Search

Muscle-invasive bladder cancer can be treated with either radical cystectomy or bladder preservation approaches, and there is a need for reliable biomarkers to guide the optimal choice of therapy. The recent elucidation of the genomic landscape and biological drivers of bladder cancer has enabled the identification of tumor molecular features that may be helpful in driving clinical decision-making. Here, we summarize recent efforts to develop molecular biomarkers that could be leveraged to guide therapeutic decisions, post-treatment monitoring, and the optimal use of bladder preservation approaches for the effective treatment of muscle-invasive bladder cancer. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is a commonly diagnosed and histologically diverse urologic malignancy. Clear cell RCC (ccRCC) is by far the most common, followed by the papillary and chromophobe subtypes. Sarcomatoid differentiation is a morphologic change that can be seen in all subtypes that typically portends a poor prognosis. In the past, treatment options for RCC were limited to cytokine-based therapy with a high-toxicity profile and low response rate. An increased understanding of the molecular basis of RCC has led to substantial improvement in treatment options in the form of targeted therapy and immunotherapy. A significant early discovery in RCC was frequent inactivation of the Von Hippel Lindau gene in ccRCC, which ultimately led to the development of vascular endothelial growth factor and mammalian target of rapamycin inhibitors. Further genomic sequencing of ccRCC tumors has identified other common mutations including BAP-1, PBRM1, SETD2, and PIK3CA. Many recent studies have explored how these mutations can affect prognosis and response to treatment. Likewise, papillary RCC has also been studied at the molecular level, which has shown a high level of mutations in the MET gene; early clinical data suggest the utility of MET targeted therapy. Finally, regarding the rarer sarcomatoid tumors, mutations in TP53 and NF2 may be important to their development. As we continue to learn more about what drives RCC at the molecular level, treatment options for RCC patients are diversifying. [ABSTRACT FROM AUTHOR]

There are very few biomarkers used to diagnose bladder cancer and no clinically approved biomarkers for prediction or prognostication of this disease. All currently available biomarkers are based on urine tests, and thus, they may not be applicable to patients with extravesical tumors. Biopsy of metastatic sites requires an invasive procedure, whereas serum-based markers, which can be easily obtained and serially measured, thus have obvious merit. These deficiencies may be overcome with advances in genome sequencing, identification of circulating tumor cells, and RNA-, protein-, and DNA-based biomarkers. Here, progress in circulating biomarkers in both superficial and invasive bladder cancer is described. [ABSTRACT FROM AUTHOR]

Sublobar resection is increasingly recognized as an effective treatment for early-stage NSCLC. However, no studies to date have investigated the potential role of preoperative ctDNA detection in guiding surgical decisions, such as opting for sublobar resection, in stage I NSCLC. Patients with solid-dominant (CTR>0.5), clinical stage I NSCLC were prospectively recruited between March 2014 and December 2020. Pre-surgical plasma samples were analyzed using a tumor-naïve, methylation-based cell-free DNA assay. The impact of sublobar resection versus lobectomy on recurrence-free survival (RFS) was assessed according to pre-surgical ctDNA status. Associations between pre-surgical ctDNA detection and clinicopathologic factors were also investigated. The analysis included 544 patients (178 women [33 %]; median age 66 [IQR, 60–71] years). Pre-surgical ctDNA was detected in 188 (35 %) patients. In patients without presurgical ctDNA, sublobar resection did not significantly increase the risk of relapse (adjusted HR, 1.01, p = 0.98). However, among ctDNA-positive patients, sublobar resection was associated with an increased risk of relapse (adjusted HR, 2.25; 95 % CI, 1.12–4.54; p = 0.024). Patients with presurgical ctDNA had higher rates of nodal upstaging (OR, 3.58; p < 0.001) and exhibited higher pathologic grade (p = 0.021), perineural invasion (p < 0.001), and lymphovascular invasion (p < 0.001). Pre-surgical tumor-naïve ctDNA analysis holds promise in identifying patients with aggressive tumors that may not be sufficiently managed with sublobar resection. This approach can help personalize treatment strategies, potentially improving outcomes for patients with early-stage NSCLC. • ctDNA positivity identifies high-risk pathological features in stage I NSCLC. • Sublobar resection increases recurrence risk in ctDNA-positive patients. • Pre-surgical ctDNA analysis supports personalized surgical strategies. [ABSTRACT FROM AUTHOR]

