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Variant allele frequency of the alterations listed in Figure 2

Change in alterations across time points

Purpose:The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study, we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC.Experimental Design:Results of 839 patients with mRCC who had ctDNA assessment with a Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed.Results:ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. Mutations identified in tissue (34.7%; 42/121) were also identified via ctDNA, whereas 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays.Conclusions:This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.

To evaluate a conceptually simple model to predict new-baseline-glomerular-filtration-rate (NBGFR) after radical nephrectomy (RN) based on split-renal-function (SRF) and renal-functional-compensation (RFC), and to compare its predictive accuracy against a validated non-SRF-based model. RN should only be considered when the tumor has increased oncologic potential and/or when there is concern about perioperative morbidity with PN due to increased tumor complexity. In these circumstances, accurate prediction of NBGFR after RN can be important, with a threshold NBGFR 45 ml/min/1.73m236 RCC patients who underwent RN (2010-2012) with preoperative imaging (CT/MRI) and relevant functional data were included. NBGFR was defined as GFR 3-12 months post-RN. SRF was determined using semi-automated software that provides differential parenchymal-volume-analysis (PVA) from preoperative imaging. Our SRF-based model was: Predicted NBGFR = 1.24 (× Global GFRThe correlation-coefficients (r) were 0.87/0.72 for SRF-based/non-SRF-based models, respectively (p = 0.005). For prediction of NBGFR 45 ml/min/1.73mPrevious non-SRF-based models to predict NBGFR post-RN are complex and omit two important parameters: SRF and RFC. Our proposed model prioritizes these parameters and provides a conceptually simple, accurate, and clinically implementable approach to predict NBGFR post-RN. SRF can be easily obtained using PVA software that is affordable, readily available (FUJIFILM-Medical-Systems), and more accurate than nuclear-renal-scans. The SRF-based model demonstrates greater predictive-accuracy than a non-SRF-based model, including the clinically-important predictive-threshold of NBGFR 45 ml/min/1.73m

To provide a narrative review of the major advances regarding ischaemia and functional recovery after partial nephrectomy (PN), along with the ongoing controversies.Key articles reflecting major advances regarding ischaemia and functional recovery after PN were identified. Special emphasis was placed on contributions that changed perspectives about surgical management. Priority was also placed on randomized trials of off-clamp vs on-clamp cohorts.A decade ago, 'Every minute counts' was published, showing strong correlations between duration of ischaemia and development of acute kidney injury (AKI) and chronic kidney disease after clamped PN. This reinforced perspectives that ischaemia was the main modifiable factor that could be addressed to improve functional outcomes and helped spur efforts towards reduced or zero ischaemia PN. These approaches were associated with strong functional recovery and some peri-operative risk, although they were generally safe in experienced hands. Further research demonstrated that, when parenchymal volume changes were incorporated into the analyses, ischaemia lost statistical significance, and percent parenchymal volume saved proved to be the main determinant. Cold ischaemia was confirmed to be highly protective, and limited warm ischaemia also proved to be safe. The reconstructive phase of PN, with avoidance of parenchymal devascularization, appears to be most important for functional outcomes. Randomized trials of on-clamp vs off-clamp PN have shown minimal impact of ischaemia on functional recovery.The past decade has witnessed great progress regarding functional recovery after PN, with many lessons learned. However, there are still unanswered questions, including: What is the threshold of warm ischaemia at which irreversible ischaemic injury begins to develop? Are some cohorts at increased risk for AKI or irreversible ischaemic injury? and Which patients should be prioritized for zero-ischaemia PN?

Immunotherapies have shown remarkable success in the treatment of multiple cancer types; however, despite encouraging preclinical activity, registration trials of immunotherapy in prostate cancer have largely been unsuccessful. Sipuleucel-T remains the only approved immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer based on modest improvement in overall survival. This immune evasion in the case of prostate cancer has been attributed to tumor-intrinsic factors, an immunosuppressive tumor microenvironment, and host factors, which ultimately make it an inert 'cold' tumor. Recently, multiple approaches have been investigated to turn prostate cancer into a 'hot' tumor. Antibodies directed against programmed cell death protein 1 have a tumor agnostic approval for a small minority of patients with microsatellite instability-high or mismatch repair-deficient metastatic prostate cancer. Herein, we present an overview of the current immunotherapy landscape in metastatic castration-resistant prostate cancer with a focus on immune checkpoint inhibitors. We describe the results of clinical trials of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer; either as single agents or in combination with other checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, novel hormonal therapies, chemotherapies, and radioligands. Finally, we review upcoming immunotherapies, including novel monoclonal antibodies, chimeric-antigen receptor (CAR) T cells, Bi-Specific T cell Engagers (BiTEs), therapies targeting the adenosine pathway, and other miscellaneous agents.

