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Gamma delta (γδ) T cells reside within human tissues including tumors, but their function in mediating antitumor responses to immune checkpoint inhibition is unknown. Here we show that kidney cancers are infiltrated by Vδ2− γδ T cells, with equivalent representation of Vδ1+ and Vδ1− cells, that are distinct from γδ T cells found in normal human tissues. These tumor-resident Vδ2− T cells can express the transcriptional program of exhausted αβ CD8+ T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although Vδ2− γδ T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted Vδ2− γδ T cells are composed of three distinct populations that lack TCF7, are clonally expanded and express cytotoxic molecules and multiple Vδ2− T-cell receptors. Human tumor-derived Vδ2− γδ T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of Vδ2− T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, Vδ2− γδ T cells within the tumor microenvironment can contribute to antitumor efficacy.

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) targeting TROP2, which has recently been approved for treatment-refractory metastatic urothelial cancer (UC). However, the variability of TROP2 expression across different bladder cancer (BC) subtypes, as well as after enfortumab vedotin (EV) exposure, remains unknown. Using gene expression data from four clinical cohorts with1400 patient samples of muscle-invasive BC and a BC tissue microarray, we found that TROP2 mRNA and protein are highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtype. In addition, TROP2 mRNA levels are correlated with NECTIN4 mRNA but are more highly expressed than NECTIN4 mRNA in patient cohorts and BC cell lines. Moreover, CRISPR/Cas9-mediated knockdown of TROP2 demonstrates that its expression is one factor governing SG sensitivity. After prolonged EV exposure, cells can downregulate NECTIN4, leading to EV resistance, but retain TROP2 expression and remain sensitive to SG, suggesting nonoverlapping resistance mechanisms to these ADCs. While our findings warrant further validation, they have significant implications for biomarker development, patient selection, and treatment sequencing in the clinic as well as clinical trial design and stratification for metastatic BC patients. PATIENT SUMMARY: In this report, we investigated the expression levels of the drug target TROP2 across different molecular subtypes of bladder cancer in multiple patient cohorts and cell lines. We found high levels of TROP2 in most subtypes except in the neuroendocrine subtype. Overall, TROP2 gene expression is higher than NECTIN4 gene expression, and cells resistant to enfortumab vedotin (EV), a NECTIN4-targeting antibody-drug conjugate, remain sensitive to sacituzumab govitecan (SG). Our findings suggest that SG may be effective across most bladder cancer subtypes, including the bladder cancers previously treated with EV.

A taxonomic review of the Chinese species of the genus Xenicotela Bates, 1884 is presented. A new species, Xenicotela griseomaculatasp. nov., is described from Chongqing, China, and a new combination, Xenicotela convexicollis (Gressitt, 1942) comb. nov., is proposed.

Supplementary Figure from Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

The tumor immune microenvironment (TIME) is commonly infiltrated by diverse collections of myeloid cells. Yet, the complexity of myeloid-cell identity and plasticity has challenged efforts to define bona fide populations and determine their connections to T-cell function and their relationship to patient outcome. Here, we have leveraged single-cell RNA-sequencing analysis of several mouse and human tumors and found that monocyte–macrophage diversity is characterized by a combination of conserved lineage states as well as transcriptional programs accessed along the differentiation trajectory. We also found in mouse models that tumor monocyte-to-macrophage progression was profoundly tied to regulatory T cell (Treg) abundance. In human kidney cancer, heterogeneity in macrophage accumulation and myeloid composition corresponded to variance in, not only Treg density, but also the quality of infiltrating CD8+ T cells. In this way, holistic analysis of monocyte-to-macrophage differentiation creates a framework for critically different immune states.

Supplementary Table from Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

Supplementary Data from Origins and Timing of Emerging Lesions in Advanced Renal Cell Carcinoma

Supplementary Figure from Origins and Timing of Emerging Lesions in Advanced Renal Cell Carcinoma

Renal cell carcinoma (RCC) with venous tumor thrombus (VTT) arising from the primary tumor occurs in approximately 10% of cases and is thought to represent more advanced disease. The intravascular nature of VTT suggests that it may serve as a source for hematogenous metastases. RCC with VTT and distant metastasis provides unique opportunities to examine the origins and emergence timing of these distinct tumor lesions, and to identify molecular correlates with disease state. We performed multi-region exome and RNA-sequencing analysis of 16 patients with RCC with VTT, with eight patients also having sequenced metastasis, to identify genomic alterations, biological pathways, and evolutionary processes contributing to VTT and metastasis, and to ask whether metastasis arises directly from or independent of VTT. No specific genomic alterations were associated with VTT. Hallmark copy-number alterations (deletions of 14q, 8p, and 4q) were associated with metastasis and disease recurrence, and secondary driver alterations tended to accumulate in metastatic lineages. Mismatch repair mutational signatures co-occurred across most tumors, suggesting a role for intracellular DNA damage in RCC. Robust phylogenetic timing analysis indicated that metastasis typically emerged before VTT, rather than deriving from it, with the earliest metastases predicted to emerge years before diagnosis. As a result, VTT in metastatic cases frequently derived from a metastatic lineage. Relative to the primary tumor, VTT upregulated immediate-early genes and transcriptional targets of the TNFα/NF-κB pathway, whereas metastases upregulated MTOR and transcriptional targets downstream of mTORC1 activation.Implications:These results suggest that VTT and metastasis formation occur independently, VTT presence alone does not necessarily imply more advanced disease with inevitably poor prognosis.

