Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma.

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

The Role of Hyperbaric Oxygen Therapy in Neuroregeneration and Neuroprotection: A Review.

Neurogenesis is a high energy-demanding process, which is why blood vessels are an active part of the neurogenic niche since they allow the much-needed oxygenation of progenitor cells. In this regard, although neglected for a long time, the "oxygen niche" should be considered an important intervenient in adult neurogenesis. One possible hypothesis for the failure of numerous neuroprotective trials is that they relied on compounds that target a highly specific neuroprotective pathway. This approach may be too limited, given the complexity of the processes that lead to cell death. Therefore, research should adopt a more multifactorial approach. Among the limited range of agents with multimodal neuromodulatory capabilities, hyperbaric oxygen therapy has demonstrated effectiveness in reducing secondary brain damage in various brain injury models. This therapy functions not only as a neuroprotective mechanism but also as a powerful neuroregenerative mechanism.

Pathological concordance rate and outcomes by subtype in advanced papillary renal cell carcinoma.

OBJECTIVE: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. METHODS: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression-free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. RESULTS: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. CONCLUSIONS: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. PATIENT SUMMARY: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial.

Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer.

BACKGROUND: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis and metastasis in preclinical models but the impact of genetic alterations in Wnt signaling genes in men with advanced prostate cancer is unknown. METHODS: We utilized the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database for this retrospective analysis. Patients with activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 were defined as Wnt-altered, while those lacking such alterations were defined as Wnt non-altered. We compared patient characteristics and clinical outcomes as well as co-occurring genetic alterations according to Wnt alteration status. RESULTS: Of the 1498 patients included, 193 (12.9%) were Wnt-altered. These men had a statistically significant 2-fold increased prevalence of liver and lung metastases as compared with Wnt non-altered patients at the time of initial diagnosis, (4.66% v 2.15% ; 6.22% v 3.07%), first metastatic disease diagnosis (10.88% v 5.29%; 13.99% v 6.21%), and CRPC development (11.40% v 6.36%; 12.95% v 5.29%). Wnt alterations were associated with more co-occurring alterations in RB1 (10.4% v 6.2%), AR (38.9% vs 25.7%), SPOP (13.5% vs 4.1%), FOXA1 (6.7% vs 2.8%), and PIK3CA (10.9% vs 5.1%). We found no significant differences in overall survival or other clinical outcomes from initial diagnosis, first metastatic disease, diagnosis of CRPC, or with AR inhibition for mCRPC between the Wnt groups. CONCLUSIONS: Wnt-altered patients with prostate cancer have a higher prevalence of visceral metastases and are enriched in RB1, AR, SPOP, FOXA1, and PIK3CA alterations. Despite these associations, Wnt alterations were not associated with worse survival or treatment outcomes in men with advanced prostate cancer.

Expert Consensus Recommendations on the Management of Treatment-emergent Adverse Events Among Men with Prostate Cancer Taking Poly-ADP Ribose Polymerase Inhibitor + Novel Hormonal Therapy Combination Therapy.

BACKGROUND AND OBJECTIVE: Recent clinical trials have shown improvement in progression-free survival in men with metastatic prostate cancer (mPC) treated with combination poly-ADP ribose polymerase (PARP) inhibitors (PARPi) and novel hormonal therapy (NHT). Regulatory bodies in the USA, Canada, Europe, and Japan have recently approved this combination therapy for mPC. Common adverse events (AEs) include fatigue, nausea and vomiting, and anemia. Nuanced AE management guidance for these combinations is lacking. The panel objective was to develop expert consensus on AE management in patients with mPC treated with the combination PARPi + NHT. METHODS: The RAND/University of California Los Angeles modified Delphi Panel method was used. AEs were defined using the Common Terminology Criteria for Adverse Events. Twelve experts (seven medical oncologists, one advanced practice registered nurse, three urologists, and one patient advocate) reviewed the relevant literature; independently rated initial AE management options for the agent suspected of causing the AE for 419 patient scenarios on a 1-9 scale; discussed areas of agreement (AoAs) and disagreement (AoDs) at a March 2023 meeting; and repeated these ratings following the meeting. Second-round ratings formed the basis of guidelines. KEY FINDINGS AND LIMITATIONS: AoDs decreased from 41% to 21% between the first and second round ratings, with agreement on at least one management strategy for every AE. AoAs included the following: (1) continue therapy with symptomatic treatment for patients with mild AEs; (2) for moderate fatigue, recommend nonpharmacologic treatment, hold treatment temporarily, and restart at a reduced dose when symptoms resolve; (3) for severe nausea or any degree of vomiting where symptomatic treatment fails, hold treatment temporarily and restart at a reduced dose when symptoms resolve; and (4) for hemoglobin 7.1-8.0 g/dl and symptoms of anemia, hold treatment temporarily and restart at a reduced dose after red blood cell transfusion. CONCLUSIONS AND CLINICAL IMPLICATIONS: This expert guidance can support management of AEs in patients with mPC receiving combination PARPi + NHT therapy. PATIENT SUMMARY: A panel of experts developed guidelines for adverse event (AE) management in patients with metastatic prostate cancer treated with a combination of poly-ADP ribose polymerase inhibitors and novel hormonal therapy. For mild AEs, continuation of cancer therapy along with symptomatic treatment is recommended. For moderate or severe AEs, cancer therapy should be stopped temporarily and restarted at the same or a reduced dose when AE resolves.