Background Genomic biomarkers that predict response to anti‐PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti‐PD1 therapy in prostate cancer. Methods To enrich for response to anti‐PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair‐deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti‐PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort. Results Nineteen of 65 patients with dMMR metastatic castration‐resistant prostate cancer were treated with anti‐PD1 therapy. The PSA50 response rate was 65%, and the median progression‐free survival (PFS) was 24 (95% confidence interval 16–54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti‐PD1 treatment and with density of CD8+ tumor‐infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti‐PD1 therapy in a validation cohort. Conclusion Tumor FSP correlated with prolonged efficacy of anti‐PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity. Implications for Practice Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair‐deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti‐PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti‐PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti‐PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts., Biomarkers of immune checkpoint inhibition sensitivity are needed. This article reports on genomic biomarkers that may predict response to anti‐PD1 therapy in prostate cancer.

Cabozantinib is an oral, tyrosine-kinase inhibitor with potent activity against VEGFR2 and MET, along with multiple other tyrosine kinases involved in cancer development and progression. Herein, we will focus on preclinical and clinical studies leading to the approval of cabozantinib in advanced renal cell carcinoma and hepatocellular carcinoma. Covered studies include NCT01100619, CABOSUN, METEOR, NCT00940225 and the CELESTIAL trial. Finally, we review future directions of cabozantinib development by highlighting some ongoing clinical trials.

Radical nephrectomy (RN) is an important consideration for the management of localized renal-cell-carcinoma (RCC) whenever the tumor appears aggressive, although reduced renal function is a concern. Split-renal-function (SRF) in the contralateral kidney and postoperative renal functional compensation (RFC) are fundamentally important for the accurate prediction of new baseline GFR (NBGFR) post-RN. SRF can be estimated either from nuclear renal scans (NRS) or from preoperative imaging using parenchymal-volume-analysis (PVA). We compare two SRF-based models for predicting NBGFR after RN with a subjective prediction of NBGFR by an experienced urologic-oncologist.187 RCC patients managed with RN (2006-16) were included based on the availability of preoperative CT/MRI and NRS, and preoperative/postoperative eGFR. NBGFR was defined as the final GFR 3-12 months post-RN. For the SRF-based approaches, SRF was derived from either NRS or PVA, and RFC was estimated at 25% based on previous independent analyses. Thus, the formula (Global GFRThe r values for subjective-assessment, NRS/SRF-based, and PVA/SRF-based approaches were 0.72/0.72/0.85, respectively (p 0.05). The PVA/SRF-based model also demonstrated significant improvement across other performance parameters.The PVA/SRF-based model more accurately predicts NBGFR post-RN than NRS/SRF-based and Subjective Estimation. PVA software (Fujifilm-medical-systems) is readily available and affordable and provides accurate SRF estimations from routine preoperative imaging. This novel approach may inform clinical management regarding RN/PN for complex RCC cases.

The American-Urological-Association(AUA) Guidelines for renal cancer(2017) recommend consideration for radical-nephrectomy(RN) over partial(PN) whenever there is increased oncologic-risk; and RN should be prioritized if three other criteria are all also met: 1) increased tumor-complexity; 2) no preexisting chronic-kidney-disease/ proteinuria, and 3) normal contralateral kidney that will likely provide estimated glomerular-filtration-rate (eGFR)45ml/min/1.73mRetrospective review of 267 consecutive RN/PN from 2019(100-RN/167-PN). High tumor-complexity was defined as R.E.N.A.L.≥9. Increased oncologic-risk was defined as tumor7cm, locally-advanced or infiltrative-features on imaging, or high-risk pathology on biopsy, if obtained. New-baseline GFR after RN was estimated using global-GFR, split-renal-function163 patients(61%) fit scenarios that are well-defined in the Guidelines. Of these, 34 had strong indications for RN, and all had RN. Twelve of 129 patients(9.3%) underwent RN despite Guidelines generally favoring PN. The remaining 104 patients(39%) did not fit within situations where the Guidelines provide specific recommendations. In these patients, RN was often performed despite functional-considerations favoring PN due to overriding concerns about oncologic-risk and/or tumor-complexity.Our data demonstrate complexity of decision-making about PN/RN as almost 40% of patients did not fit well-described AUA Guidelines descriptors. Compliance was generally strong although occasional overutilization of RN remains a concern in our series, and will be addressed with additional education. Further studies will be required to assess the generalizability of our findings in other institutions/settings.