NECTIN4 mRNA gene expression across the (A) TCGA, (B) Decipher, and (C) Lund molecular subtypes in the Decipher commercial cohort (n=529). The p value from Kruskal-Wallis testing is shown for each panel.

(A) Validation of knockdown by cell surface staining of NECTIN4 protein expression in HT-1376 cells using CRISPRi/dCas9 and five unique sgRNAs targeting different regions of NECTIN4 gene and promoter. The sgNECTIN4-a guide was used for subsequent experiments. (B) Confirmation of sgNECTIN4 CRISPRi/dCas9-mediated NECTIN4 mRNA knockdown in HT-1376 cells by quantitative PCR, **p90%. (C) Phase-contrast, brightfield microscopy of HT-1376 cells in Control and NECTIN4 knockdown cells to show the morphology of cells. Scale bar = 400 mm. (D) Validation of knockdown by cell surface staining of NECTIN4 protein expression in HT-1197 cells using CRISPRi/dCas9. (E) EV dose-response WST proliferation assay in HT-1197 Control (black) and NECTIN4 (KD) knockdown (purple) cells.

(A) NECTIN4 surface protein expression in TCCSUP Control and TCCSUP NECTIN4 OE cells. (B) EV dose-response clonogenic assay in TCCSUP Control and TCCSUP NECTIN4 OE cells.

The p values from pairwise comparisons amongst the molecular subtypes for each cohort using the Wilcoxon rank-sum test are shown.

Gene expression analysis of NECTIN4 correlates. (A) Correlation between NECTIN4 and GATA3 mRNA expression across the Seiler 2017 (left), Sjödahl 2012 (middle), and TCGA (right) cohorts. (B) Correlation between NECTIN4 and FOXA1 mRNA expression across Seiler 2017 (left), Sjödahl 2012 (middle), and TCGA (right) cohorts. (C) Correlation between NECTIN4 and PPARG mRNA expression across Seiler 2017 (left), Sjödahl 2012 (middle), and TCGA (right) cohorts. (D) Centroid values from the consensus molecular classifier by Kamoun et al. for NECTIN4, FOXA1, GATA3, and PPARG. (E) Kaplan-Meier curves of overall survival stratified by quartiles of NECTIN4 mRNA expression in TCGA (p=0.11), Sjödahl 2012 (p=0.6), and Seiler 2017 (p=0.06) cohorts.

Purpose:Enfortumab vedotin (EV) is an antibody–drug conjugate (ADC) targeting NECTIN4 (encoded by the PVRL4/NECTIN4 gene) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In this study, we sought to (i) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and (ii) determine whether NECTIN4 expression mediates EV sensitivity or resistance.Experimental Design:Molecular subtyping and NECTIN4 expression data from seven muscle-invasive bladder cancer clinical cohorts (n = 1,915 total specimens) were used to assess NECTIN4 expression across molecular subtypes. The outcome of the transcriptomic analysis was relative NECTIN4 expression in the consensus molecular subtypes of bladder cancer. Expression of NECTIN4 was validated in bladder cancer cell lines. NECTIN4 was stably overexpressed or knocked down in basal and luminal bladder cancer cell lines and EV drug sensitivity assays were performed, as measured by cell proliferation and clonogenic assays.Results:NECTIN4 expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes. NECTIN4 expression is positively correlated with luminal markers GATA3, FOXA1, and PPARG across all cohorts. NECTIN4 expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of NECTIN4 leads to EV resistance.Conclusions:Sensitivity to EV is mediated by expression of NECTIN4, which is enriched in luminal subtypes of bladder cancer. These findings may have implications for biomarker development, patient selection, and the inclusion of molecular subtyping in ongoing and future EV clinical trials.See related commentary by Teo and Rosenberg, p. 4950

(A) Scatter plot of GATA3 versus NECTIN4 mRNA expression demonstrates a positive correlation between GATA3 and NECTIN4 mRNA expression in bladder cancer cell lines, with a Spearman correlation coefficient of 0.595, p=7.4E-5. (Source: DepMap) (B) Distribution of cell dependency scores for NECTIN4 from CRISPR knockout and RNAi knockdown experiments in 625 and 711 cell lines, respectively, which were obtained from DepMap. A score of 0 denotes that the gene is not essential for cell life, whereas -1 denotes that the gene is a common essential gene.