Genetic Testing in Men With Metastatic Castration-Resistant Prostate Cancer.

This cross-sectional study assesses homologous recombination repair mutation genetic testing and associated characteristics among men with metastatic castration-resistant prostate cancer (mCRPC).

Prospective Study of Homologous Recombination Repair Gene Mutation Prevalence in Patients With Advanced Prostate Cancer From Latin America: Challenges and Future Approaches.

PURPOSE: The prevalence of homologous recombination repair gene mutations (HRRm) in patients with metastatic castration-resistant prostate cancer (mCRPC) in Latin America and the Caribbean (LAC) is unknown. Prevalence of homologous Recombination repair (HRR) gene mutatiOns in patientS with metastatic castration resistant ProstatE Cancer in LaTin America (PROSPECT) aimed to determine this prevalence and to describe the demographic and clinical characteristics of the participants. MATERIALS AND METHODS: This was a prospective, cross-sectional, multicenter study across 11 cancer centers in seven LAC countries. After informed consent, all eligible participants underwent genomic testing by provided blood samples for germline HRR testing; they also provided PC tissue blocks if available for somatic HRR testing. RESULTS: Between April 2021 and April 2022, 387 patients (median age, 70 years [49-89], 94.3% Eastern Cooperative Oncology Group 0-1) with mCRPC were enrolled in the study. Almost 40% of them had a family history of cancer, and the overall time from their initial PC and mCRPC diagnosis was 3 years and 1 year, respectively. The overall prevalence of germline HRRm was 4.2%. The mutations detected included the genes CHEK2 (n = 4, 1%), ATM (n = 3, 0.8%), BRCA2 (n = 3, 0.8%), BRIP1 (n = 2, 0.5%), RAD51B (n = 2, 0.5%), BRCA1 (n = 1, 0.3%), and MRE11 (n = 1, 0.3%). The prevalence of somatic HRRm could not be assessed because of high HRR testing failure rates (79%, 199/251) associated with insufficient DNA, absence of tumor cells, and poor-quality DNA. CONCLUSION: Despite the study's limitations, to our knowledge, PROSPECT was the first attempt to describe the prevalence of HRRm in patients with PC from LAC. Notably, the germline HRRm prevalence in this study was inferior to that observed in North American and European populations. The somatic HRR testing barriers identified are being addressed by several projects to improve access to HRR testing and biomarker-based therapies in LAC.

Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer.

Antibody-drug conjugates and bicycle toxin conjugates represent a tremendous advance in drug delivery technology and have shown great promise in the treatment of urothelial cancer. Previously approved systemic therapies, including chemotherapy and immunotherapy, are often impractical due to comorbidities, and outcomes for patients with advanced disease remain poor, even when receiving systemic therapy. In this setting, antibody-drug and bicycle toxin conjugates have emerged as novel treatments, dramatically altering the therapeutic landscape. These drugs harness unique designs consisting of antibody or bicycle peptide, linker, and cytotoxic payload with more targeted delivery than conventional chemotherapy, thus eliminating malignant cells while reducing systemic toxicities. Potential targets investigated in urothelial cancer include Nectin-4, TROP2, HER2, and EphA2. Initial clinical trials demonstrated efficacy in treatment of refractory advanced urothelial cancer, as well as improvement in quality of life. These initial studies led to FDA approval of two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. Moreover, antibody-drug and bicycle toxin conjugates are being studied in ongoing clinical trials in frontline treatment of advanced disease as well as for localized cancer. These studies highlight the potential for additional future therapies with novel targets, novel antibodies, cytotoxic and immunomodulatory payloads, and unique structural designs enhancing efficacy and safety. There is increasing evidence that combinations with other cancer therapies, especially immunotherapy, improve treatment outcomes. The combination of enfortumab vedotin and pembrolizumab was recently approved for first-line treatment of advanced urothelial carcinoma. Despite the great promise of these novel drugs, robust predictive biomarkers are needed to determine the patients who would maximally benefit. This review surveys the rationale and current state of the evidence for these new drugs and describes future directions actively being explored.