693 Background: The American Urologic Association (AUA) recommends estimation of the postoperative glomerular filtration rate (GFR) in patients with a renal mass to help decide between partial nephrectomy (PN) or radical nephrectomy (RN). If postoperative GFR2, a PN should be prioritized. Most existing methods to predict postoperative GFR are rarely implemented in the clinical setting due to complexity. Previously validated models based on clinical equations or kidney volumes from hand-segmented or semi-automated segmentations are quite accurate but have seen limited uptake in clinical practice. We hypothesize that we could develop an artificial intelligence (AI)-GFR prediction that would be calculated automatically on a preoperative computed tomography (CT) scan and predict a postoperative GFR as accurately as a validated clinical model. Methods: 300 patients undergoing PN or RN for renal tumor from the 2021Kidney and Kidney Tumor Segmentation Challenge(KiTS21) were analyzed. We excluded 7 patients having bilateral tumors. Preoperative GFR was the closest recorded value preoperatively and postoperative GFR≥90 days postoperatively. Split-renal-function (SRF) was determined in a fully automated way from preoperative imaging and our previously developed deep learning segmentation model. We programmed the algorithm to estimate postoperative GFR as 1.24×preoperative GFR×contralateral SRF for RN; and as 89% of the preoperative GFR for PN. We compared AI-predicted GFR to a validated clinical model (GFR=35+preoperative GFR(x0.65)-18(if radical nephrectomy)-age(x0.25)+3(if tumor size >7 cm)-2 (if diabetes)). We compared the AI and clinical model estimations of GFR to the measured postoperative GFR using correlation coefficients (R) and compared the ability of AI models to predict a postoperative GFR2, the AI and clinical models performed similarly (AUC of 0.89 and 0.9, respectively). Conclusions: Our study demonstrates the feasibility of a fully automated prediction of postoperative GFR based on CT imaging and baseline GFR with comparable predictive accuracy to existing validated clinical prediction models. These AI-generated predictions can be implemented for decision-making, with no clinical details, clinician time, or measurements needed.

144 Background: Kinase inhibitors have been ineffective in prostate cancer and have no known role in androgen biosynthesis. Inheritance of the adrenal-permissive HSD3B1(1245C) allele encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from non-gonadal precursor steroids and confers poor clinical outcomes in castration-resistant prostate cancer (CRPC). About half of all men with prostate cancer inherit the adrenal-permissive HSD3B1 allele. Multiple clinical studies demonstrate that adrenal-permissive HSD3B1 allele inheritance confers more rapid progression on ADT and others also suggest worse CRPC outcomes even after treatment with abiraterone or enzalutamide. However, there is no known method to clinically block 3βHSD1. Furthermore, 3βHSD1 is not known to be phosphorylated. Methods: Mass spectrometry was used to identify protein phosphorylation sites and steroid metabolites, genetic and pharmacologic methods were used to identify the kinase required for 3βHSD1 phosphorylation and mouse xenograft studies were performed with BMX inhibition. The identified mechanism was used to design and launch a multicenter phase 2 study of the BMX inhibitor abivertinib in combination with abiraterone in men with metastatic CRPC. Results: 3βHSD1 enzyme activity requires tyrosine phosphorylation at Y344 by the BMX kinase. Androgen biosynthesis is blocked by a phosphorylation-defective 3βHSD1 344F, or BMX genetic knockdown, or BMX pharmacologic inhibition. BMX inhibition using zanubrutinib suppresses CRPC growth in the C4-2 and VCaP xenograft models by blocking intratumoral androgen synthesis and tumor androgen receptor (AR) signaling. Discovery of this mechanism provides the rationale for the phase 2 Maverick trial of abivertinib, a BMX inhibitor, combined with abiraterone, in men with CRPC with adrenal-permissive HSD3B1 allele inheritance (NCT05361915). Eligibility includes 1) presence of metastatic CRPC, 2) measurable and/or non-measurable disease, and 3) confirmed positivity of adrenal-permissive HSD3B1(1245C) allele inheritance via central testing (cap heterozygosity at 50%). Patients will be enrolled in 2 arms: 1) abiraterone naïve (n=45) and 2) abiraterone progressing (n=55). All patients will receive treatment with abivertinib 200mg twice daily with abiraterone 1000mg daily and prednisone 5mg by mouth twice daily. The primary outcome is 6-month radiographic progression-free survival. On-treatment biopsies will be used to inform mechanisms of response and resistance in patients. Conclusions: BMX is required for 3βHSD1 phosphorylation, androgen biosynthesis and CRPC progression with the adrenal-permissive HSD3B1(1245C) allele. The Maverick trial will test clinical proof-of-concept of BMX inhibition in men with adrenal-permissive HSD3B1(1245C) inheritance. Clinical trial information: NCT05361915 .