Association between NECTIN4 mRNA expression and clinical characteristics for the MOL cohort for (A) sex (p=0.61), (B) age (p=0.47), (C) clinical stage (p=0.063), and (D) pathological stage (p=0.012). The p value from Kruskal-Wallis testing is shown for each panel.

Association between NECTIN4 mRNA expression and clinical characteristics in the Seiler cohort for (A) sex (p

(A) Immunohistochemistry (IHC) staining of NECTIN4 protein in UMUC3-Control and UMUC3-NECTIN4 OE tumor xenografts. (B) Rabbit IgG isotype negative control of UMUC3-Control and UMUC3-NECTIN4 OE tumor xenografts.

(A) NECTIN4 surface protein expression in UMUC-14, 647V and HT-1376 cells. Gray denotes unstained control cells and red denotes NECTIN4-PE antibody stain. (B) Combined histograms of NECTIN4 surface protein expression in UMUC-14 (purple), 647V (green) and HT-1376 (blue) cells. (C) Western blot of NECTIN4 protein expression in whole cell lysates of UMUC-14, 647V and HT-1376 cells. (D) Phase-contrast brightfield microscopy of UMUC-14 and 647V bladder cancer cells. Scale bar = 200 mm. (E) EV dose-response assay in UMUC-14 (purple, basal), 647V (green, basal) and HT-1376 (blue, luminal) cells.

NECTIN4 guide RNA and qPCR primer sequences used for CRISPRi knockdown and qPCR experiments, respectively.

Clinical characteristics of the cohorts included in study. Of note, the Seiler cohort pathological tumor stage is after neoadjuvant chemotherapy (i.e. ypT). ** age > 90 censored to protect patient privacy

PURPOSE The utility of blue light cystoscopy (BLC) in patients receiving bacillus Calmette-Guerin (BCG) during post-treatment cystoscopy is not well understood. Our objective was to determine if BLC improves recurrence detection in patients with nonmuscle-invasive bladder cancer (NMIBC) undergoing BCG. MATERIALS AND METHODS Using the prospective multi-institutional Cysview® Registry (2014-2019), patients with NMIBC who received BCG within 1 year prior to BLC were identified. Primary outcomes were recurrences and whether lesions were detected on white light cystoscopy (WLC), BLC or both. We calculated the percentage of cystoscopies with recurrences that were missed with WLC alone. The cystoscopy-level BLC false-positive rate was the proportion of cystoscopies with biopsies only due to BLC suspicious lesions without recurrence. RESULTS Of 1,703 BLCs, 282 cystoscopies were in the analytic cohort. The overall recurrence rate was 45.0% (127). With only WLC, 13% (16/127) of recurrences would have been missed as 5.7% (16/282) of cystoscopies performed had a recurrence only identified with BLC. Among 16 patients with recurrence missed with WLC, 88% (14) had carcinoma in situ. The cystoscopy-level BLC false-positive rate was 5% (15). CONCLUSIONS BLC helped detect recurrences after recent BCG that would have been missed with WLC alone. Providers should consider BLC for high-risk patients undergoing BCG and should discuss the risk of false-positives with these patients. As clinical trials of novel therapies for BCG-unresponsive disease increase and there are no clear guidelines on BLC use for post-treatment cystoscopies, it is important to consider how variable BLC use could affect enrollment in and comparisons of these studies.

The tumor immune microenvironment (TIME) is commonly infiltrated by diverse collections of myeloid cells. Yet, the complexity of myeloid-cell identity and plasticity has challenged efforts to define bona fide populations and determine their connections to T-cell function and their relationship to patient outcome. Here, we have leveraged single-cell RNA-sequencing analysis of several mouse and human tumors and found that monocyte–macrophage diversity is characterized by a combination of conserved lineage states as well as transcriptional programs accessed along the differentiation trajectory. We also found in mouse models that tumor monocyte-to-macrophage progression was profoundly tied to regulatory T cell (Treg) abundance. In human kidney cancer, heterogeneity in macrophage accumulation and myeloid composition corresponded to variance in, not only Treg density, but also the quality of infiltrating CD8+ T cells. In this way, holistic analysis of monocyte-to-macrophage differentiation creates a framework for critically different immune states.

