Neoadjuvant Cisplatin, Gemcitabine, and Docetaxel in Sarcomatoid Bladder Cancer: Clinical Activity and Whole Transcriptome Analysis.

Background: Sarcomatoid urothelial cancer of the bladder (SBC) is a rare, but aggressive histological subtype for which novel treatments are needed.

Objective: We evaluated the clinical activity and safety of neoadjuvant cisplatin plus gemcitabine plus docetaxel (CGD) in muscle-invasive patients with SBC and assessed SBC tumor biology by whole transcriptome RNA sequencing.

Methods: A single-institution, retrospective analysis of muscle-invasive SBC patients treated with neoadjuvant CGD with molecular analysis.

Frontline immune checkpoint inhibitors in patients ≥ 90 years with advanced urothelial cancer: a single center experience.

Introduction: Immune checkpoint inhibitors (ICIs) are approved for advanced urothelial cancer alone and as first-line in combination with enfortumab vedotin. Platinum based chemotherapy which is another frontline choice is often not a treatment option for older patients due to comorbidities that increase with age. Despite ICIs being better tolerated compared to traditional chemotherapy little is known about their efficacy and toxicity in patients ≥ 90 years due to the rarity of this population in clinical trials.

Development and Validation of a Multivariable Nomogram Predictive of Post-Nephroureterectomy Renal Function.

Background And Objective: The timing of perioperative nephrotoxic chemotherapy for upper tract urothelial carcinoma (UTUC) remains controversial and strongly depends on predicted platinum eligibility after radical nephroureterectomy (RNU). The study objective was to develop and validate a multivariable nomogram to predict estimated glomerular filtration rate (eGFR) following RNU.

Methods: This was a multi-institutional retrospective study of patients with UTUC treated with RNU from 2000 to 2020 at seven high-volume referral centers.

Oncologic Outcomes in Patients with Residual Upper Tract Urothelial Carcinoma Following Neoadjuvant Chemotherapy.

Background And Objective: Growing evidence supports the use of neoadjuvant chemotherapy (NAC) for upper tract urothelial carcinoma (UTUC). However, the implications of residual UTUC at radical nephroureterectomy (RNU) after NAC are not well characterized. Our objective was to compare oncologic outcomes for pathologic risk-matched patients who underwent RNU for UTUC who either received NAC or were chemotherapy-naïve.

Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma.

Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response.

Improved bladder cancer antitumor efficacy with a recombinant BCG that releases a STING agonist.

Despite the introduction of several new agents for the treatment of bladder cancer (BC), intravesical BCG remains a first line agent for the management of non-muscle invasive bladder cancer. In this study we evaluated the antitumor efficacy in animal models of BC of a recombinant BCG known as BCG--OE that releases the small molecule STING agonist c-di-AMP. We found that compared to wild-type BCG (BCG-WT), in both the orthotopic, carcinogen-induced rat MNU model and the heterotopic syngeneic mouse MB-49 model BCG--OE afforded improved antitumor efficacy.

Intravenous BCG vaccination reduces SARS-CoV-2 severity and promotes extensive reprogramming of lung immune cells.

Bacillus Calmette-Guérin (BCG) confers heterologous immune protection against viral infections and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here, we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model. BCG vaccination conferred a modest reduction on lung SCV2 viral load, bronchopneumonia scores, and weight loss, accompanied by a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes.

Identifying candidate de novo genes expressed in the somatic female reproductive tract of Drosophila melanogaster.

Most eukaryotic genes have been vertically transmitted to the present from distant ancestors. However, variable gene number across species indicates that gene gain and loss also occurs. While new genes typically originate as products of duplications and rearrangements of preexisting genes, putative de novo genes-genes born out of ancestrally nongenic sequence-have been identified.

Identifying candidate genes expressed in the somatic female reproductive tract of .

Most eukaryotic genes have been vertically transmitted to the present from distant ancestors. However, variable gene number across species indicates that gene gain and loss also occurs. While new genes typically originate as products of duplications and rearrangements of pre-existing genes, putative genes - genes born out of previously non-genic sequence - have been identified.

Novel urinary tract obstruction marker discovery by multi-marker profiling of urinary extracellular vesicles derived from a rat UTO model.

Introduction: Congenital urinary obstruction is a common cause of end-stage renal disease in the pediatric population. However, non-invasive diagnostics to predict which patients will benefit from early intervention are lacking.

Methods: Using a rat model of upper and lower urinary tract partial obstruction and the Nanostring nCounter Fibrosis V2 Panel, we evaluated the mRNA cargo of urinary small extracellular vesicles (sEVs) and mRNA expression patterns of kidney and bladder tissues from rats with lower tract urinary obstruction and upper tract urinary obstruction.

Comparison of clinicopathological characteristics, gene expression profiles, mutational analysis, and clinical outcomes of pure and mixed small-cell carcinoma of the bladder.

Aims: Small cell bladder carcinoma (SCBC) is a rare, divergent form of urothelial carcinoma (UC). We aimed to determine whether pure (n = 16) and mixed (SCBC and UC; n = 30) tumours differed in pathology, gene expression characteristics, genetic alterations, and clinical outcomes.