244 Background: Pre-existing DM is associated with increased PCa specific and all-cause mortality in men with prostate cancer (PMID: 27652121). However, the underlying reasons are unclear. We hypothesized that transcriptomic profile of metastatic PCa pts with diagnosis of DM prior to the diagnosis of metastatic disease and start of systemic therapy will be different from those without DM. Methods: In this IRB-approved retrospective study, advanced PCa pts with available RNA profiling of treatment naïve tumor tissue through a CLIA-certified laboratory were included. Based on pre-existing DM prior to onset of metastatic disease, pts was grouped into DM and non-DM. Differential gene expression analysis between the two groups was performed using DeSeq2. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify pathways enriched in each cohort. Gene ontology analysis using TopGO software was done to identify the biological process occurring at the molecular level of these differentially expressed genes. All bioinformatic analysis was conducted in R studio, version 4.1.1. Results: 75 pts were eligible and included: 20 DM vs 55 non-DM. Baseline characteristics (DM vs non-DM): median age 63.5 vs 64 years; median PSA at diagnosis 20 vs 18.85ng/mL; de novo disease: 55% vs 43.6%; Gleason score ≥8: 60% vs 74.5%. DM pts had upregulation of the following pathways: TNF alpha signaling, inflammatory response, IL-6 JAK STAT3 signaling, heme metabolism, and the p53 pathway vs non-DM pts. Gene ontology analysis and individual differential gene expression profiles will be reported at the meeting. Conclusions: Our study found that pre-existing DM is associated with upregulation of inflammatory pathways in pts with PCa These hypothesis-generating results need external validation. Identification of transcriptomic biomarkers in these subsets of pts may help with further drug development. [Table: see text]

235 Background: GS is the most powerful prognostic predictor in prostate adenocarcinoma. However, the underlying reasons of disease aggressiveness as a function of GS are currently unknown. Herein we sought to investigate the corresponding differences in gene expression profiles of pts with prostate adenocarcinoma with respect to GS. Methods: In this IRB approved retrospective study, eligibility criteria included histologically confirmed prostate adenocarcinoma and available RNA sequencing results from treatment naïve primary prostate tissue by a CLIA certified lab. Pts were categorized into two cohorts: low GS (GS

683 Background: In renal cell carcinoma (RCC), partial nephrectomy (PN) is indicated for patients with solitary kidney, chronic kidney disease, or bilateral tumors. A subset of these patients, however, may have large and complex renal masses not initially suitable for PN. Neoadjuvant Tyrosine Kinase Inhibitor therapy has shown promising results in cytoreducing renal tumors and may permit PN in circumstances not otherwise feasible. Methods: This was a single arm phase II clinical trial of neoadjuvant axitinib in patients with complex (RENAL nephrometry score 10-12 and cT1b-cT3M0) biopsy-proven clear cell RCC with strong indications for partial nephrectomy (PN), and in whom radical nephrectomy may result in dialysis dependence. Axitinib 5 mg was administered orally twice daily for 8 weeks prior to surgery. Primary outcome was reduction in longest tumor diameter; secondary outcomes included tumor response (RECIST), change in RENAL score, feasibility of PN, change in estimated glomerular filtration rate (DeGFR), and post-surgical complications. Results: 26 patients were enrolled. 19 (73.1%) patients had ≥ clinical T3a staged tumors. Post therapy, 17 (65.4%) patients had ≥T3a staged tumors. Axitinib resulted in reductions in tumor size (7.7 vs. 6.3 cm, p