Broadband dielectric spectroscopy of blood above 50 GHz is scarce due to hardware limitations, affordability, and complexity. This study explores the use of a rectangular waveguide as a probe for analysing human blood in the 55 to 95 GHz range, at temperatures from 23 °C to 36 °C, and Haemoglobin levels between 0 and 16 g/dL, focusing on practical aspects such as sample preparation and the setup's mechanical, thermal, and calibration requirements. The research highlights the effectiveness of the Short-Open-Load calibration method, evidenced by precise measurements of saline solutions. Furthermore, analysis of 84 human blood samples indicates that while Haemoglobin levels introduce some uncertainty in dielectric constant measurements, dielectric loss readings remain consistent across temperature and Haemoglobin variations, with a low uncertainty of under 2.65%, indicating the potential use of this parameter in future millimetre-wave techniques for non-invasive testing of blood analytes. • Open-ended waveguide allows dielectric characterisation of fluids above 50 GHz. • Time critical reducing dielectric effects caused by Erythrocyte Sedimentation Rate. • Blood's dielectric loss more sensitive to haemoglobin changes than dielectric constant. • Higher haemoglobin content dampens dielectric constant changes caused by temperature. [ABSTRACT FROM AUTHOR]

The current standard of care for high-risk non-muscle invasive bladder cancer (HR-NMIBC) is Bacillus Calmette Guerin (BCG), however, it carries a non-responder rate of 30-50% with high risk of progression and side effect profile. Sequential intravesical gemcitabine and docetaxel (Gem/Doce) is an increasingly utilized treatment for HR-NMIBC, although prospective validation is pending. Our previous analyses have demonstrated an increased abundance of Lactobacillus rhamnoses GG (LGG) within the tumor stroma of responders, thus, we aimed to assess the role of intravesical LGG instillation as potential therapy in tumor-bearing mice. We used the BBN model to recapitulate the histological and genetic characteristics of human bladder cancer in C57BL/6 mice. Upon ultrasound confirmation of tumor, mice were treated with live LGG (106 CFU) given via intravesical instillation for six weeks. Tumor burden was measured weekly with US. Additional comparative therapy included saline, BCG (106 CFU), and Gem/Doce. (Figure 1A) Cytokine urine analysis utilizing CodePlex Secretome Adaptive Panel* was collected at week 4. Immunohistochemistry was performed with bladder tissue and T-lymphocyte and total CD8 T-lymphocytes per high-power field were calculated. Following monocyte purification and stimulation, we assessed differentiation into macrophage and dendritic cells in both BCG and LGG group using FACS Aria, and processed results through Cell Quest. Additional supernatant cytokine production of monocytes, T-cells, and monocytes and T-cells to LGG and BCG was evaluated using Human CodePlex Adaptive Panel**. Complete response was seen in LGG (4/10), NS (0/10), BCG (2/10), and Gem/Doce (4/10) with tumor volume in LGG and Gem/Doce (5.1 cm3, 5.6 cm3). (Figure 1B). Week 4 urine cytokine demonstrated increased expression of KC (CXCL-1, 538.95 pg/ml), IP-10(CXCL10, 355.17 pg/ml), IL-6(477.05 pg/ml), IL-4(89.35 pg/ml), IL-1B (240.21 pg/ml) and MIP-1a (210.67 pg/ml) in LGG group (p<0.001).(Figure 1E) IHC of LGG demonstrated an increased Tumor/Stroma T-cell Infiltration;(0.93;±0.70).(Figure 1C, D) In vitro stimulation of human monocytes (CD14+/CD16+) and T-cells (CD3+/CD8+/CD4+) with LGG resulted in increased of IL-6 (1.82±;0.82pg/ml), IL-7 (0.68±0.14 pg/ml), and Granzyme B (0.64;±;1.91 pg/ml),;(Figure 1F) with increasing differentiation to immature dendritic cells (CD1+/CD11C-) (88.41 vs 54.33%) Analysis of a murine intravesical therapy model revealed superior tumor response in both LGG and Gemcitabine/Docetaxel groups compared to control NS and standard of care BCG in the treatment of BBN induced tumor. Analysis of urinary LGG cytokine profile demonstrates enhanced immune activation through dendritic cell differentiation and Th2 pathway with direct antitumor effects through enhanced apoptosis.**(GM-CSF, Granzyme B, IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, IL-17A, IP-10, MCP-1, MIP-1α, MIP-1β, Perforin, sCD137, TNF-α, TNF-β).*(GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17A, IP-10, KC, MCP-1, MIP-1α, RANTES, TNF-α) [ABSTRACT FROM AUTHOR]

