Localised non-metastatic sarcomatoid renal cell carcinoma: a 31-year externally verified study.

OBJECTIVE: To evaluate post-nephrectomy outcomes and predictors of cancer-specific survival (CSS) between patients with localised sarcomatoid renal cell carcinoma (sRCC) and those with Grade 4 RCC (non-sRCC), as most sRCC research focuses on advanced or metastatic disease with limited studies analysing outcomes of patients with localised non-metastatic sRCC. PATIENTS AND METHODS: A total of 564 patients with localised RCC underwent partial or radical nephrectomy between June 1988 to March 2019 for sRCC (n = 204) or World Health Organization/International Society of Urological Pathology Grade 4 non-sRCC (n = 360). The CSS at every stage between groups was assessed. Phase III ASSURE clinical trial data were used to externally validate the CSS findings. The Mann-Whitney U-test and chi-squared test compared outcomes and the Kaplan-Meier method evaluated CSS, overall survival (OS) and recurrence-free survival. Clinicopathological features associated with RCC death were evaluated using Cox proportional hazards regression. RESULTS: The median follow-up was 31.5 months. The median OS and CSS between the sRCC and Grade 4 non-sRCC groups was 45 vs 102 months and 49 vs 152 months, respectively (P < 0.001). At every stage, sRCC had worse CSS compared to Grade 4 non-sRCC. Notably, pT1 sRCC had worse CSS than pT3 Grade 4 non-sRCC. Negative predictors of CSS were sarcomatoid features, non-clear cell histology, positive margins, higher stage (pT3/pT4), and use of minimally invasive surgery (MIS). ASSURE external verification showed worse CSS in patients with sRCC (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.12-2.36; P = 0.01), but not worse outcomes in MIS surgery (HR 1.39, 95% CI 0.75-2.56; P = 0.30). CONCLUSIONS: Localised sRCC had worse CSS compared to Grade 4 non-sRCC at every stage. Negative survival predictors included positive margins, higher pathological stage, use of MIS, and non-clear cell histology. sRCC is an aggressive variant even at low stages requiring vigilant surveillance and possible inclusion in adjuvant therapy trials.

Biophysical model of muscle spindle encoding.

Muscle spindles encode mechanosensory information by mechanisms that remain only partially understood. Their complexity is expressed in mounting evidence of various molecular mechanisms that play essential roles in muscle mechanics, mechanotransduction and intrinsic modulation of muscle spindle firing behaviour. Biophysical modelling provides a tractable approach to achieve more comprehensive mechanistic understanding of such complex systems that would be difficult/impossible by more traditional, reductionist means. Our objective here was to construct the first integrative biophysical model of muscle spindle firing. We leveraged current knowledge of muscle spindle neuroanatomy and in vivo electrophysiology to develop and validate a biophysical model that reproduces key in vivo muscle spindle encoding characteristics. Crucially, to our knowledge, this is the first computational model of mammalian muscle spindle that integrates the asymmetric distribution of known voltage-gated ion channels (VGCs) with neuronal architecture to generate realistic firing profiles, both of which seem likely to be of great biophysical importance. Results predict that particular features of neuronal architecture regulate specific characteristics of Ia encoding. Computational simulations also predict that the asymmetric distribution and ratios of VGCs is a complementary and, in some instances, orthogonal means to regulate Ia encoding. These results generate testable hypotheses and highlight the integral role of peripheral neuronal structure and ion channel composition and distribution in somatosensory signalling.

A pilot study of inflatable penile prosthesis placement in transgender neophallus using Tutoplast® pericardium graft sock technique.