Introduction Men with a detectable PSA after radical prostatectomy (RP) are often offered salvage therapy while those with an undetectable PSA are monitored. We aim to better characterize the natural history of men with an initially undetectable PSA who subsequently developed a detectable PSA > 6 months after RP. Methods Retrospective analysis of men who underwent RP for clinically localized prostate cancer at the University of California, San Francisco from 2000 to 2022. The primary outcome was biochemical recurrence, defined as 2 consecutive PSA > = 0.03 ng/mL starting 6 months after surgery. Secondary outcomes were salvage treatment, post-salvage treatment, metastasis free survival (MFS), prostate cancer specific mortality (PCSM), and all-cause mortality (ACM). This cohort was compared to a previously described cohort who had an immediately detectable post-operative PSA. Results From our cohort of 3348 patients, we identified 2868 men who had an undetectable post-op PSA. Subsequently, 642 men had a delayed detectable PSA at a median of 25 months (IQR 15, 43) with median follow-up of 72 months after RP. PSA at time of failure was p = 0.02) and PSA doubling time (PSA-DT) of p Conclusions Men who develop a detectable PSA > 6 months post-operatively may have excellent long-term outcomes, even in the absence of salvage therapy.

Understanding how community assembly processes drive biodiversity patterns is a central goal of community ecology. While it is generally accepted that ecological communities are assembled by both stochastic and deterministic processes, quantifying their relative importance remains challenging. Few studies have investigated how the relative importance of stochastic and deterministic community assembly processes vary among taxa and along gradients of habitat degradation. Using data on 1,645 arthropod species across seven taxonomic groups in Malaysian Borneo, we quantified the importance of stochastic and deterministic assembly processes across a gradient of logging intensity. Dispersal limitation was the dominant process for most taxa at all levels of logging intensity. The relationship between logging and community assembly varied depending on the specific combination of taxa and stochasticity metric used, but, in general, the processes that govern invertebrate community assembly were remarkably robust to changes in land use intensity.

Background The rare p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) was found to increase Alzheimer’s disease (AD) risk. This mutation is located at the cleavage site of TREM2 extracellular domain. Ectopic expression of TREM2-H157Y in HEK293 cells resulted in increased TREM2 shedding. However, the physiological outcomes of the TREM2 H157Y mutation remain unknown in the absence and presence of AD related pathologies. Methods We generated a novel Trem2 H157Y knock-in mouse model through CRISPR/Cas9 technology and investigated the effects of Trem2 H157Y on TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathologies by conducting biochemical assays, targeted mass spectrometry analysis of TREM2, hippocampal electrophysiology, immunofluorescent staining, in vivo micro-dialysis, and cortical bulk RNA sequencing. Results Consistent with previous in vitro findings, Trem2 H157Y increases TREM2 shedding with elevated soluble TREM2 levels in the brain and serum. Moreover, Trem2 H157Y enhances synaptic plasticity without affecting microglial density and morphology, or TREM2 signaling. In the presence of amyloid pathology, Trem2 H157Y accelerates amyloid-β (Aβ) clearance and reduces amyloid burden, dystrophic neurites, and gliosis in two independent founder lines. Targeted mass spectrometry analysis of TREM2 revealed higher ratios of soluble to full-length TREM2-H157Y compared to wild-type TREM2, indicating that the H157Y mutation promotes TREM2 shedding in the presence of Aβ. TREM2 signaling was further found reduced in Trem2 H157Y homozygous mice. Transcriptomic profiling revealed that Trem2 H157Y downregulates neuroinflammation-related genes and an immune module correlated with the amyloid pathology. Conclusion Taken together, our findings suggest beneficial effects of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD risk, we speculate TREM2 H157Y in humans might increase AD risk through an amyloid-independent pathway, such as its effects on tauopathy and neurodegeneration which merit further investigation.

Objective To evaluate the Cancer of the Bladder Risk Assessment (COBRA) score in The Cancer Genome Atlas (TCGA) bladder cancer cohort. Second, to investigate the utility of the COBRA score within each bladder cancer molecular subtype following radical cystectomy (RC) and determine if it can help identify candidates for adjuvant therapies and clinical trials. Methods Among the TCGA bladder cancer cohort (n = 412), RC pathology reports were reviewed to calculate COBRA scores. Kaplan-Meier survival curves along with univariable and multivariable Cox proportional hazard models were used to determine the clinical utility of the COBRA score to predict overall survival (OS) within the overall cohort and within each molecular subtype (if n>30 within subtype). Results In the analytic cohort (n = 273) there was a median follow-up of 18 months. Higher COBRA score was associated with significant increased risk of death in both univariable (HR = 1.52 per point [PP] 95% CI [1.32, 1.75)] and multivariable models (HR = 1.54 PP 95% CI [1.32, 1.79]). This remained true in multivariable models stratified by molecular subtype for basal (HR = 1.37 PP 95% CI [1.07, 1.74]), luminal infiltrated (HR = 1.70 PP 95% CI [1.10, 2.64]), and luminal papillary (HR = 1.62 PP 95% CI [1.28, 2.06]) tumors. Conclusion Our findings validate the COBRA score in the TCGA bladder cancer cohort. This suggests the COBRA score can be used in conjunction with molecular subtyping information to help guide clinical decision-making following RC to improve risk stratification and allow for earlier identification of candidates for adjuvant therapies and clinical trials.