Bladder cancer, the most prevalent urological malignancy worldwide, accounts for a staggering 600,000 new cases annually. Its etiology is complex and multifactorial, influenced by various risk factors. Recent advances in genomic research, particularly genome-wide association studies (GWAS), have led to the discovery of new single nucleotide polymorphisms (SNPs) and associations in diverse cohorts. GWASs have proven to be a powerful tool for identifying links between genetic variants and SNPs. Additionally, phenome-wide association studies (PheWAS) have explored associations between specific genetic variants and a wide range of phenotypes, enabling the identification of genetic variants associated not only with bladder cancer but also with other diseases and traits that may share genetic risk factors. Our study, conducted using data from the UK Biobank's prospective cohort, aims to combine the findings from GWAS and PheWAS to identify both epidemiological and genetic risk factors associated with bladder cancer. 375,981 healthy individuals and 5,090 bladder cancer patients analyzed. Genotype calling, quality control, and imputation processes;previously described. Generic risk variants, like;single nucleotide polymorphisms (SNPs), selected based on conventional genome-wide significance thresholds (p<5×10-6) and specific criteria (MAF >0.01 and r 2 <0.001 for LD). Functional GWAS analysis using FUMA;performed to annotate GWAS results, prioritize genes,assess chromatic interaction mapping and tissue enrichment.To explore association between bladder cancer and other phenotypes, PheWas (phenome-wide association studies) associations conducted using GLM function in R. Covariates like sex, smoking, age, alcohol consumption, air pollution exposure, daily traffic intensity, dietary habits, and workplace exposure were included in all associations. Logistic regression models with log-transformed odds ratios;used for binary dependent variables. Statistical inferences relied on two-sided tests at significance level of 0.05, unless specified differently. The analysis done;using SAS software v.9.4 (SAS Institute, Cary, NC) and R v.3.6.0 software. Our study identified;SNPs;associated with increased bladdercancer risk, including variants in;PSCA;TMEM129;TERT;LYNX1-SLURP2;LSP1, and;HIPK1;(Fig1A). Protective associations for bladder cancer with SNPs within;UGTA1, THEM6, RAPGEF5, LY6K, LY6D, LNCOC1, JRK, and CLPTML;(Figure1A,B). Gene prioritization using FUMA and tissue mapping with chromatin interaction analysis revealed 9 lead SNPs across 8 genomic risk loci, with exonic SNPs exhibiting highest Combined Annotation Dependent Depletion;(CADD) scores indicating deleteriousness (Figure1C,D). Additionally, gene set enrichment analysis of common SNPs uncovered significant associations with biological processes like;Flavonoid & Xenobiotic Glucuronidation and Glucuronosyltransferase, closely linked to bladdercancer (Fig1E). PheWAS analysis revealed four phenotypes linked to bladder cancer risk, including prostate cancer (rs2242652), seborrheic keratosis and skin conditions (rs2242652), and BPH (rs31489) (Figure1F). Regression analysis for modifiable risk factors;demonstrated significant associations with bladder cancer susceptibility for BMI, heavy smoking, and male sex. Conversely, alcohol intake 3-4 drinks/week is protective. The study sheds light on various relevant SNPs and novel associations among germline mutations in bladder cancer, which have not been previously reported. Through further functional analysis, we discovered germline variants associated with glucuronosyltransferase activity, providing supporting evidence of toxin metabolism and its impact on bladder cancer risk. Additionally, our PheWAS analysis revealed co-associations with prostate cancer, prostatic hyperplasia, and dermatologic conditions linked to specific SNPs.Furthermore, our study reaffirmed well-known risk factors associated with bladder cancer, including sex and smoking, while also highlighting the protective effect of moderate alcohol consumption in the context of carcinogenesis.These findings have the potential to offer valuable insights into common pathways underlying bladder cancer, inform screening recommendations, and identify potential therapeutic targets for the disease. [ABSTRACT FROM AUTHOR]

Objective: To assess prescribing and refilling trends of narcotics in postoperative urology patients at our institution. Although the opioid epidemic remains a public health threat, no series has assessed prescribing patterns across urologic surgery disciplines following discharge.Methods: All urologic surgeries were retrospectively reviewed from May 2017-April 2018. Demographics, comorbidities, and postoperative pain management strategies were analyzed. Narcotics usage following surgery were reported in total morphine equivalents (TME). Opioid refill rate was characterized by medical specialty and stratified by urologic discipline.Results: 817 cases were reviewed. Mean age and TME at discharge was 57±15.6 years and 35.43±19.5 mg, respectively. 13.6% (mean age 55±15.9) received a narcotic refill following discharge (mean TME/refill 37.7±28.9 mg). A higher proportion of patients with a pre-operative opioid prescription received a refill compared to opioid naïve patients (38.2% vs 21.6%, P < .01). Refill rate did not differ between urologic subspecialties (P = .3). Urologists were only responsible for 20.4% of all refills filled, despite all patients continuing follow-up with their surgeon. Procedures with the highest rates of post-operative refills were in oncology, male reconstruction/trauma and endourology. Patients with a history of chronic pain (OR 1.9, CI 1.1-3.3) preoperative narcotic prescription (OR 1.6, CI 1.0-2.6), and higher ASA score (OR 1.8, CI 1.6-2.8) were more likely to obtain a postoperative opioid prescription refill.Conclusion: Approximately 1 in 7 postoperative urology patients receive a postoperative narcotics refill; however, nearly two-thirds receive refills exclusively from non-urologic providers. Attempts to avoid overprescribing of postoperative narcotics need to account for both surgeon and nonsurgeon sources of opioid refills. [ABSTRACT FROM AUTHOR]