Placement of an inflatable penile prosthesis (IPP) in a transgender patient's neophallus carries unique considerations versus cis-gender IPP placement in mitigating infection, erosion, and overall complication rates. An example of this includes the lack of an anatomical corpus cavernosum and crura for cylinder placement and anchoring. Multiple grafting approaches and materials have been utilized to mitigate possible cylinder instability and improve anchoring. Here we describe our experience and surgical technique in IPP neophallus placement utilizing a single cylinder with distal and proximal cylinder human cadaver pericardium (Tutoplast®, IOP Ophthalmics, Costa Mesa, CA, USA) grafts. Our goals were to determine postoperative satisfaction and device functionality in patients undergoing transgender neophallus IPP placement using our technique. Both patients report satisfaction and no complications at last follow-up (currently up to 14 and 23 months post-operatively, respectively) with satisfactory erectile function and ability to perform penetrative intercourse. In neophallus IPP placement, the anatomical differences compared to cis-gender IPP operations require unique considerations such as cylinder grafting material selection for proximal cylinder fixation and mitigation of device erosion rates. Optimization of grafting material in neophallus IPP placement in an effort to reduce erosion rates has become increasingly important as frequency of this operation increases. Utilizing human cadaver pericardium graft in distal and proximal cylinder coverage shows beneficial preliminary outcomes in our patients.

History-dependent muscle resistance to stretch remains high after small, posturally relevant pre-movements.

The contributions of intrinsic muscle fiber resistance during mechanical perturbations to standing and other postural behaviors are unclear. Muscle short-range stiffness is known to vary depending on the current level and history of the muscle's activation, as well as the muscle's recent movement history; this property has been referred to as history dependence or muscle thixotropy. However, we currently lack sufficient data about the degree to which muscle stiffness is modulated across posturally relevant characteristics of muscle stretch and activation. We characterized the history dependence of muscle's resistance to stretch in single, permeabilized, activated, muscle fibers in posturally relevant stretch conditions and activation levels. We used a classic paired muscle stretch paradigm, varying the amplitude of a 'conditioning' triangular stretch-shorten cycle followed by a 'test' ramp-and-hold imposed after a variable inter-stretch interval. We tested low (<15%), intermediate (15-50%) and high (>50%) muscle fiber activation levels, evaluating short-range stiffness and total impulse in the test stretch. Muscle fiber resistance to stretch remained high at conditioning amplitudes of <1% optimal fiber length, L0, and inter-stretch intervals of >1 s, characteristic of healthy standing postural sway. An ∼70% attenuation of muscle resistance to stretch was reached at conditioning amplitudes of >3% L0 and inter-stretch intervals of <0.1 s, characteristic of larger, faster postural sway in balance-impaired individuals. The thixotropic changes cannot be predicted solely on muscle force at the time of stretch. Consistent with the disruption of muscle cross-bridges, muscle resistance to stretch during behavior can be substantially attenuated if the prior motion is large enough and/or frequent enough.

Comparison of satisfaction with penile prosthesis implantation in patients with prostate cancer radiation therapy versus radical prostatectomy.

Background: Penile prosthesis surgery (PPS) is a commonly used treatment for erectile dysfunction (ED), either as first-line therapy or in cases refractory to other treatment options. In patients with a urologic malignancy such as prostate cancer, surgical interventions like radical prostatectomy (RP) as well as non-surgical treatments such as radiation therapy can all induce ED. PPS as a treatment for ED has high satisfaction rates in the general population. Our aim was to compare sexual satisfaction in patients with prosthesis implantation for ED following RP versus ED following radiation therapy for prostate cancer. Methods: A retrospective chart review from our institutional database was conducted to identify patients who underwent PPS at our institution from 2011 to 2021. Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire data at least 6 months from implant operative date available was required for inclusion. Eligible patients were placed in one of two groups depending on etiology of ED-following RP or prostate cancer radiation therapy. To prevent crossover confounding; patients with history of pelvic radiation were excluded from the RP group and patients with history of RP were excluded from the radiation group. Data were obtained from 51 patients in the RP group and 32 patients in the radiation therapy group. Mean EDITS scores and additional survey questions were compared between the radiation and RP groups. Results: There was a significant difference in mean survey responses for 8 of the 11 questions in the EDITS questionnaire between the RP group and the radiation group. Additional survey questions administered also found RP patients reported significantly higher rate of satisfaction with size of penis post-operatively versus the radiation group. Conclusions: These preliminary findings, while requiring large-scale follow-up, suggest that there is greater sexual satisfaction and penile prosthesis device satisfaction in patients undergoing IPP placement following RP versus radiation therapy for prostate cancer. Use of validated questionnaires should continue to be utilized in quantifying device and sexual satisfaction following PPS.