Review of recent advances in novel treatments of urothelial cancer Two new types of drugs, called antibody-drug conjugates (ADCs) and bicycle toxin conjugates (BTCs) have shown great promise in treating urothelial cancer. Both types of drugs consist of a structure targeting a specific protein on bladder cancer cells, linked to a drug that can kill cells. This allows for effective treatment of cancer with potentially less toxicity due to the targeted nature of these treatments. We discuss the potential targets in urothelial cancer and the drugs in these classes that could treat each target. Two of these drugs, enfortumab vedotin and sacituzumab govitecan, are in clinical use for cancers that have spread, while the others are in clinical trials. Moreover, the combination of enfortumab vedotin and pembrolizumab, an immunotherapy drug, has excellent results and was recently approved for first-line treatment of urothelial cancer that has spread. Additional studies are looking into these treatments for cancers that have not spread. In the future, management of side effects, determination of which patients benefit, and overcoming when the drugs become no longer effective will be important.

Characterization of FOLH1 Expression in Renal Cell Carcinoma.

PURPOSE: Given the emergence of PSMA-targeted diagnostic agents and therapeutics, we sought to investigate patterns of FOLH1 expression in RCC and their impacts on RCC outcomes. METHODS: We conducted a pooled multi-institutional analysis of patients with RCC having undergone DNA and RNA next-generation sequencing. FOLH1-high/low expression was defined as the ≥75th/<25th percentile of RNA transcripts per million (TPM). Angiogenic, T-effector, and myeloid expression signatures were calculated using previously defined gene sets. Kaplan-Meier estimates were calculated from the time of tissue collection or therapy start. RESULTS: We included 1,724 patients in the analysis. FOLH1 expression was significantly higher in clear cell (71%) compared to non-clear cell RCC tumors (19.0 versus 3.3 TPM, p < 0.001) and varied by specimen site (45% primary kidney/55% metastasis, 13.6 versus 9.9 TPM, p < 0.001). FOLH1 expression was correlated with angiogenic gene expression (Spearman = 0.76, p < 0.001) and endothelial cell abundance (Spearman = 0.76, p < 0.001). While OS was similar in patients with FOLH1-high versus -low ccRCC, patients with FOLH1-high clear cell tumors experienced a longer time on cabozantinib treatment (9.7 versus 4.6 months, respectively, HR 0.57, 95% CI 0.35-0.93, p < 0.05). CONCLUSIONS: We observed differential patterns of FOLH1 expression based on histology and tumor site in RCC. FOLH1 was correlated with angiogenic gene expression, increased OS, and a longer duration of cabozantinib treatment.

Renal cell carcinoma histologic subtypes exhibit distinct transcriptional profiles.

Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real-world patient cohort, including ccRCC and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1+/TMBhi/MSIhi). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.

Repeat Next-Generation Sequencing Testing on Progression in Men With Metastatic Prostate Cancer Can Identify New Actionable Alterations.

PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB. RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients. CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.

Natural Killer Cell Infiltration in Prostate Cancers Predict Improved Patient Outcomes.