Methods And Results: Forty (87%) patients received first-line chemotherapy.

Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation.

A growing body of evidence supports the presence of a population of cells in glioblastoma (GBM) with a stem cell-like phenotype which shares certain biological markers with adult neural stem cells, including expression of SOX2, CD133 (PROM1), and NES (nestin). This study was designed to determine the relationship between the expression of these stem cell markers and the clinical outcome in GBM patients. We quantified the intensity of expression of the proteins CD133 and SOX2 by immunohistochemistry (IHC) in a cohort of 86 patients with IDH-wildtype GBM, and evaluated patient outcomes using Kaplan-Meier and Cox proportional hazards analysis.

Dynamic single-cell RNA sequencing reveals BCG vaccination curtails SARS-CoV-2 induced disease severity and lung inflammation.

COVID-19 continues to exact a toll on human health despite the availability of several vaccines. Bacillus Calmette Guérin (BCG) has been shown to confer heterologous immune protection against viral infections including COVID-19 and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model together with immune profiling and single cell RNA sequencing (scRNAseq).

Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer.

In addition to its role as a TB vaccine, BCG has been shown to elicit heterologous protection against many other pathogens including viruses through a process termed trained immunity. Despite its potential as a broadly protective vaccine, little has been done to determine if BCG-mediated trained immunity levels can be optimized. Here we re-engineer BCG to express high levels of c-di-AMP, a PAMP recognized by stimulator of interferon genes (STING).

A Molecular Inquiry into the Role of Antibody-Drug Conjugates in Bacillus Calmette-Guérin-exposed Non-muscle-invasive Bladder Cancer.

The treatment landscape for advanced urothelial cancer has changed dramatically owing to the US Food and Drug Administration approval and introduction of antibody-drug conjugates (ADCs), including enfortumab vedotin and sacituzumab govitecan. Efforts have begun to use these therapies in earlier disease states, specifically bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). We assessed gene expression associated with these newly approved therapies in a novel cohort of treatment-naïve NMIBC tumors before and after BCG therapy.

BCG invokes superior STING-mediated innate immune response over radiotherapy in a carcinogen murine model of urothelial cancer.

Radiation and bacillus Calmette-Guérin (BCG) instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response; however, comparison of STING pathway molecules and the immune landscape following treatment in urothelial carcinoma has not been performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response.

Inter and Intra-Rater Reliability of Measuring Photometric Craniovertebral Angle Using a Cloud-Based Video Communication Platform.

Objective: Due to social distancing guidelines during the Coronavirus (COVID-19) pandemic, most providers and patients have wanted to avoid close contact. This makes physical therapy (PT) assessments difficult because of the lack of empirical evidence about the reliability of various clinical measurements performed in a virtual environment. One such procedure is the photometric measurement of craniovertebral (CV) angle.

New and topics: enfortumab vedotin mechanisms of response and resistance in urothelial cancer - What do we understand so far?

Enfortumab vedotin (EV) was FDA approved in December 2019 for platinum- and checkpoint-refractory urothelial cancer based on an exceptional 44% response rate, and is currently approved for use after platinum and checkpoint inhibitor therapy. Enfortumab is an antibody-drug conjugate that targets Nectin-4, which is widely expressed in urothelial cancer. Despite this ample target, clinical benefit is not achieved by all patients, and mechanisms of treatment resistance are undescribed.

Molecular subtypes of upper tract urothelial cancer: Setting the stage for precision therapy.

A comprehensive genomic characterization of a large, high-quality cohort of upper tract urothelial carcinomas (UTUCs) in this issue of Cancer Cell reveals that UTUCs can be divided into five DNA-based molecular subtypes. Feasibility data establish that molecular subtyping can be performed non-invasively by sequencing tumor DNA in urine.

Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes.

The antibody-drug conjugate enfortumab-vedotin acts by targeting nectin-4, a protein that is nearly ubiquitously expressed in conventional urothelial cancer. However, expression of nectin-4 in morphologic variants of urothelial carcinoma and nonurothelial histotypes was unknown. Immunohistochemistry for nectin-4 using was performed on 169 patients including 83 with nonmuscle invasive bladder cancer and 86 patients with muscle invasive bladder cancer.

Immune Microenvironment in Gallbladder Adenocarcinomas.

Programmed death-1 (PD1) expression has not been reported in gallbladder adenocarcinoma. In this study we examined PD1 expression in gallbladder cancer to explore the correlation between PD1 expression and the clinicopathologic parameters. We found that 98% (46/47) cases expressed programmed death-ligand 1 (PD-L1) with 85% cases being PD-L1 3+.

Relative genetic diversity of the rare and endangered ssp. and associated soil microbes within a southern California ecological preserve.

Shaw's Agave ( ssp. ) is an endangered maritime succulent growing along the coast of California and northern Baja California. The population inhabiting Point Loma Peninsula has a complicated history of transplantation without documentation.