A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53−/−). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression. [ABSTRACT FROM AUTHOR]

Background: Cancer diagnostics and surgery have been disrupted by the response of health care services to the coronavirus disease 2019 (COVID-19) pandemic. Progression of cancers during delay will impact on patients' longterm survival. Patients and methods: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013e2017. We modelled per-patient delay of 3 and 6 months and periods of disruption of 1 and 2 years. Using health care resource costing, we contextualise attributable lives saved and life-years gained (LYGs) from cancer surgery to equivalent volumes of COVID-19 hospitalisations. Results: Per year, 94 912 resections for major cancers result in 80 406 long-term survivors and 1 717 051 LYGs. Perpatient delay of 3/6 months would cause attributable death of 4755/10 760 of these individuals with loss of 92 214/208 275 life-years, respectively. For cancer surgery, average LYGs per patient are 18.1 under standard conditions and 17.1/15.9 with a delay of 3/6 months (an average loss of 0.97/2.19 LYGs per patient), respectively. Taking into account health care resource units (HCRUs), surgery results on average per patient in 2.25 resourceadjusted life-years gained (RALYGs) under standard conditions and 2.12/1.97 RALYGs following delay of 3/6 months. For 94 912 hospital COVID-19 admissions, there are 482 022 LYGs requiring 1 052 949 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.08 LYG and 0.46 RALYGs. Conclusions: Modest delays in surgery for cancer incur significant impact on survival. Delay of 3/6 months in surgery for incident cancers would mitigate 19%/43% of LYGs, respectively, by hospitalisation of an equivalent volume of admissions for community-acquired COVID-19. This rises to 26%/59%, respectively, when considering RALYGs. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued. [ABSTRACT FROM AUTHOR]

Preclinical bladder cancer drug development depends on the accurate assessment of tumor burden in mice, with a preference for longitudinal in vivo imaging. We aimed to compare transabdominal micro-ultrasound imaging (MUI) and computer tomography (CT) Urogram for the detection and measurement of bladder cancer in a mouse model. Male C57/B6 mice at least 6 weeks old received BBN at a dose of 0.05% in drinking water ad libitum for 6 weeks. Bladder tumor presence was evaluated by CT urogram via retro-orbital injection of 1/10 dilution of iodinated contrast and Vega®;ultrasound imaging (SonoVol).starting at week 19 with confirmation of bladder tumors.After imaging,mice were euthanized by CO 2 with secondary cervical dislocation. Bladders were removed and divided in the sagittal plane, and fixed in 10% formalin. Three-dimensional (3-D) UL and CT data sets were collected. ROIs were drawn around the tumor borders for every slice to assess tumor size in a 3-D dimensional plane and the image analysis software. 4 μm sections of bladder tissue were cut and stained with hematoxylin-eosin (HE) for histopathological analysis. All slides were anonymized and digitized at 40x, and 100x magnification using a high-resolution scanner. Statistical analysis performed in R. Average tumor volume detected by US at 19 weeks was (10.48mm3) vs CT (17.09mm3) with one tumor undetectable by CT at 19 weeks. Tumor size increased at 22-23 weeks by US to (47.33mm3) and CT (47.51mm3), albeit 4/7 tumors on CT Urogram were unable to be measured due to uncertainty. When assessing US vs CT imaging sensitivity (Sn), specificity (Sp)and accuracy (Ac) for prediction were: Sn 100% vs 54.55%, Sp 89% vs 95%, Ac 75% vs 61.54%, respectively.; CT imaging alone was unable to determine status of tumor presence in 7 mice, with histopathologic confirmation of tumors in three of those mice (1 CIS, 2 T3+) indicating difficulty in identification of advanced disease and flat tumors. US allowed for visualization of both samples of CIS due to bladder wall thickening allowing for early tumor detection, and tumor growth kinetics. In the present study, we have utilized a multimodal approach of US and CT Urogram imaging of murine BBN model of bladder cancer with histopathologic confirmation. Due to increased accuracy of US imaging, this approach would be better suited for future testing of therapeutic agents. Ultrasound imaging provides enhanced visualization tumor growth kinetics, including anatomical and functional aspects of tumor development and treatment response. [ABSTRACT FROM AUTHOR]