Background Optimal treatment selection for localized renal tumors is challenging because of their variable biologic behavior and limitations in the preoperative assessment of tumor aggressiveness. The authors investigated the emerging hyperpolarized (HP) 13 C magnetic resonance imaging (MRI) technique to noninvasively assess tumor lactate production, which is strongly associated with tumor aggressiveness. Methods Eleven patients with renal tumors underwent HP 13 C pyruvate MRI before surgical resection. Tumor 13 C pyruvate and 13 C lactate images were acquired dynamically. Five patients underwent 2 scans on the same day to assess the intrapatient reproducibility of HP 13 C pyruvate MRI. Tumor metabolic data were compared with histopathology findings. Results Eight patients had tumors with a sufficient metabolite signal-to-noise ratio for analysis; an insufficient tumor signal-to-noise ratio was noted in 2 patients, likely caused by poor tumor perfusion and, in 1 patient, because of technical errors. Of the 8 patients, 3 had high-grade clear cell renal cell carcinoma (ccRCC), 3 had low-grade ccRCC, and 2 had chromophobe RCC. There was a trend toward a higher lactate-to-pyruvate ratio in high-grade ccRCCs compared with low-grade ccRCCs. Both chromophobe RCCs had relatively high lactate-to-pyruvate ratios. Good reproducibility was noted across the 5 patients who underwent 2 HP 13 C pyruvate MRI scans on the same day. Conclusions The current results demonstrate the feasibility of HP 13 C pyruvate MRI for investigating the metabolic phenotype of localized renal tumors. The initial data indicate good reproducibility of metabolite measurements. In addition, the metabolic data indicate a trend toward differentiating low-grade and high-grade ccRCCs, the most common subtype of renal cancer. Lay summary Renal tumors are frequently discovered incidentally because of the increased use of medical imaging, but it is challenging to identify which aggressive tumors should be treated. A new metabolic imaging technique was applied to noninvasively predict renal tumor aggressiveness. The imaging results were compared with tumor samples taken during surgery and showed a trend toward differentiating between low-grade and high-grade clear cell renal cell carcinomas, which are the most common type of renal cancers.

The clinical course of localized prostate cancer varies widely, from indolent disease unlikely to need treatment to aggressive disease requiring intensive, multimodal therapy. Traditionally, treatment decisions have been based on clinical and pathologic factors, including serum prostate specific antigen (PSA), clinical stage, and Gleason score. However, these factors have limited ability to describe the underlying tumor biology. Tissue-based genomic tests have emerged as a promising tool to more accurately characterize prostate cancer biology and predict clinical course. Using prostate cancer tissue obtained at pre-treatment biopsy or radical prostatectomy, these tests exploit the expression of specific genes involved in key biological pathways and, as a result, have the potential to aid clinical decision-making. The current review summarizes available data describing the clinical use of 5 commercially available tissue-based genomic assays in a number of clinical scenarios.

At every stage of the prostate cancer journey from screening and diagnosis to management of advanced disease, patients and clinicians face dilemmas and decisions that can impact long-term outcomes. Although traditional risk stratification in prostate cancer is based on serum prostate specific antigen, clinical stage and Gleason score, in recent years, biomarkers have been developed that may be useful in several clinical scenarios. Biomarkers that can accurately predict an individual patient’s risk, prognosis, and response to specific treatments could lead to improvements in decision-making and clinical care. Although there is evidence to support the use of biomarkers to guide management decisions, the optimal scenario in which to use them, how to interpret the results, and how to incorporate those results into clinical decision-making can be confusing. Nevertheless, in the era of personalized and precision medicine, it is important for clinicians to be aware of what tests are available, what clinical questions they seek to answer, and what limitations they have. This review focuses on the serum and urine biomarkers for the management of prostate cancer that have been under intense investigation in recent years.