BACKGROUND: Natural killer (NK) cells are non-antigen specific innate immune cells that can be redirected to targets of interest using multiple strategies, although none are currently FDA-approved. We sought to evaluate NK cell infiltration into tumors to develop an improved understanding of which histologies may be most amenable to NK cell-based therapies currently in the developmental pipeline. METHODS: DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from tumors from 45 cancer types (N = 90,916 for all cancers and N = 3365 for prostate cancer) submitted to Caris Life Sciences. NK cell fractions and immune deconvolution were inferred from RNA-seq data using quanTIseq. Real-world overall survival (OS) and treatment status was determined and Kaplan-Meier estimates were calculated. Statistical significance was determined using X2 and Mann-Whitney U tests, with corrections for multiple comparisons where appropriate. RESULTS: In both a pan-tumor and prostate cancer (PCa) -specific setting, we demonstrated that NK cells represent a substantial proportion of the total cellular infiltrate (median range 2-9% for all tumors). Higher NK cell infiltration was associated with improved OS in 28 of 45 cancer types, including (PCa). NK cell infiltration was negatively correlated with common driver mutations and androgen receptor variants (AR-V7) in primary prostate biopsies, while positively correlated with negative immune regulators. Higher levels of NK cell infiltration were associated with patterns consistent with a compensatory anti-inflammatory response. CONCLUSIONS: Using the largest available dataset to date, we demonstrated that NK cells infiltrate a broad range of tumors, including both primary and metastatic PCa. NK cell infiltration is associated with improved PCa patient outcomes. This study demonstrates that NK cells are capable of trafficking to both primary and metastatic PCa and are a viable option for immunotherapy approaches moving forward. Future development of strategies to enhance tumor-infiltrating NK cell-mediated cytolytic activity and activation while limiting inhibitory pathways will be key.

Late-onset delirious mania: Does it ring a bell?

BACKGROUND: Bell's mania was first described in 1849, and other terms have been used to describe this condition, including delirious mania, mania with delirium, and excited delirium. However, no international diagnostic manual has included mania as an independent diagnostic tool. The criteria for delirious mania were proposed by Bond et al. METHODS: We present a case of a man without a personal or family psychiatric history who experienced his first manic episode of delirium and psychosis at 76 years old. CONCLUSIONS: The case described in this study is compatible with mood disorders, the original description of Bell's mania, and Bond's definition of delirious mania. Although rare, extremely late-onset primary mania can occur without personal or family psychiatric history. The initial clinical presentation of delirium requires a thorough medical investigation, including magnetic resonance imaging (MRI) and lumbar puncture with neuronal antibodies. The addition of delirious mania to the group of bipolar disorders in future editions of The International Classification of Diseases (ICD) and Diagnostic and Statistical Manual of Mental Disorders (DSM) has therapeutic and prognostic implications. The Bond criteria can provide valuable information in this respect. Further investigations are necessary to clarify the pathophysiology and epidemiology of delirious mania.

Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration.

BACKGROUND: AR gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these gene alterations in the context of ARTA treatment and clinical outcomes remains unclear. METHODS: Patients with castration-resistant prostate cancer (CRPC) who had undergone genomic testing and received ARTA treatment were identified in the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) database. Patients were stratified according to the timing of genomic testing relative to the first ARTA treatment (pre-/post-ARTA). Clinical outcomes such as time to progression, PSA response, and overall survival were compared based on alteration types. RESULTS: In total, 540 CRPC patients who received ARTA and had tissue-based (n = 321) and/or blood-based (n = 244) genomic sequencing were identified. Median age was 62 years (range 39-90) at the time of the diagnosis. Majority were White (72.2%) and had metastatic disease (92.6%) at the time of the first ARTA treatment. Pre-ARTA genomic testing was available in 24.8% of the patients, and AR mutations and amplifications were observed in 8.2% and 13.1% of the patients, respectively. Further, time to progression was longer in patients with AR amplifications (25.7 months) compared to those without an AR alteration (9.6 months; p = 0.03). In the post-ARTA group (n = 406), AR mutations and AR amplifications were observed in 18.5% and 35.7% of the patients, respectively. The most common mutation in post-ARTA group was L702H (9.9%). CONCLUSION: In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.

Harvesting the Power of Green Synthesis: Gold Nanoparticles Tailored for Prostate Cancer Therapy.

Biosynthetic gold nanoparticles (bAuNPs) present a promising avenue for enhancing bio-compatibility and offering an economically and environmentally responsible alternative to traditional production methods, achieved through a reduction in the use of hazardous chemicals. While the potential of bAuNPs as anticancer agents has been explored, there is a limited body of research focusing on the crucial physicochemical conditions influencing bAuNP production. In this study, we aim to identify the optimal growth phase of Pseudomonas aeruginosa cultures that maximizes the redox potential and coordinates the formation of bAuNPs with increased efficiency. The investigation employs 2,6-dichlorophenolindophenol (DCIP) as a redox indicator. Simultaneously, we explore the impact of temperature, pH, and incubation duration on the biosynthesis of bAuNPs, with a specific emphasis on their potential application as antitumor agents. Characterization of the resulting bAuNPs is conducted using ATR-FT-IR, TEM, and UV-Vis spectroscopy. To gain insights into the anticancer potential of bAuNPs, an experimental model is employed, utilizing both non-neoplastic (HPEpiC) and neoplastic (PC3) epithelial cell lines. Notably, P. aeruginosa cultures at 9 h/OD600 = 1, combined with biosynthesis at pH 9.0 for 24 h at 58 °C, produce bAuNPs that exhibit smaller, more spherical, and less aggregated characteristics. Crucially, these nanoparticles demonstrate negligible effects on HPEpiC cells while significantly impacting PC3 cells, resulting in reduced viability, migration, and lower IL-6 levels. This research lays the groundwork for the development of more specialized, economical, and ecologically friendly treatment modalities.