Genomic and morphologic heterogeneity in clear cell renal cell carcinoma (ccRCC) presents a barrier to prognostication and treatment decisions. Data from pathology are used with clinical markers to predict disease progression after nephrectomy. However, determining the risk of cancer recurrence, and survival with metastatic cancer remains challenging. Recently, analysis of histologic growth patterns (HGP) in ccRCC revealed promising associations with survival outcomes.To investigate whether HGPs can be used to predict overall survival (OS) after nephrectomy, we examined 24 HGPs in primary tumors of 147 patients that included 107 patients with metastatic disease.The median number of HGPs per case was 5 and was greater in metastatic and larger tumors. After adjustment for 6 pathologic and demographic variables, HGPs were significantly associated with OS post nephrectomy. Small nests, expansile nests and nests with high nuclear to cytoplasmic ratio were associated with favorable outcomes; while spindled low grade, fused nests/solid sheets, rhabdoid, and sarcomatoid patterns were associated with unfavorable outcomes. A 3-tiered and a 2-tiered risk model were developed based on combinations of HGPs. The models performed equally well as WHO/ISUP nucleolar plus necrosis grade (necrosis grade), and better than WHO/ISUP nucleolar grade alone in predicting OS at the median OS of 6 years. Pairwise correlations between HGPs revealed 2 tumor evolutionary branches that differed in risk of metastatic disease: one with mesenchymal differentiation, and other with epithelial tubulopapillary differentiation. While 44 of 107 (41%) patients with metastatic ccRCC displayed evidence of mesenchymal differentiation, mesenchymal features were only observed in 1 of 40 (3%) patients without evidence of metastatic disease.These findings suggest that HGPs may provide a novel path to refine the estimation of OS after nephrectomy and to determine the molecular basis of tumor evolution.

Background: Both novel hormonal therapies and docetaxel are approved for treatment of metastatic prostate cancer (mPC, in castration sensitive or refractory settings). Present knowledge gaps include lack of real-world data on treatment patterns in patients with newly diagnosed mPC, and comparative effectiveness of novel hormonal therapies (NHT) versus docetaxel after treatment with a prior NHT. Methods: Herein we extracted patient-level data from a large real-world database of patients with mPC in United States. Utilization of NHT or docetaxel for mPC and comparative effectiveness of an alternate NHT versus docetaxel after one prior NHT was evaluated. Comparative effectiveness was examined via Cox proportional hazards model with propensity score matching weights. Each patient’s propensity for treatment was modeled via random forest based on 22 factors potentially driving treatment selection. Results: The majority of patients (54%) received only androgen deprivation therapy for mPC. In patients treated with an NHT, alternate NHT was the most common next therapy and was associated with improved median overall survival over docetaxel (abiraterone followed by docetaxel vs. enzalutamide (8.7 vs. 15.6 months, adjusted hazards ratio, aHR 1.32, p = 0.009, and enzalutamide followed by docetaxel vs. abiraterone (9.7 vs. 13.2 months aHR 1.40, p = 0.009). Limitations of the study include retrospective design.

INTRODUCTION AND OBJECTIVE:Accurate prediction of new baseline glomerular filtration rate (NBGFR) after radical nephrectomy (RN) has significant clinical implications for renal cell carcinoma (RCC)...

INTRODUCTION AND OBJECTIVE:AUA Guidelines for renal cancer (2017) recommend consideration for radical nephrectomy (RN) over partial (PN) whenever there is ↑ oncologic risk (OR); and RN should then ...