The rationale for performing bilateral oophorectomy during cystectomy in females diagnosed with bladder cancer (BC) is multifaceted;however, the incidence of ovarian cancer (OC) germline mutations in females diagnosed with BC remains unknown. Additionally, there is a scarcity of data regarding the co-occurrence and;timing of these two malignancies. Given the well-established benefits of retaining the ovaries, including in postmenopausal women, our study sought to achieve three objectives: determine the frequency of recognized OC germline variants among females with BC, evaluate;the temporal and simultaneous occurrence of these two malignancies, and assess;the risk of other neoplastic conditions and family history in women harboring OC germline mutations and with a diagnosis of BC. Using the UK Biobank, a long-term prospective population-based database;from the United Kingdom encompassing both;genotypic and phenotypic data from 501,232 patients, we analyzed OC germline variants as reported by NCCN in a cohort of females diagnosed with bladder cancer (n=1,346). We restricted the analysis to high and moderate-impact variants for initial regression and pathogenic/likely pathogenic (P/LP) variants as reported by ClinVar, and evaluated the concomitant presence of other malignancies, family history, and age of presentation. 3.4% of women in our cohort exhibited the presence of 15 distinct germline variants which were previously established to be linked with varying degrees of OC development. CHEK2 and PALB2 mutations represented the highest ratio of overall/pathogenic variants (15.8% and 6.6% respectively) (Figure 1). Although females with P/LP OC germline mutations demonstrated a significantly amplified risk of development of OC, the diagnosis of OC preceded that of bladder cancer by 11.3 (±12.5 years) and 15.6 (±11.3 years) in all cases;(Figure 2), even in those without established OC germline mutations. Females who exhibited P/LP OC germline variants were also observed to have a higher likelihood of reporting maternal and sibling breast cancer (14.63% vs. 8.12%, p=0.04 and 9.76% vs. 3.98%, p=0.02, respectively), maternal colon cancer (9.76% vs. 4.21%), and reduced maternal life expectancy compared to non-P/LP patients (75.34 vs. 68.15 years, p=0.0014). Our study provides evidence against routine recommendation for bilateral oophorectomy during cystectomy in female BC patients. Furthermore, the study highlights that females with OC germline mutations who have been diagnosed with BC may be at a heightened risk of developing other malignancies, including breast cancer and melanoma, following their bladder cancer diagnosis, accentuating the necessity of devising personalized oncological management approaches in our female BC patients. [ABSTRACT FROM AUTHOR]

• A cost-effectiveness model was developed to compare gemcitabine-docetaxel to bacillus Calmette-Guérin (BCG). • Intravesical gemcitabine-docetaxel was less costly than BCG. • The 2 treatments resulted in the same impact to quality of life. Treatment naïve patients with high-risk non-muscle invasive bladder cancer (NMIBC) are treated with bacillus Calmette-Guérin (BCG) therapy as the standard of care. Recently, intravesical sequential gemcitabine-docetaxel in the BCG-naïve setting was shown to be well-tolerated and effective, raising the possibility of a new first line intravesical therapy. Cost effectiveness of this intervention remains unknown; therefore, we designed a cost effectiveness study evaluating BCG vs. sequential gemcitabine-docetaxel in patients with high risk NMIBC. Using TreeAgePro 2019 software, we developed a Markov model to evaluate BCG vs. gemcitabine-docetaxel from the U.S. Medicare perspective with a 2-year time horizon. Model probabilities and utilities were derived from published literature. Direct costs were obtained from Medicare cost databases. Our primary outcomes were effectiveness (measured in quality adjusted life years [QALYs]), cost and the incremental cost-effectiveness ratio with a willingness to pay threshold of $100,000. Our results indicate that while both treatments resulted in similar QALYs of 1.76, the mean costs per patient at 2 years were $12,363 and $7,090 for BCG and gemcitabine-docetaxel, respectively. Therefore, the BCG strategy was dominated by the gemcitabine-docetaxel strategy as it was equally effective and less costly. One way sensitivity analyses were completed and gemcitabine-docetaxel remained a cost-effective strategy. The findings of this preliminary cost-effectiveness analysis are novel in that they highlight a well tolerated, efficacious drug that is less expensive than the traditional gold standard therapy. In modern medicine, we are more often challenged by agents with marginally increased efficacy but at significantly higher costs; gemcitabine-docetaxel represents a rare entity which is a success for both patients and healthcare systems alike. [ABSTRACT FROM AUTHOR]

ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed in Phase I/II trials in several advanced malignancies. Binding and reporter assays have shown that ONC201 is a selective antagonist of the dopamine D2-like receptors, specifically, DRD2 and DRD3. We hypothesized that ONC201's interaction with DRD2 plays a role in ONC201's anticancer effects. Using cBioportal and quantitative reversetranscription polymerase chain reaction analyses, we confirmed that DRD2 is expressed in different cancer cell types in a cell type-specific manner. On the other hand, DRD3 was generally not detectable. Overexpressing DRD2 in cells with low DRD2 levels increased ONC201-induced PARP cleavage, which was preceded and correlated with an increase in ONC201-induced CHOP mRNA expression. On the other hand, knocking out DRD2 using CRISPR/Cas9 in three cancer cell lines was not sufficient to abrogate ONC201's anticancer effects. Although ONC201's anticancer activity was not dependent on DRD2 expression in the cancer cell types tested, we assessed the cytotoxic potential of DRD2 blockade. Transient DRD2 knockdown in HCT116 cells activated the integrated stress response and reduced cell number. Pharmacological antagonism of DRD2 significantly reduced cell viability. Thus, we demonstrate in this study that disrupting dopamine receptor expression and activity can have cytotoxic effects that may at least be in part due to the activation of the integrated stress response. On the other hand, ONC201's anticancer activity goes beyond its ability to antagonize DRD2, potentially due to ONC201's ability to activate other pathways that are independent of DRD2. Nevertheless, blocking the dopamine D1-like receptor DRD5 via siRNA or the use of a pharmacological antagonist promoted ONC201-induced anticancer activity. [ABSTRACT FROM AUTHOR]