Current Landscape of Surgical Assessment Models in Urology Residency Training.

PURPOSE: Assessing trainees' surgical proficiency is an important aspect of urological surgical training. The current standard is the Urology Milestone Project, initially implemented in 2013. This evaluation is limited in that it contains only 3 questions on surgical competency per surgical modality with assessments occurring semi-annually without real-time operative feedback. However, since the Urology Milestones Project's inception a plethora of competency-based surgical assessment tools have been described. We aim to perform a comprehensive review of the literature of these available tools and analyze their strengths and weaknesses as a way of providing a repository of available assessment strategies for further development of a more comprehensive and standardized assessment tool. MATERIALS AND METHODS: A review of the primary literature was performed using key words such as "surgical assessment tools urology," "surgical assessment tools prostate," "bladder surgical assessment tools," "renal surgical assessment tools urology," and "surgical assessment tools urology task specific." Technical and nontechnical skill assessments were included. One reviewer identified and analyzed studies that published assessment tools for use in surgical and urological training. RESULTS: A total of 1,497 articles published between 1997-2022 were identified. Of these, 34 met the inclusion criteria. Eighteen (52.9%) were specialty nonspecific and 16 (47.1%) were specific for urological training. Of the 18 tools developed for general surgical principles, 12 (66.7%) had some form of validity, 9 (50.0%) were significantly reliable, and 2 (11.1%) were externally validated. Of the 16 tools developed specifically for use in urology training, 13 (81.3%) had some form of validity, 7 (43.8%) were significantly reliable, and none were externally validated. Of these 16 tools, 12 (75.0%) were procedure-specific and 4 (25.0%) were developed for general use in endourological procedures. CONCLUSIONS: Surgical training is evolving toward a competency-based model, as evidenced by the increase in assessment tools created within the past 10 years. These instruments not only provide objective feedback to trainees, but also monitor progression. However, they are heterogeneous in construct and utilization. There remains a need for the adoption of a standardized, valid, and reliable tool, ie, both procedure-specific and generalizable across multiple procedures for use in urology training.

Spatiotemporal evolution of the clear cell renal cell carcinoma microenvironment links intra-tumoral heterogeneity to immune escape.

BACKGROUND: Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance. METHODS: Here, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC. Primary endpoints were safety and feasibility of neoadjuvant nivolumab. Then, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI-treated patients. Deep multi-regional whole-exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy. RESULTS: Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts. CONCLUSIONS: These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment. TRIAL REGISTRATION: The study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015.

Complication rates in concurrent inflatable penile prosthesis and incontinence surgery: Comparing the penoscrotal versus perineal incision approach.

The main objective of this study was to assess the IPP complication rates of patients undergoing placement via perineal incision versus more traditional penoscrotal approach in synchronous dual implantation. We identified 38 patients who underwent dual implantations of an IPP and AUS or urethral sling from 2011 to 2021 at a single tertiary center, 24 via perineal and 14 via penoscrotal incision. All IPP implants were done by a single surgeon. IPP postoperative complications were captured using the Clavien-Dindo classification at three separate time points, < 30 days, 30 days - 6 months, and > 6 months. The perineal group had two complications, IPP explantation due to rectourethral fistula (Grade III, > 6 months), and IPP explantation due to chronic genital pain (Grade III, > 6 months). The penoscrotal group had three complications, post-operative urinary retention requiring catheterization (Grade I, < 30 days), incision site infection (Grade I, < 30 days), and IPP explantation due to infection (Grade III, 30 days to < 6 months). There was no statistically significant difference in rate of patients with IPP complications between the two groups (p = 0.546) or in rate of IPP device malfunction (p = 0.264). These preliminary findings suggest that the single perineal incision is a viable surgical approach in synchronous dual implantation.