Emerging Insights in Small-Cell Carcinoma of the Genitourinary Tract: From Diagnosis to Novel Therapeutic Horizons.

Small-cell carcinomas (SCCs) of the genitourinary (GU) tract are rare malignancies with high metastatic potential. The most common primary sites are the bladder and prostate, but case reports of primary SCC of the kidney, ureter, and urethra also exist. The majority of patients present with gross hematuria, irritative or obstructive urinary symptoms, and symptoms of locoregionally advanced or metastatic disease at initial presentation. SCC of the bladder presents with nodal or metastatic involvement in the majority of cases and requires the use of platinum-based chemotherapy in combination with surgery and/or radiation. SCC of the prostate is most commonly seen in the metastatic castrate-resistant setting, and aggressive variant disease presents with a greater propensity for visceral metastases, osteolytic lesions, and relatively low serum prostate-specific antigen for volume of disease burden. Multiple retrospective and prospective randomized studies support the use of a multimodal approach combining platinum-based systemic therapy regimens with radiation and/or surgery for localized disease. This evidence-based strategy is reflected in multiple consensus guidelines. Emerging data suggest that small-cell bladder and prostate cancers transdifferentiate from a common progenitor of conventional urothelial bladder carcinoma and prostatic acinar adenocarcinoma, respectively. Areas of active basic research include efforts to identify the key genetic and epigenetic drivers involved in the emergence of small cell cancers to exploit them for novel therapies. Here, we review these efforts, discuss diagnosis and currently supported management strategies, and summarize ongoing clinical trials evaluating novel therapies to treat this rare, aggressive GU cancer.

Symptom Clusters in Patients With Advanced Cancer: A Prospective Longitudinal Cohort Study to Examine Their Stability and Prognostic Significance.

This study's purpose was to assess symptom cluster (SC) stability during disease progression and determine their strength of association with survival in patients with advanced cancer . Consecutively eligible patients with advanced cancer not receiving cancer-specific treatment and referred to a Tertiary Palliative Care Clinic were enrolled in a prospective cohort study. At first consultation (D0) and in subsequent consultations at day 15 (D15) and day 30 (D30), patients rated 9 symptoms through the Edmonton Symptom Assessment System scale (0-10) and 10 others using a Likert scale (1-5). Principal components factor analysis with varimax rotation was used to determine SCs at each consultation. Of 318 patients with advanced cancer, 301 met eligibility criteria with a median age of 69 years (range 37-94). Three SCs were identified: neuro-psycho-metabolic (NPM), gastrointestinal, and sleep impairment, with some variations in their constitution over time. Exploratory factor analysis accounted for 40% of variance of observed variables in all SCs. Shorter median survival was observed continuously for NPM cluster (D0 23 vs. 58 days, P < .001; D15 41 vs. 104 days, P=.004; D30 46 vs. 114 days, P = .002), although the presence of 2 or more SCs on D0 and D15 also had prognostic significance (D0: 21 vs. 45 days, P = .005; D30: 50 vs. 96 days, P = .040). In a multivariable model, NPM cluster (D0 hazard ratio estimate: HR 1.64; 95%CI, 1.17-2.31; P = .005; D15 HR: 2.51; 95%CI, 1.25-5.05; P = .009; D30 HR: 3.9; 95%CI, 1.54-9.86; P = .004) and hospitalization (D0 HR: 2.27; 95%CI, 1.47-3.51; P < .001; D15 HR: 2.43; 95%CI, 1.18-5.01; P = .016; D30 HR: 3.41; 95%CI, 1.35-8.62; P = .009) were independently and significantly associated with worse survival. Three clinically relevant SCs were identified, and their constitution had small variations, maintaining a stable set of nuclear symptoms through disease progression. Presence of the NPM cluster and hospitalization maintained their prognostic value over time.

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.