Objective To quantitate the risk of clinically significant renal function deterioration after radical cystectomy (RC), which could result in supratherapeutic levels of low-molecular-weight heparin (LMWH) and increased risk of bleeding events with the use of extended pharmacologic venous thromboembolism prophylaxis (EPVTEP) after hospital discharge. Methods Patients undergoing RC between 2006 and 2011 were identified from the institutional registry. Estimated glomerular filtration rate (eGFR) was calculated and categorized as preoperative, discharge, and nadir. Perioperative eGFR trends in patients who would have been candidates for EPVTEP were evaluated. Results Three hundred four patients with eGFR >30 mL/min/1.73 m 2 at the time of hospital discharge were included in the analysis as potentially eligible for EPVTEP. Large portion of patients (43%) exhibited decline in eGFR after discharge. Importantly, 13.0% of patients (n = 40), who would have qualified for EPVTEP at discharge, experienced nadir GFR below the 30-mL/min/1.73 m 2 threshold value at which LMWH would have become supratherapeutic. The odds ratio for developing a GFR <30 mL/min/1.73 m 2 was 9.1 (95% confidence interval, 4.3-19.3; P <.001), comparing those with a discharge GFR ≥60 mL/min/1.73 m 2 with those with a discharge GFR <60 mL/min/1.73 m 2 . Conclusion More than 10% experienced an eGFR, which would have rendered LMWH supratherapeutic and potentially would have placed the patient at risk for clinically significant bleeding. Although postoperative venous thromboembolic event after RC is a recognized concern, a better understanding of the risks of EPVTEP is needed before this strategy is universally adopted in patients undergoing RC. [ABSTRACT FROM AUTHOR]

Objective: To determine if radiographically less complex renal lesions are deemed clinically less "worrisome" and therefore are more likely to be considered for active surveillance (AS).Methods: We examined our prospective institutional database to identify and compare patients with localized renal cell carcinoma undergoing an initial period of AS or immediate surgery. Multivariate logistic regression was used to examine covariates associated with receipt of AS.Results: Of 1,059 patients with available anatomic complexity data, 195 underwent an initial period of AS (median duration of AS 25.6 mo [interquartile range: 11.8-52.8 mo]). Compared with patients undergoing immediate surgical treatment, patients selected for AS had lower overall nephrometry scores (NS) with tumors that were smaller, further from the sinus or urothelium, more often polar, and less often hilar (P<0.0015 all comparisons). After adjustment for age, largest tumor size, individual components of NS, total NS, and Charlson comorbidity index, total NS (odds ratio [OR] = 1.9 [CI: 1.4-2.5]), "R" score of 1 (OR = 5.2 [CI: 1.8-15.2]), "N" score of 1 (OR = 2.3 [CI: 1.5-3.6]), "L" score of 1 (OR = 1.4 [CI: 0.84-2.2]), and nonhilar tumor location (OR = 2.7 [CI: 1.2-5.8]) increased the probability of being selected for AS compared with immediate surgery. Findings remained significant in a subanalysis of T1a renal masses.Conclusions: Lower tumor anatomic complexity was strongly associated with the decision to proceed with AS in patients with stage I renal mass. Not only may these data afford new insights into renal mass treatment trends, but the findings may also prove useful in the development of objective protocols to most appropriately select patients for AS. [ABSTRACT FROM AUTHOR]

Objective To assess the association between nephrometry score (NS) and prolonged warm ischemia time (WIT) in patients undergoing robotic partial nephrectomy (RPN) for clinically localized renal masses. Methods We queried our prospectively maintained kidney cancer database to identify all patients undergoing RPN for localized tumors from 2007-2012. Patient and tumor characteristics were compared between complexity groups using analysis of variance and chi square tests. Multivariate logistic regression models were used to examine the relationship between NS complexity and warm ischemia >30 minutes. Results Three hundred seventy-five patients (mean age, 59 ± 11 years; mean Charlson comorbidity index, 1.0 ± 1.3) undergoing RPN under warm ischemia for clinically localized renal tumors (mean tumor size, 3.1 ± 1.5 cm; mean NS, 6.8 ± 1.8) met inclusion criteria and had NS available. Stratified by complexity, groups differed with respect to age at surgery, tumor size, proximity to the hilum, collecting system entry, estimated blood loss, and operative time (all P values ≤.05). Significant differences in mean WIT were observed when comparing low (19.4 ± 12.1 minutes), intermediate (28.6 ± 12.8 minutes), and high (36.1 ± 13.7 minutes) NS complexity groups (P <.0001). Adjusting for confounders, patients with intermediate (odds ratio, 2.1; confidence interval, 1.2-3.9) and high (odds ratio, 3.7; confidence interval, 1.1-11.8) NS complexity were more likely to require prolonged WIT when compared with patients with low complexity tumors. Conclusion In our large institutional cohort, quantification of anatomic complexity using the NS is associated with WIT >30 minutes in patients undergoing RPN for localized renal tumors. This provides further evidence that standardized reporting of tumor anatomic complexity affords meaningful outcome comparisons. [ABSTRACT FROM AUTHOR]

Background: Determining meta-analysis of transcriptional profiling of muscle-invasive bladder cancer (MIBC) through Gene Expression Omnibus (GEO) datasets has not been investigated. This study aims to define gene expression profiles in MIBC and to identify potential candidate genes and pathways.Objectives: To review and evaluate gene expression studies in MIBC through publicly available RNA sequencing (RNA-Seq) and microarray data in order to identify potential prognostic and therapeutic targets for MIBC.Methods: A systematic literature search of the Ovid MEDLINE, PubMed, and Wiley Cochrane Central Register of Controlled Trials databases was performed using the terms "gene," "gene expression," and "bladder cancer" January 1, 1990 through March 2021 focused on populations with MIBC.Results: In the final analysis, GEO datasets were included. Fixed effect model was employed in the meta-analysis. Gene networking connections and gene-set functional analyses of the identified genes as differentially expressed in MIBC were performed using ImaGEO and GeneMANIA software. A heatmap for the upregulated and downregulated genes was generated along with the correlated pathways.Conclusion: A total of 9 genes were reported in this analysis. Six genes were reported as upregulated (ProTα, SPINT1, UBE2E1, RAB25, KPNB1, HDAC1) and 3 genes as downregulated (NUP188, IPO13, NUP124). Genes were found to be involved in "ubiquitin mediated proteolysis," "protein processing in endoplasmic reticulum," "transcriptional misregulation in cancer," and "RNA transport" pathways. [ABSTRACT FROM AUTHOR]

Imidazolium salts have shown great promise as anticancer materials. A new imidazolium salt (TPP1), with a triphenylphosphonium substituent, has been synthesized and evaluated for in vitro and in vivo cytotoxicity against bladder cancer. TPP1 was determined to have a GI 50 ranging from 200 to 250 μM over a period of 1 h and the ability to effectively inhibit bladder cancer. TPP1 induces apoptosis, and it appears to act as a direct mitochondrial toxin. TPP1 was applied intravesically to a bladder cancer mouse model based on the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Cancer selectivity of TPP1 was demonstrated, as BBN-induced tumors exhibited apoptosis but normal adjacent urothelium did not. These results suggest that TPP1 may be a promising intravesical agent for the treatment of bladder cancer. Image 1 • A triphenylphosphonium substituted imidazolium salt (TPP1) has been synthesized. • TPP1 induces in vitro cytotoxicity against select bladder cancer cell lines. • Apoptosis has been determined to be the mode of cell death for TPP1. • In vivo testing illustrated the selectivity of TPP1 to bladder tumors in murine models. [ABSTRACT FROM AUTHOR]

Circulating tumor DNA (ctDNA) is a promising, non-invasive biomarker for preclinical detection and monitoring of various cancers. The utility of ctDNA assessment in renal cell carcinoma (RCC) in not well established. Here, we evaluate the potential of a bespoke, multiplex PCR, whole exome sequencing (WES)-based approach for ctDNA detection. The cohort consisted of 42 patients with stage Ib-IV RCC who underwent complete surgical resection. ctDNA was measured in plasma samples drawn pre-surgery (n = 34; baseline) and at post-operative time points (n = 41) using the bespoke assay targeting patient-specific tumor variants. A median of 11.7 ng (1.4-175 ng) of cfDNA was extracted from a median plasma volume of 3.2 mL (1.2-3.8 mL). ctDNA was detected with a mean mutant molecules/mL of 5.3 (0.22-62). Baseline ctDNA was detected in 41% (14/34) of patients. Presence of ctDNA was significantly associated with increased tumor size (mean 9.7 vs 7.1cm, p < 0.05), advanced tumor stage (stage III-IV vs I-II, p < 0.05) and poorly differentiated tumors (grade III-IV vs II, p < 0.0001). In the postoperative setting, 8/8 ctDNA-positive patients relapsed (positive predictive value (PPV=100%), while 16/33 ctDNA-negative patients relapsed (NPV=52%). Positive ctDNA status was associated with reduced relapse-free survival at post-surgical timepoints (HR: 2.8; 95% CI:1.2-6.6). None of the post-surgical samples from a control cohort of 17 non-relapsing patients were ctDNA-positive (specificity of 100%; median follow up of 64 months). Presence of presurgical ctDNA strongly correlates with advanced stage RCC. Despite low plasma volumes, the bespoke assay detected ctDNA in 41% of baseline samples. Postoperative ctDNA presence is correlated with clinical relapse. However, absence of ctDNA does not preclude recurrence as RCC is known to shed limited amounts of ctDNA. Higher sample volumes and multiregion tumor biopsies could enhance detection rates. This personalized approach has the potential to be used for ctDNA-based detection of relapse in patients with advanced stage RCC. Natera, Inc.; Fox Chase Cancer Center. Natera, Inc.; Fox Chase Cancer Center. M. Balcioglu: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. H. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. S. Dashner: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. S. Shchegrova: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. E. Kalashnikova: Full / Part-time employment: Natera, Inc. H. Pawar: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. R.G. Uzzo: Advisory / Consultancy: Janssen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Argos. A. Aleshin: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. H. Sethi: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. R. Salari: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. M. Louie: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. B. Zimmermann: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. P. Abbosh: Advisory / Consultancy, Advisory: Janssen; Advisory / Consultancy, Advisory: AstraZeneca. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Abstract: We report a case in which mild therapeutic hypothermia was used successfully in a patient with coma after cardiorespiratory arrest induced by hanging. [Copyright &y& Elsevier]

Purpose Lymphopenia as a likely index of poor systemic immunity is an independent predictor of inferior outcome in patients with clear cell renal cell carcinoma (RCC). We sought to evaluate the prognostic relevance of preoperative absolute lymphocyte count (ALC) in a cohort of patients with papillary RCC (PRCC). Materials and methods A prospectively maintained, renal cancer database was analyzed. Patients with preoperative ALC, within 3 months before surgery, were eligible for the study. Those with multifocal or bilateral renal tumors were excluded. Correlations between ALC and age, gender, smoking, Charlson comorbidity index, pathologic T category, PRCC subtype, and TNM stage were evaluated. Differences in overall survival (OS) and cancer-specific survival by ALC status were assessed using the log-rank test and cumulative incident estimators, respectively. Cox proportional hazards model was used for multivariable analyses. Results A total of 192 patients met the inclusion criteria. As a continuous variable, preoperative ALC was associated with higher TNM stage ( P = 0.001) and older age ( P = 0.01). As a dichotomous variable, lymphopenia (<1,300 cells/µl) was associated with higher TNM stage ( P = 0.003). On multivariable analyses, controlling for covariates, after a median follow-up of 37.3 months, lymphopenia was associated with inferior OS (hazard ratio = 2.3 [95% CI: 1.2–4.3], P = 0.011) and trended to significance for cancer-specific survival ( P = 0.071). Among patients with nonmetastatic disease and lymphopenia, OS at 37.5 months was shorter compared with those with normal ALC (83% vs. 93%, P = 0.0006). Conclusions In patients with PRCC, lymphopenia is associated with lower survival independent of TNM stage, age, and histology. ALC may provide an additional preoperative prognostic factor. [ABSTRACT FROM AUTHOR]

Introduction Linear growth rate (LGR) is the most commonly employed trigger for definitive intervention in patients with renal masses managed with an initial period of active surveillance (AS). Using our institutional cohort, we explored the association between tumor anatomic complexity at presentation and LGR in patients managed with AS. Methods and materials Enhancing renal masses managed expectantly for at least 6 months were included for analysis. The association between Nephrometry Score and LGR was assessed using generalized estimating equations, adjusting for the age, Charlson score, race, sex, and initial tumor size. Results Overall, 346 patients (401 masses) met the inclusion criteria (18%≥cT1b), with a median follow-up of 37 months (range: 6–169). Of these, 44% patients showed progression to definitive intervention with a median duration of 27 months (range: 6–130). On comparing patients managed expectantly to those requiring intervention, no difference was seen in median tumor size at presentation (2.2 vs. 2.2 cm), whereas significant differences in median age (74 vs. 65 y, P <0.001), Charlson comorbidity score (3 vs. 2, P <0.001), and average LGR (0.23 vs. 0.49 cm/y, P <0.001) were observed between groups. Following adjustment, for each 1-point increase in Nephrometry Score sum, the average tumor LGR increased by 0.037 cm/y ( P = 0.002). Of the entire cohort, 6 patients (1.7%) showed progression to metastatic disease. Conclusions The demonstrated association between anatomic tumor complexity at presentation and renal masses of LGR of clinical stage 1 under AS may afford a clinically useful cue to tailor individual patient radiographic surveillance schedules and warrants further evaluation. [ABSTRACT FROM AUTHOR]