Complication Rates in Patients Using Intracavernosal Injection Therapy for Erectile Dysfunction With or Without Concurrent Anticoagulant Use-A Single-Center, Retrospective Pilot Study.

BACKGROUND: Intracavernosal injection therapy (ICI) is an effective intervention used to treat erectile dysfunction (ED). It has been proposed that caution should be exercised when prescribing ICI to patients currently taking anticoagulants (AC) due to the theoretical increased risk of bleeding, however, there is limited literature describing complication rates of actively anticoagulated patients utilizing ICI. AIM: We sought to determine whether there was a difference in bleeding and other complications in a cohort of patients using ICI therapy with or without concurrent AC use. METHODS: We reviewed our institutional electronic health record and identified 168 patients who were seen in our clinic from January to August 2020 who had either currently or previously utilized ICI therapy for ED treatment. These patients were surveyed regarding their ICI therapy as well as given the erectile dysfunction inventory for treatment satisfaction questionnaire. Data from 85 patients was obtained; 43 concurrently using AC during ICI therapy and 42 with no AC use. Fisher's exact test for categorical variables and a 2-tailed t-test were used with P < .05 considered to be significant. OUTCOME: Documented bleeding events (eg, bruising, hematoma), complications, and mean erectile dysfunction inventory for treatment satisfaction scores were compared between the 2 groups. RESULTS: There were more absolute bleeding complications in the AC group vs the no AC group, with 3 of 43 AC patients (7%, 95% confidence interval: 2.4-18.6) and 0/42 no AC patients (0%, 95% confidence interval: 0-8.4) experiencing some type of bleeding complication on ICI. However, there was no statistically significant difference found in overall or stratified documented bleeding events and complications between the 2 groups. CLINICAL IMPLICATIONS: Patients with concurrent AC usage on ICI therapy reported a higher rate of absolute bleeding complications than our non-AC group. STRENGTHS AND LIMITATIONS: The strength of this study is addressing question of safety of ICI therapy in patients with concurrent AC usage. Limitations include single-center retrospective study design and underpowered sample size limiting confidence with which conclusions from data should guide future patient counseling regarding ICI risks. CONCLUSION: Findings from a single-center cohort of patients suggest that ICI therapy may be a safe and effective treatment modality for ED in patients with concurrent anticoagulant usage, however, given the higher rate of absolute bleeding events in our AC cohort, future assessment in a higher-powered study is warranted in determining a more accurate estimation of risk or propensity for bleeding complications in patients on AC using ICI therapy. Blum KA, Mehr JP, Green T, et al. Complication Rates in Patients Using Intracavernosal Injection Therapy for Erectile Dysfunction With or Without Concurrent Anticoagulant Use-A Single-Center, Retrospective Pilot Study. Sex Med 2022;10:100535.

A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma.

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. SIGNIFICANCE: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221.

Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies.

Malignancy can be suppressed by the immune system. However, the classes of immunosurveillance responses and their mode of tumor sensing remain incompletely understood. Here, we show that although clear cell renal cell carcinoma (ccRCC) was infiltrated by exhaustion-phenotype CD8+ T cells that negatively correlated with patient prognosis, chromophobe RCC (chRCC) had abundant infiltration of granzyme A-expressing intraepithelial type 1 innate lymphoid cells (ILC1s) that positively associated with patient survival. Interleukin-15 (IL-15) promoted ILC1 granzyme A expression and cytotoxicity, and IL-15 expression in chRCC tumor tissue positively tracked with the ILC1 response. An ILC1 gene signature also predicted survival of a subset of breast cancer patients in association with IL-15 expression. Notably, ILC1s directly interacted with cancer cells, and IL-15 produced by cancer cells supported the expansion and anti-tumor function of ILC1s in a murine breast cancer model. Thus, ILC1 sensing of cancer cell IL-15 defines an immunosurveillance mechanism of epithelial malignancies.