BACKGROUND: In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib. METHODS: We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)–positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety. RESULTS: A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1–positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P

Purpose Progression from metastatic castration-sensitive prostate cancer (mCSPC) to a castration-resistant (mCRPC) state heralds the lethal phenotype of prostate cancer. Identifying genomic alterations associated with mCRPC may help find new targets for drug development. In the majority of patients, obtaining a tumor biopsy is challenging because of the predominance of bone-only metastasis. In this study, we hypothesize that machine learning (ML) algorithms can identify clinically relevant patterns of genomic alterations (GAs) that distinguish mCRPC from mCSPC, as assessed by next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA). Experimental Design Retrospective clinical data from men with metastatic prostate cancer were collected. Men with NGS of cfDNA performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory at time of diagnosis of mCSPC or mCRPC were included. A combination of supervised and unsupervised ML algorithms was used to obtain biologically interpretable, potentially actionable insights into genomic signatures that distinguish mCRPC from mCSPC. Results GAs that distinguish patients with mCRPC (n = 187) from patients with mCSPC (n = 154) (positive predictive value = 94%, specificity = 91%) were identified using supervised ML algorithms. These GAs, primarily amplifications, corresponded to androgen receptor, Mitogen-activated protein kinase (MAPK) signaling, Phosphoinositide 3-kinase (PI3K) signaling, G1/S cell cycle, and receptor tyrosine kinases. We also identified recurrent patterns of gene- and pathway-level alterations associated with mCRPC by using Bayesian networks, an unsupervised machine learning algorithm. Conclusion These results provide clinical evidence that progression from mCSPC to mCRPC is associated with stereotyped concomitant gain-of-function aberrations in these pathways. Furthermore, detection of these aberrations in cfDNA may overcome the challenges associated with obtaining tumor bone biopsies and allow contemporary investigation of combinatorial therapies that target these aberrations. Implications for Practice The progression from castration-sensitive to castration-resistant prostate cancer is characterized by worse prognosis and there is a pressing need for targeted drugs to prevent or delay this transition. This study used machine learning algorithms to examine the cell-free DNA of patients to identify alterations to specific pathways and genes associated with progression. Detection of these alterations in cell-free DNA may overcome the challenges associated with obtaining tumor bone biopsies and allow contemporary investigation of combinatorial therapies that target these aberrations.

Purpose: The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study, we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC. Experimental Design: Results of 839 patients with mRCC who had ctDNA assessment with a Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed. Results: ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. Mutations identified in tissue (34.7%; 42/121) were also identified via ctDNA, whereas 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays. Conclusions: This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.

Objective This study aimed to systematically review the relative effectiveness of preincision cefazolin with or without adjunctive prophylaxis (macrolides or metronidazole) vs cefazolin alone in decreasing the incidence of postcesarean delivery surgical site infections. Data Sources We performed a systematic search on PubMed, Ovid EMBASE, Google Scholar, ClinicalTrials.gov , and the Cochrane Central Register of Controlled Trials from October 25, 2020, to November 25, 2020, to identify studies comparing cefazolin with adjunctive macrolides or metronidazole with cefazolin alone. The reference lists were reviewed, and a manual search of articles published after the last database search was performed. Study Eligibility Criteria Overall, 3 randomized controlled trials and 1 prospective observational study of reproductive-age women undergoing cesarean deliveries were included in the study. We excluded studies of women who were immunocompromised (eg, patients who were HIV positive) or women with a diagnosis of chorioamnionitis before cesarean delivery. All patients received first-line cefazolin (either cefazolin 1 g or 2 g). We compared preincision cefazolin alone with preincision cefazolin plus adjunctive therapy (500 mg, oral or intravenous formulations of azithromycin, metronidazole, or clarithromycin). Methods A total of 6 review authors independently assessed the risk of bias for each study, using the Cochrane Risk of Bias criteria. Synthesis and further appraisal were done using the Grading of Recommendations, Assessment, Development, and Evaluation levels and the American College of Obstetricians and Gynecologists appraisal guidelines. Disagreements were resolved by discussion. Treatment effects were evaluated using meta-analysis, and pooled relative risks and 95% confidence intervals were generated using random-effects models using the Review Manager 5 software (version 5.4.1). Results Overall, 3 randomized controlled trials and 1 prospective observational study representing 2613 women met the criteria for inclusion. Significant reductions in surgical site infections (relative risk, 0.46; 95% confidence interval, 0.34–0.63; 3 randomized controlled trials) and the duration of hospital stay (weighted mean difference, −1.46; 95% confidence interval, −2.21 to −0.71; 2 randomized controlled trials) were observed with preincision cefazolin and adjunctive prophylaxis compared with cefazolin alone. No significant difference was observed in maternal febrile morbidity (relative risk, 0.38; 95% confidence interval, 0.11–1.25; 2 randomized controlled trials). Conclusion Our findings have provided evidence for the use of preincision adjunctive extended-spectrum prophylaxis with cefazolin over cefazolin alone. However, future investigations are required to establish the relative efficacies of different adjunctive antibiotic options.

BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) may present with primary metastases (synchronous disease) or develop metastases during follow-up (metachronous disease). The impact of time to metastasis on patient outcome is poorly characterised.OBJECTIVE: To characterise overall survival (OS) and time to treatment failure (TTF) based on time to metastasis in mRCC patients treated with targeted therapy (tyrosine kinase inhibitors [TKIs]).DESIGN, SETTING, AND PARTICIPANTS: We used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare synchronous (metastases within ≤3 mo of initial diagnosis of cancer) versus metachronous disease (evaluated by >3-12 mo, >1-2 yr, >2-7 yr, and >7 yr intervals).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS and TFF were assessed using Kaplan-Meier curves. Cox multivariable regressions analyses (MVAs) were adjusted for baseline factors.RESULTS AND LIMITATIONS: Of 7386 patients with mRCC treated with first-line TKIs, 3906 (53%) and 3480 (47%) had synchronous and metachronous metastasis, respectively. More patients with synchronous versus metachronous disease had higher T stage (T1-2: 19% vs 34%), N1 disease (21% vs 6%), presence of sarcomatoid differentiation (15.8% vs 7.9%), Karnofsky performance status 3-12 mo, >1-2 yr, >2-7 yr, and >7 yr correlated with poor TTF (5.6 mo vs 7.3, 8.0, 10.8, and 13.3 mo, p CONCLUSIONS: Timing of metastases after initial RCC diagnosis may impact the outcomes from targeted therapy in mRCC.PATIENT SUMMARY: We looked at the impact of the timing of metastatic outbreak on survival outcomes in kidney cancer patients treated with targeted therapy. We found that the longer time to metastatic development was associated with improved outcome.

Cataracts involve the deposition of the crystallin proteins in the vertebrate eye lens, causing opacification and blindness. They are associated with either genetic mutation or protein damage that accumulates over the lifetime of the organism. Deamidation of Asn residues in several different crystallins has been observed and is frequently invoked as a cause of cataract. Here, we investigated the properties of Asp variants, deamidation products of γD-crystallin, by solution NMR, X-ray crystallography, and other biophysical techniques. No substantive structural or stability changes were noted for all seven Asn to Asp γD-crystallins. Importantly, no changes in diffusion interaction behavior could be detected. Our combined experimental results demonstrate that introduction of single Asp residues on the surface of γD-crystallin by deamidation is unlikely to be the driver of cataract formation in the eye lens.

More than half of patients diagnosed with renal cell carcinoma (RCC) are age 65 or older. However, older patients are often unable to meet eligibility criteria for clinical trial enrollment due to multiple factors, such as comorbidities and polypharmacy, which leads to under-representation of this population in clinical trials. Given this, efficacy data from the registration trials may not apply to older patients. Our objective was to evaluate the efficacy of first-line and salvage-line treatment in older patients, and compare efficacy between older and younger patients with metastatic RCC (mRCC).Pivotal phase three clinical trials for first-line and salvage-line treatments were included if they reported overall survival (OS) or progression-free survival (PFS) results stratified by age (/≥65 years). The meta-analysis of OS and PFS stratified by age/≥65 years was conducted in the context of Bayesian hierarchical log-linear models with both within and between study variance components.In the first-line setting, data suggests that Nivolumab plus Ipilimumab is the most efficacious treatment for older patients (PFS hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.23-1.45, probability best 39.7%). In the salvage-line setting, Cabozantinib is likely the most efficacious therapy for older patients (PFS HR 0.15, 95% CI 0.08-0.28, probability best 77.2%). Evidence suggests that the majority of first-line treatments have worse efficacy in older patients compared to younger patients.For older patients, first-line Nivolumab plus Ipilimumab and salvage-line Cabozantinib may offer the best survival outcomes. Most first-line drugs for mRCC have inferior performance in older patients compared to their younger counterparts.