been recent scrutiny of private equity involvement in the healthcare market by federal and state governmental agencies who are concerned about the corporatization and financialization of healthcare in the United States. Data is emerging that patient costs increase, quality of healthcare decreases, physician autonomy decreases, and physician burnout and moral injury increases when corporate interests like private equity enter the medical market. Like other medical specialties, the field of radiology has been affected by corporatization and radiologists should understand how private equity interests may affect individual radiologists and the radiology workforce on a larger scale.

Gene Function is a Driver of Activin Signaling Pathway Evolution Following Whole-Genome Duplication in Rainbow Trout (Oncorhynchus mykiss).

The genomes of plant and animal species are influenced by ancestral whole-genome duplication (WGD) events, which have profound impacts on the regulation and function of gene networks. To gain insight into the consequences of WGD events, we characterized the sequence conservation and expression patterns of ohnologs in the highly duplicated activin receptor signaling pathway in rainbow trout (RBT). The RBT activin receptor signaling pathway is defined by tissue-specific expression of inhibitors and ligands and broad expression of receptors and Co-Smad signaling molecules. Signaling pathway ligands exhibited shared expression, while inhibitors and Smad signaling molecules primarily express a single dominant ohnolog. Our findings suggest that gene function influences ohnolog evolution following duplication of the activin signaling pathway in RBT.

Engineering transcriptional regulation for cell-based therapies.

A major aim in the field of synthetic biology is developing tools capable of responding to user-defined inputs by activating therapeutically relevant cellular functions. Gene transcription and regulation in response to external stimuli are some of the most powerful and versatile of these cellular functions being explored. Motivated by the success of chimeric antigen receptor (CAR) T-cell therapies, transmembrane receptor-based platforms have been embraced for their ability to sense extracellular ligands and to subsequently activate intracellular signal transduction. The integration of transmembrane receptors with transcriptional activation platforms has not yet achieved its full potential. Transient expression of plasmid DNA is often used to explore gene regulation platforms in vitro. However, applications capable of targeting therapeutically relevant endogenous or stably integrated genes are more clinically relevant. Gene regulation may allow for engineered cells to traffic into tissues of interest and secrete functional proteins into the extracellular space or to differentiate into functional cells. Transmembrane receptors that regulate transcription have the potential to revolutionize cell therapies in a myriad of applications, including cancer treatment and regenerative medicine. In this review, we will examine current engineering approaches to control transcription in mammalian cells with an emphasis on systems that can be selectively activated in response to extracellular signals. We will also speculate on the potential therapeutic applications of these technologies and examine promising approaches to expand their capabilities and tighten the control of gene regulation in cellular therapies.

Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis. In support of this hypothesis, ccRCC cells acquire exogenous cholesterol through the high-density lipoprotein receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we showed that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is also essential for ccRCC cell survival. Development of an HSD3B7 enzymatic assay and screening for small-molecule inhibitors uncovered the compound celastrol as a potent HSD3B7 inhibitor with low micromolar activity. Repressing HSD3B7 expression genetically or treating ccRCC cells with celastrol resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target. SIGNIFICANCE: The bile acid biosynthetic enzyme HSD3B7 is essential for ccRCC cell survival and can be targeted to induce accumulation of cholesterol-derived oxysterols and apoptotic cell death.

Practitioner perceptions of trauma video review.

PURPOSE: Multidisciplinary trauma team education through trauma video review (TVR) is a useful performance improvement tool, but video recording resuscitations may cause providers anxiety. We examined perceptions of educational value and anxiety associated with being reviewed in TVR. METHODS: Trauma team members were asked to complete an anonymous online survey. Educational scores (E scores) and anxiety scores (A score) were calculated from survey responses. Respondents were divided into groups by roles: trainees (T; medical students, residents, and fellows), attending surgeons (A), and nurses (N). Kruskal-Wallis test was used for statistical testing. FINDINGS: A total of 39 subjects completed the survey (T = 17, 43%; A = 8, 23%; N = 14, 35%). TVR scored high in educational value (median E score 90; IQR = 78-96) but provoked moderate anxiety (median A score 27; IQR = 20-36). No significant differences in E scores were seen between groups. A scores were not significantly different between groups N and T (20 vs 33; P = .11) or groups T and A (33 vs. 35; P = 1.0) but were significantly higher in group A than in group N (36 vs 20; P = .04). CONCLUSIONS: Despite perceptions of educational value, TVR is associated with anxiety among providers, which is different between groups. Continued assessment of perceptions regarding TVR may allow for modifications to maintain educational value while decreasing anxiety.

Salvage Cryoablation for Recurrent Prostate Cancer Following Primary External Beam Radiotherapy or Primary Cryotherapy: A Propensity Score Matched Analysis of Mid-term Oncologic and Functional Outcomes.

INTRODUCTION: Local prostate cancer recurrence following radiotherapy (XRT) or cryoablation (CRYO) may be addressed with salvage cryotherapy (SCT), although little is known about how the primary treatment modality affects SCT results. Oncologic and functional outcomes of patients who underwent SCT after primary XRT (XRT-SCT) or cryoablation (CRYO-SCT) were studied. METHODS: Data was collected using the Duke Prostate Cancer database and the Cryo On-Line Data (COLD) registry. The primary outcome was biochemical progression-free survival (BPFS).  Urinary incontinence, rectourethral fistula, and erectile dysfunction were secondary outcomes. The Kaplan-Meier log-rank test and univariable/multivariable Cox proportional hazards (CPH) models were utilized to evaluate BPFS between groups. RESULTS: 419 XRT-SCT and 63 CRYO-SCT patients met inclusion criteria, that was reduced to 63 patients in each cohort after propensity matching. There was no difference in BPFS at 2 and 5 years both before (P = .5 and P = .7) and after matching (P = .6 and P = .3). On multivariable CPH, BPFS was comparable between treatment groups (CRYO-SCT, HR=1.1, [0.2-2.2]).  On the same analysis, BPFS was lower in D'Amico high-risk (HR 3.2, P < .01) and intermediate-risk (HR 1.95, P < .05) categories compared to low-risk. There was no significant difference in functional outcomes between cohorts. CONCLUSION: Following primary cryotherapy, salvage cryoablation provides comparable intermediate oncological outcomes and functional outcomes compared to primary radiotherapy.

Use of oxygen at the end of life: on what basis are decisions made?

Discussing and conducting research on end-of-life issues is often difficult. However, it is important to initiate a dialogue about various topics surrounding death and dying. This paper looks at the available scientific literature relating to oxygen use at the end of life, describes associated attitudes and beliefs, and presents some brief examples of institutional practices. The aim is to stimulate thoughtful reflection and encourage research on this important topic. There is limited research regarding oxygen use at the end of life, and many questions remain. Despite the difficulty with research in this area, there is a need to expand the data and awareness in this field. Several authors have questioned the use of oxygen in end-of-life care, and the evidence that oxygen use may not always be indicated is growing.