Outcomes for Atypical Tumor Recurrences Following Minimally Invasive Kidney Cancer Operations.

Background: We managed a cohort of patients treated with minimally invasive surgery (MIS) for a kidney tumor presenting with atypical tumor recurrence (ATR) involving port sites, intraperitoneal carcinomatosis, and nephrectomy bed/perinephric tumor implants. Objective: To determine the clinical characteristics, management, and oncologic outcomes for patients with localized renal cell carcinoma (RCC) who develop ATR following curative-intent MIS for partial or radical nephrectomy. Design setting and participants: The study cohort comprised patients from 1999 to 2021 with localized RCC managed at Memorial Sloan Kettering Cancer Center (New York, NY, USA) after MIS for partial or radical nephrectomy who developed ATR. Outcome measurements and statistical analysis: We collected data on clinicopathologic characteristics, treatments, time to ATR, and overall survival. Results and limitations: The median age of the 58 RCC patients was 61 yr. Forty-one patients (71%) were male, 26 (45%) had robot-assisted operations, and 39 (67%) had clear cell RCC. Twenty-nine patients had stage pT1 disease (50%) and ten (17%) had positive surgical margins. The most common ATR site was perinephric/nephrectomy bed implants (n = 28, 48%). Management included: surgical resection alone (n = 11, 19%), systemic therapy alone (n = 12, 21%), surgical resection and systemic therapy (n = 17, 29%), and palliative care (n = 8, 14%). At median follow-up of 59 mo (interquartile range [IQR] 28-92), the median time to ATR was 12 mo (IQR 5-28). Overall survival at 5 yr was 69.0% (95% confidence interval 57.4-83.1%) with only nine patients alive with no evidence of disease. Limitations include the potential for referral, detection, and selection biases, as well as uncertainty regarding the true incidence of ATR. Conclusions: ATR following MIS for partial or radical nephrectomy is an understudied, poor prognostic event which leads to a heavy treatment burden. Further investigation into its etiology and means of prevention is warranted. Patient summary: Patients experiencing recurrence of kidney cancer in an atypical site require a heavy treatment burden and have a guarded overall prognosis. Continued research is needed to determine the precise incidence of these recurrences and identify methods for mitigating them.

Somatic mutations as preoperative predictors of metastases in patients with localized clear cell renal cell carcinoma - An exploratory analysis.

OBJECTIVE: Recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) have been associated with treatment outcomes; however, current preoperative predictive models do not include known genetic predictors. We aimed to explore the value of common somatic mutations in the preoperative prediction of metastatic disease among patients treated for localized ccRCC. MATERIALS AND METHODS: After obtaining institutional review board approval, data of 254 patients with localized ccRCC treated between 2005 and 2015 who underwent genetic sequencing was collected. The mutation status of VHL, PBRM1, SETD2, BAP1 and KDM5C were evaluated in the nephrectomy tumor specimen, which served as a proxy for biopsy mutation status. The Raj et al. preoperative nomogram was used to predict the 12-year metastatic free probability (MFP). The study outcome was MFP; the relationship between MFP and mutation status was evaluated with Cox-regression models adjusting for the preoperative nomogram variables (age, gender, incidental presentation, lymphadenopathy, necrosis, and size). RESULTS: The study cohort included 188 males (74%) and 66 females (26%) with a median age of 58 years. VHL mutations were present in 152/254 patients (60%), PBRM1 in 91/254 (36%), SETD2 in 32/254 (13%), BAP1 in 19/254 (8%), and KDM5C in 19/254 (8%). Median follow-up for survivors was 8.1 years. Estimated 12-year MFP was 70% (95% CI: 63%-75%). On univariable analysis SETD2 (HR: 3.30), BAP1 (HR: 2.44) and PBRM1 (HR: 1.78) were significantly associated with a higher risk of metastases. After adjusting for known preoperative predictors in the existing nomogram, SETD2 mutations remained associated with a higher rate of metastases after nephrectomy (HR: 2.09, 95% CI: 1.19-3.67, P = 0.011). CONCLUSION: In the current exploratory analysis, SETD2 mutations were significant predictors of MFP among patients treated for localized ccRCC. Our findings support future studies evaluating genetic alterations in preoperative renal biopsy samples as potential predictors of treatment outcome.

Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy.

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.

Comparison of Satisfaction With Penile Prosthesis Implantation in Patients With Radical Prostatectomy or Radical Cystoprostatectomy to the General Population.

INTRODUCTION: Penile prosthesis implantation is a widely used treatment option for erectile dysfunction. Data is limited with regard to patient satisfaction with a penile prosthesis following radical prostatectomy/cystoprostatectomy vs patients with erectile dysfunction of other etiologies. AIM: To examine patient satisfaction with penile prosthesis implantation and determine if a difference in satisfaction exists in post-prostatectomy/cystoprostatectomy patients vs patients with erectile dysfunction of other etiologies. We hypothesize that etiology does not affect satisfaction. METHODS: A total of 164 patients underwent penile prosthesis implantation at our institution between August 2017 and December 2019, with 102 patients completing a validated 14 item questionnaire, Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), at 6 months postoperation. Demographics, surgical characteristics, and erectile dysfunction etiology were recorded. Patients were assigned to one of 2 groups: postprostatectomy/postcystoprostatectomy erectile dysfunction or other etiologies. The study group was further analyzed between radical prostatectomy or radical cystoprostatectomy. MAIN OUTCOME MEASURES: Satisfaction based on key EDITS questions with postradical prostatectomy/cystoprostatectomy vs patients with erectile dysfunction of other etiologies. RESULTS: Responses to 3 questions were analyzed: overall satisfaction, expectations met in the past 4 weeks, and confidence in the ability to participate in sexual activity. Chi-square analysis was performed to determine the difference in responses. No difference was seen in overall satisfaction (P = .96), expectations (P = .78), or confidence (P = .78) between groups. On subgroup analysis, there was no difference in reported overall satisfaction (P = .47) or confidence (P = .080) between postprostatectomy and postcystoprostatectomy patients. Postprostatectomy and postcystoprostatectomy patients differed in whether the penile prosthesis implantation met expectations (P = .033). Postprostatectomy patients reported a mean score of 3.5/4 compared to postcystoprostatectomy patients, who reported a mean of 3.0/4. CONCLUSIONS: Our analysis suggests that key erectile function scores are not significantly different between postprostatectomy/postcystoprostatectomy patients compared to other etiologies. The difference in measures between postprostatectomy and postcystoprostatectomy patients is not significant or of unclear significance. Registration # of clinical trial: HSC-MS-19-0320 Howell S, Palasi S, Green T, et al. Comparison of Satisfaction With Penile Prosthesis Implantation in Patients With Radical Prostatectomy or Radical Cystoprostatectomy to the General Population. Sex Med 2021;9:100300.

Putative Drivers of Aggressiveness in TCEB1-mutant Renal Cell Carcinoma: An Emerging Entity with Variable Clinical Course.