To evaluate the clinical, pathological, and survival outcomes of bladder cancer in patients aged 18–40 years. We identified 362,091 bladder cancer patients from the National Cancer Database between 2004–2013 and compared patients aged 18–40 years to those > 40 years of age with univariate analysis using Chi-square tests. A subset analysis was performed on patients who underwent cystectomy. Multivariable Cox regression was used for overall survival analysis. Our final analysis included 314,177 patients with 3314 (1.1%) patients aged 18–40 years. Patients aged 18–40 years had a lower male-to-female ratio (2.4 versus 3.0), a greater proportion of low-grade tumors (72.7% versus 48.3%, p

Due to significant risks of cancer recurrence and progression, and limited options after intravesical Bacillus Calmette Guerin (BCG) therapy, there is a critical unmet need to identify novel treatments for those patients with BCG-unresponsive bladder cancer. There is active investigation of immunotherapies which provide both biologic and clinical rationales for indoleamine-2,3- dioxygenase inhibitors in salvage therapy for non-muscle invasive bladder cancer.

Objectives Disparities in guideline-based treatment (GBT) for genitourinary cancers are commonly presented individually, impeding comprehensive examinations of institutional drivers. In this study, we utilize the National Cancer Database to characterize the prevalence of disparities in GBT for prostate (PCa), bladder (BCa), and kidney (KCa) cancer within the same facility to evaluate whether disparities cluster at the institutional level. Methods Patients diagnosed with clinically localized (cT2-4aNX-1MX-0) bladder, (cT2b-4NX-0MX-0) prostate, or (cT2a-3cNX-1MX-0) kidney cancer between 2004-2017 within each National Cancer Database dataset were included. We collected clinicodemographics, treatment received, and facility data. GBT was defined according to NCCN Guidelines by TNM staging. We calculated rates of GBT by cancer type and race and compared rates between White and non-White patients (non-Hispanic Black, Hispanic, and Asian) using Chi-squared tests. Pairwise correlations in GBT rates between PCa, BCa, and KCa treated across the facilities were estimated using Pearson correlation coefficients, where the facilities with Citation Format: Samuel L. Washington, Julie A. Szymaniak, Pedro Gallardo, Chengshi Jin, Li Zhang, Sima Porten, Maxwell V. Meng, Matthew R. Cooperberg, Peter R. Carroll. Facility-level disparities in the delivery of guideline-based treatment across genitourinary cancers [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A059.

We present a genome assembly from an individual male

Background: The p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) has been reported to increase Alzheimer’s disease (AD) risk. This mutation in the extracellular domain of TREM2 localizes at the cleavage site and was shown to enhance shedding and impair phagocytosis in vitro by ectopic expression of TREM2-H157Y in HEK293 cells. However, the physiological and AD-related outcomes of TREM2 H157Y mutation in vivo remain unknown.Methods: We generated a novel Trem2 H157Y knock-in mouse model through CRISPR-Cas9 technology and investigated how Trem2 H157Y mutation impacts TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathology by conducting biochemical assays, immunofluorescent staining, hippocampal electrophysiology, and in vivo micro-dialysis in awake, free-moving animals.Results: Consistent with previous in vitro findings, TREM2-H157Y increases the amount of soluble TREM2 (sTREM2) in the cortex and serum of mutant mice compared to the wild type controls. Interestingly, the Trem2 H157Y variant enhances synaptic plasticity without affecting microglial density and morphology. In the presence of amyloid pathology, TREM2-H157Y surprisingly accelerates Aβ clearance and reduces amyloid burden and microgliosis. Conclusion: Taken together, our findings support a beneficial effect of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD, we speculate TREM2-H157Y might increase AD risk through an amyloid-independent pathway, as such its effects on tauopathy and neurodegeneration merit further investigation.

INTRODUCTION AND OBJECTIVE:Histologic variants in bladder cancer are clinically aggressive tumors associated with poor prognosis. The rarity of these tumors has made transcriptomic characterization...

INTRODUCTION AND OBJECTIVE: The COVID-19 pandemic brought unprecedented changes to urologic care in order to minimize risks of transmission. At UCSF, we performed a prospective pilot study of the home-based, mail-in urine CxBladder Monitor (CxM) test to inform the urgency of surveillance cystoscopy in patients with nonmuscle invasive bladder cancer (NMIBC). METHODS: From March-June 2020, patients with NMIBC due for surveillance cystoscopy were offered CxM prior to scheduling a clinic visit. Based on prior studies, a CxM score ≥3.5 was used to proceed with cystoscopy while a score below that threshold led to deferring (negative predictive value 97%) cystoscopy. Outcomes of interest included whether in-office cystoscopy was deferred or performed based on CxM and detection of urothelial cancer at immediate or next surveillance cystoscopy. RESULTS: 52 patients (73% men) were included in this study. Median age was 71 (IQR 65-78) years with a median of 4.0 (IQR 2.5- 6.1) years since initial bladder cancer diagnosis;3 (6%) had a history of upper tract urothelial carcinoma (UTUC). By AUA risk stratification criteria, 14 (27%), 17 (33%), and 20 (41%) were low, intermediate, and high-risk, respectively. 50% of patients had experienced recurrence since diagnosis (median 2, IQR 1-4). CxM score was ≥3.5 in 17 (33%) patients. These patients were more likely to have high grade disease at diagnosis (78% vs 64%, p=0.06) but did not differ by age, gender, race, history of UTUC, T stage, or prior recurrences versus patients with CxM results

BackgroundOptimal treatment selection for localized renal tumors is challenging because of their variable biologic behavior and limitations in the preoperative assessment of tumor aggressiveness. The authors investigated the emerging hyperpolarized (HP) 13 C magnetic resonance imaging (MRI) technique to noninvasively assess tumor lactate production, which is strongly associated with tumor aggressiveness.MethodsEleven patients with renal tumors underwent HP 13 C pyruvate MRI before surgical resection. Tumor 13 C pyruvate and 13 C lactate images were acquired dynamically. Five patients underwent 2 scans on the same day to assess the intrapatient reproducibility of HP 13 C pyruvate MRI. Tumor metabolic data were compared with histopathology findings.ResultsEight patients had tumors with a sufficient metabolite signal-to-noise ratio for analysis; an insufficient tumor signal-to-noise ratio was noted in 2 patients, likely caused by poor tumor perfusion and, in 1 patient, because of technical errors. Of the 8 patients, 3 had high-grade clear cell renal cell carcinoma (ccRCC), 3 had low-grade ccRCC, and 2 had chromophobe RCC. There was a trend toward a higher lactate-to-pyruvate ratio in high-grade ccRCCs compared with low-grade ccRCCs. Both chromophobe RCCs had relatively high lactate-to-pyruvate ratios. Good reproducibility was noted across the 5 patients who underwent 2 HP 13 C pyruvate MRI scans on the same day.ConclusionsThe current results demonstrate the feasibility of HP 13 C pyruvate MRI for investigating the metabolic phenotype of localized renal tumors. The initial data indicate good reproducibility of metabolite measurements. In addition, the metabolic data indicate a trend toward differentiating low-grade and high-grade ccRCCs, the most common subtype of renal cancer.Lay summaryRenal tumors are frequently discovered incidentally because of the increased use of medical imaging, but it is challenging to identify which aggressive tumors should be treated. A new metabolic imaging technique was applied to noninvasively predict renal tumor aggressiveness. The imaging results were compared with tumor samples taken during surgery and showed a trend toward differentiating between low-grade and high-grade clear cell renal cell carcinomas, which are the most common type of renal cancers.

The COVID-19 public health emergency forced the conversion of in-person SUO fellowship interviews into virtual interviews. We sought to understand applicant perspectives and preferences related to virtual interviews and whether programs should consider virtual interviews in the future. We distributed a survey to 2020 SUO Fellowship interview participants at 4 SUO urologic oncology fellowship programs. Response items were on a Likert scale scored 1-5 with higher scores indicating greater agreement with the survey item construct. Survey responses were collated and thematic mapping used to describe open text responses. Descriptive statistics were used for analysis of survey and open text results. Fifty-eight SUO fellowship applicants completed the survey. Virtual interviews successfully promoted interaction with SUO fellowship program faculty (mean 4.6, SD 0.6), outlined program research opportunities (mean 4.5, SD 0.7), and proffered opportunities to ask questions about the fellowship (mean 4.7, SD 0.5). Applicants exhibited weakly positive orientation to the adequacy of the virtual format (mean 3.5, SD 1.1). 63% of applicants would prefer a virtual format in the future. Qualitative feedback noted the benefits of virtual interviews were lower cost and reduced time away from residency. SUO fellowship applicants exhibited mixed preferences for virtual and in-person interviews. Although virtual fellowship interviews have benefits such as cost savings and time efficiency, notable weaknesses included challenges observing the culture of the programs. Following the pandemic, SUO fellowship programs may consider virtual interviews but should consider incorporating opportunities for informal interactions between faculty, fellows, and fellow applicants.

Background: Unicameral bone cysts (UBCs) are frequently associated with pathologic fracture due to aggressive osteolysis. Methods/Results: We present a case series (n=5) with complex or refractory bone cysts treated with doxycycline injections that exhibited increased ossification and symptom resolution at short term follow up with minimal side effects. Conclusions: In addition to its antibiotic properties, doxycycline is also known to inhibit matrix metalloproteinases, angiogenesis, and osteoclast activity suggesting that UBCs are dependent on MMP, VEGF or RANKL-mediated osteolysis. Further investigation is warranted regarding the use of doxycycline injections in UBCs.

BACKGROUND: Optimal treatment selection for localized renal tumors is challenging because of their variable biologic behavior and limitations in the preoperative assessment of tumor aggressiveness. The authors investigated the emerging hyperpolarized (HP) (13)C magnetic resonance imaging (MRI) technique to noninvasively assess tumor lactate production, which is strongly associated with tumor aggressiveness. METHODS: Eleven patients with renal tumors underwent HP (13)C pyruvate MRI before surgical resection. Tumor (13)C pyruvate and (13)C lactate images were acquired dynamically. Five patients underwent 2 scans on the same day to assess the intrapatient reproducibility of HP (13)C pyruvate MRI. Tumor metabolic data were compared with histopathology findings. RESULTS: Eight patients had tumors with a sufficient metabolite signal-to-noise ratio for analysis; an insufficient tumor signal-to-noise ratio was noted in 2 patients, likely caused by poor tumor perfusion and, in 1 patient, because of technical errors. Of the 8 patients, 3 had high-grade clear cell renal cell carcinoma (ccRCC), 3 had low-grade ccRCC, and 2 had chromophobe RCC. There was a trend toward a higher lactate-to-pyruvate ratio in high-grade ccRCCs compared with low-grade ccRCCs. Both chromophobe RCCs had relatively high lactate-to-pyruvate ratios. Good reproducibility was noted across the 5 patients who underwent 2 HP (13)C pyruvate MRI scans on the same day. CONCLUSIONS: The current results demonstrate the feasibility of HP (13)C pyruvate MRI for investigating the metabolic phenotype of localized renal tumors. The initial data indicate good reproducibility of metabolite measurements. In addition, the metabolic data indicate a trend toward differentiating low-grade and high-grade ccRCCs, the most common subtype of renal cancer.

Colour polymorphism offers rich opportunities for studying the eco-evolutionary mechanisms that drive the adaptations of local populations to heterogeneous and changing environments. We explored the colour morph diversity and composition in a Chrysomela lapponica leaf beetle across its entire distribution range to test the hypothesis that environmental and climatic variables shape spatio-temporal variation in the phenotypic structure of a polymorphic species. We obtained information on 13 617 specimens of this beetle from museums, private collections and websites. These specimens (collected from 1830-2020) originated from 959 localities spanning 33 degrees latitude, 178 degrees longitude and 4200 m altitude. We classified the beetles into five colour morphs and searched for environmental factors that could explain the variation in the level of polymorphism (quantified by the Shannon diversity index) and in the relative frequencies of individual colour morphs. The highest level of polymorphism was found at high latitudes and altitudes. The colour morphs differed in their climatic requirements; their composition was independent of the geographic distance that separated populations but changed with collection year, longitude, mean July temperature and between-year temperature fluctuations. The proportion of melanic beetles, in line with the thermal melanism hypothesis, increased with increasing latitude and altitude and decreased with increasing climate seasonality; it also declined during the past century, but only at high latitudes and altitudes where recent climate warming was especially strong. The observed patterns suggest that colour polymorphism is especially advantageous for populations inhabiting unpredictable environments, presumably due to the different climatic requirements of coexisting colour morphs. This article is protected by copyright. All rights reserved.

To analyze differences in length of stay, opioid use, and other perioperative outcomes in patients undergoing radical cystectomy with urinary diversion who received either liposomal bupivacaine (LB) or epidural analgesia.This was a single center, retrospective cohort study of patients undergoing open radical cystectomy with urinary diversion from 2015-2019 in the early recovery after surgery (ERAS) pathway. Patients received either LB or epidural catheter analgesia for post-operative pain control. LB was injected at the time of fascial closure to provide up to 72 hours of local analgesia. The primary outcome was post-operative length of stay. Secondary outcomes were post-operative opioid use, time to solid food, time to ambulation, and direct hospitalization costs. Multivariable Cox proportional hazards regression was used to determine associations between analgesia type and discharge.LB use was independently associated with shorter post-operative length of stay compared to epidural use (median (IQR) 4.9 days (3.9-5.8) vs 5.9 days (4.9-7.9), P.001), less total opioid use (mean 188.3 vs 612.2 OME, P.001), earlier diet advancement (mean 1.6 vs 2.4 days, P.001), and decreased overall direct costs ($23,188 vs $29,628, P.001). 45% of patients who received LB were opioid-free after surgery, none in the epidural group. On multivariable Cox proportional hazards regression modeling, LB use was independently associated with earlier discharge (HR 2.1, IQR 1.0-4.5).Use of LB in open radical cystectomy is associated with reduced LOS, less opioid exposure, and earlier diet advancement.