BACKGROUND: TCEB1-mutant renal cell carcinoma (RCC) is a rare variant of RCC with clear-cell features. Owing to its unique morphological and molecular features it has recently been proposed as a separate entity. Initial series suggested an indolent, early-stage phenotype. Here we expand our clinical cohort and describe a more detailed genomic analysis looking for potential drivers of aggressiveness. DESIGN, SETTING, AND PARTICIPANTS: We identified five new cases in our institutional sequencing cohort, four of whom were found to have high-stage disease (American Joint Committee on Cancer stage III/IV). Twelve previously reported cases were pooled for comparison purposes (Sato, The Cancer Genome Atlas, TRACERx Renal). OUTCOME MEASURES AND STATISTICAL ANALYSIS: We used our previously validated pipeline to analyze somatic mutations and copy number alterations (CNAs) in seven tumor samples with available data and estimated the number of cancer cells bearing each somatic mutation. The oncogenic potential of mutations was assessed using OncoKB and two other algorithms. Mann-Whitney U tests were used to evaluate differences in genomic markers between stage groups. RESULTS AND LIMITATIONS: All tumors showed biallelic inactivation of the TCEB1 gene according to a combination of somatic mutation and CNA analyses. Mutations were always found in residues involved in hydrophobic interactions with VHL. We found that high-stage tumors had additional oncogenic mutations (median 1, interquartile range [IQR] 1-1 vs 2, IQR 2-2; median difference 1, 95% confidence interval [CI] 1-1; p= 0.002) and showed whole-genome doubling events. They also seemed to have a higher burden of somatic CNAs (median fraction CNA genome 0.10, IQR 0.10-0.15 vs 0.63, IQR 0.58-0.68), however, this finding did not reach statistical significance (median difference 0.49, 95% CI 0.33-0.63; p=0.052). CONCLUSIONS: TCEB1-mutant RCC can show variable behavior ranging from very indolent to aggressive. Specific molecular events leading to high genomic instability seem to be associated with aggressiveness. This study expands the clinical spectrum of TCEB1-mutant RCC. PATIENT SUMMARY: We present four cases of aggressive TCEB1-mutant renal cell carcinoma, a rare type of kidney cancer. In-depth analysis of the genomes of these tumors revealed certain abnormalities that might explain this aggressive behavior.

Predictors of long-term renal function after kidney surgery for patients with preoperative chronic kidney disease.

INTRODUCTION: We evaluated the trajectory of estimated glomerular filtration rate (eGFR) after kidney surgery in patients with kidney cancer and chronic kidney disease (CKD). METHODS: We identified 1204 consecutive patients in our institutional database with preoperative CKD undergoing partial or radical nephrectomy from 1998-2016. Postoperative eGFR was tracked, with patients censored when receiving dialysis or kidney transplantation. A multivariable mixed-effects models assessed associations between preoperative baseline patient and tumor characteristics, and longitudinal eGFR. The Kaplan-Meier method and multivariable Cox regression were used to estimate overall survival, cancer-specific survival, and cumulative incidence of dialysis. RESULTS: Preoperatively, 892 (74.1%), 271 (22.5%), and 41 (3.4%) patients had CKD stage 3a, 3b, and 4/5, respectively. There were 55 patients dialyzed and 355 deaths (99 from kidney cancer). Median followup was 8.1 years, with 25 781 postoperative eGFR measurements. Factors associated with decreasing eGFR postoperatively included radical nephrectomy, male gender, older age, increased body mass index (BMI), and cardiovascular risk factors. We observed a significant interaction effect between time from surgery and preoperative CKD stage: the eGFR of stage 3a patients improved, while stage ≥3b declined (p<0.001). The two-year and five-year cumulative incidence of dialysis was 1.8% (1.1-2.6%) and 3.1% (2.2-4.2%), respectively. The cumulative incidence of dialysis, with death as a competing event, significantly differed by preoperative CKD stage. CONCLUSIONS: Preoperative CKD stage ≥3b is independently associated with a higher risk of declining renal function, dialysis, and mortality. With careful selection, patients with preoperative CKD withstand kidney surgery with low rates of dialysis.

Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics.

Despite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of mammalian muscle spindle Ia afferents - including movement history dependence, and nonlinear scaling with muscle stretch velocity - emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to 'encode' aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease.