Search

Layered double hydroxides (LDH) are regarded as attractive pseudocapacitive materials due to their impressive capacitive qualities that may be adjustable to their morphological features. However, the layered structure of LDH renders them susceptible to structural aggregation, which inhibits effective electrolyte transport and limits their practical applicability after limited exposure to active areas. Herein, we propose a simple template-free strategy to synthesize hierarchical hollow sphere NiMn-LDH material with high surface area and exposed active as anode material for supercapacitor application. The template-free approach enables the natural nucleation of Ni-Mn ions resulting in thin sheets that self-assemble into a hollow sphere, offering expended interlayer spaces and abundant redox-active active sites. The optimal NiMn-LDH-12 achieved a specific capacitance of 1010.4 F g−1 at a current density of 0.2 A g−1 with capacitance retention of 70% at 5 A g−1 after 5000 cycles with lower charge transfer impedance. When configured into an asymmetric supercapacitors (ASC) device as NiMn-LDH//AC, the material realized a specific capacitance of 192.4 F g−1 at a current density of 0.2 A g−1 with a good energy density of 47.9 Wh kg−1 and a power density of 196.8 W kg−1. The proposed morphological-tuning route is promising for designing template-free NiMn-LDHs spheres with practical pseudocapacitive characteristics.

Rasagiline mesylate (RSM) is a hydrophilic drug with poor oral bioavailability (36%) because of hepatic first-pass metabolism. The present study focuses on delivering RSM directly to the brain through its inclusion within transferosomal in situ gel administered through the intranasal (IN) route. Transferosomes were formed by the thin-film hydration method with the aid of Design-Expert® software by varying the edge activator (EA) type in the absence or presence of cholesterol. By desirability calculations, the optimum formulation was composed of phosphatidylcholine and sodium deoxycholate as an EA (5:1% w/w) with no cholesterol. The optimum formulation was 198.63 ± 34.98 nm in size and displayed an entrapment efficiency of 95.73 ± 0.09%. Transmission electron microscopy revealed discrete and spherical vesicles. Optimized transferosomes were further incorporated into an in situ gel composed of 0.5% pectin, 15% Pluronic® F-127, and 5% Pluronic® F-68 and tested for the in vivo performance. The systemic as well as brain kinetics were assessed in rats by comparing the IN-administered in situ gel to the IV aqueous solution. The optimum in situ gel showed safety and biocompatibility on rats’ nasal mucosa with enhanced brain bioavailability (131.17%). Drug targeting efficiency and direct transport percentage indices (304.53% and 67.16%, respectively) supported successful brain targeting offering direct nose-to-brain drug delivery.

Background: Reversion mutations in BRCA1/2, resulting in restoration of the open reading frame, have been identified as a mechanism of resistance to platinum-based chemotherapy or PARP inhibition. We sought to explore the incidence of BRCA1/2 reversion mutations in different tumor types. Methods: We retrospectively analyzed molecular profiling results from primary and/or metastatic tumor samples submitted by multiple institutions. The samples underwent DNA and RNA sequencing at a CLIA/CAP-certified clinical lab. Reversion mutations were called only in patients whose available clinical records showed the use of PARP inhibitors or platinum agents prior to tumor profiling. Results: Reversion mutations were identified in 75 of 247,926 samples profiled across all tumor types. Among patients carrying pathogenic or likely pathogenic BRCA1/2 mutations, reversion mutations in BRCA1/2 genes were seen in ovarian cancer (OC) (30/3424), breast cancer (BC) (27/1460), endometrial cancer (4/564), pancreatic cancer (2/340), cholangiocarcinoma (2/178), prostate cancer (5/461), cervical cancer (1/117), cancer of unknown primary (1/244), bladder cancer (1/300), malignant pleural mesothelioma (1/10), and a neuroendocrine tumor of the prostate. We identified 22 reversion mutations in BRCA1 and 8 in BRCA2 in OC. In BC, we detected 6 reversion mutations in BRCA1 and 21 in BRCA2. We compared molecular profile results of 14 high-grade serous ovarian cancers (HGSOC) with reversion mutations against 87 control HGSOC with pathogenic BRCA1/2 mutations without reversion mutations. Tumors with reversion mutations trended to have had lower ER expression (25% vs. 64%, p = 0.024, q = 0.82) and higher KDM6A mutation rate (15% vs. 0, p = 0.016, q = 0.82). Conclusions: We present one of the largest datasets reporting reversion mutations in BRCA1/2 genes across various tumor types. These reversion mutations were rare; this may be because some patients may not have had repeat profiling post-treatment. Repeat tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Wastewater samples were collected from Al-Rustumia wastewater treatment plant. The methodology which was used to measure radon activity levels was long-term air measurements with passive solid-state alpha track detector CR-39. The collected samples include wastewater before and after treatment for 5 months which started from September 2017 to January 2018. The results show that the average values of radon activity level for untreated and treated wastewater samples were 0.049 Bq L−1 and 0.036 Bq L−1, respectively. Dissolved radon concentrations for the study samples were also calculated and their values were 1.270 Bq L−1 and 0.937 Bq L−1, respectively. The calculated radon surface exhalation rate for wastewater samples before treatment was 0.048 Bq m−2 h−1 and after treatment was 0.035 Bq m−2 h−1. These values are lower than the maximum acceptable radon levels as given by United States Environmental Protection Agency. As well as, the results reveal that radon activity level decreases after treatment process implementation, and there are no considerable variations with different times of the year.

Abstract Background Periodontitis is a common oral inflammation, which is a risk factor for adverse pregnancy outcomes. Intakes of vitamin D and calcium are inversely associated with occurrence and progression of periodontitis. This study aims to assess the feasibility of a multi-component intervention, including provision of milk powder supplemented with calcium and vitamin D and periodontal therapy (PT), for improving maternal periodontal health and metabolic and inflammatory profiles of low-income Brazilian pregnant women with periodontitis. Methods The IMPROVE trial is a feasibility randomised controlled trial (RCT) with a 2 × 2 factorial design with a parallel process evaluation. Pregnant women with periodontitis, aged 18–40 years and with

MXenes-Ti3C2Tx, based on their versatile surface characteristics, has rapidly advanced as an interactive substrate to develop electrochemical sensors for clinical applications. Herein, Ni embedded Ti3C2Tx (MX−Ni) composites were prepared using a self-assembly approach where Ti3C2Tx sheets served as an interactive conductive substrate as well as a protective layer to nickel nanoparticles (Ni NPs), preventing their surface oxidation and aggregation. The composite displayed a cluster-like morphology with an intimate interfacial arrangement between Ni, Ti3C2Tx and Ti3C2Tx-derived TiO2. The configuration of MX−Ni into an electrochemical sensor realized a robust cathodic reduction current against methylmalonic acid (MMA), a biomarker to vitamin B12 deficiency. The synergism of Ni NPs strong redox characteristics with conductive Ti3C2Tx enabled sensitive signal output in wide detection ranges of 0.001 to 0.003 µM and 0.0035 to 0.017 µM and a detection sensitivity down to 0.12 pM of MMA. Importantly, the sensor demonstrated high signal reproducibility and excellent operational capabilities for MMA in a complex biological matrix such as human urine samples.

Purpose: Health determinants vary according to geographic region and may affect the outcomes of patients with metastatic renal cell carcinoma (mRCC) treated during clinical trials of targeted therapy. Here, we investigate the overall survival (OS) of patients with mRCC treated in the era of targeted therapy by geographic region. Methods: We conducted a pooled analysis of patients with mRCC who were treated during phase II or III clinical trials. Clinical characteristics and survival data were collected. Statistical analyses were performed with the Kaplan-Meier method and log-rank test in univariable analysis. Results: Overall, 4,736 patients were included in the analysis. Patient characteristics differed according to geographic region. No statistically significant differences in OS were observed when the United States/Canada (USC) was compared with the following other regions: Latin America, Asia/Oceania/Africa, and Eastern Europe. In a univariable analysis, OS differed among patients enrolled in trials in USC compared with Western Europe (20.3 v 17.4 months; hazard ratio, 1.15; 95% CI, 1.03 to 1.3; P = .015), but it did not differ in a multivariable analysis. All-grade treatment-related adverse events (AEs) were observed more frequently in USC. There were no significant differences in grade 3 to 5 AEs among groups. Conclusion: Despite different baseline characteristics, OS was similar among patients enrolled in clinical trials across different geographic regions. Access to clinical trials as well as disease biology, AE reporting, and quality of care may contribute to potential differences in outcomes.

A carbide-free bainitic microstructure is suitable for achieving a combination of ultra high strength and high ductility. In this work, a steel containing nominally 0.34C-2Mn-1.5Si-1Cr (wt.%) was produced via industrial hot rolling and laboratory heat treatments. The austenitization (900°C, 30 min.) and austempering (300-400°C, 3 h) treatments were done in salt bath furnaces. The austempering treatments were designed to approximately simulate the coiling step, following hot rolling and run-out-table cooling, when the bainitic transformation would take place and certain amount of austenite would be stabilized due to suppression of carbide precipitation. The microstructures and various mechanical properties (tensile properties, bendability, flangeability, and room and subzero temperature impact toughness) relevant for applications were characterized. It was found that the mechanical properties were highly dependent on the stability of the retained austenite, presence of martensite in the microstructure and the size of the microstructural constituents. The highest amount of retained austenite (~ 27 wt.%) was obtained in the sample austempered at 375°C but due to lower austenite stability and coarser overall microstructure, the sample exhibited lower tensile ductility, bendability, flangeability and impact toughness. The sample austempered at 400°C also showed poor properties due to the presence of initial martensite and coarse microstructure. The best combination of mechanical properties was achieved for the samples austempered at 325-350°C with a lower amount of retained austenite but with the highest mechanical stability.

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr270. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2-mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress.

Opinion statementThe treatment landscape of renal cell carcinoma (RCC) has evolved significantly over the past three decades. Active surveillance and tumor ablation are alternatives to extirpative therapy in appropriately selected patients. Stereotactic body radiation therapy (SBRT) is an emerging noninvasive alternative to treat primary RCC tumors. The advent of immune checkpoint inhibitors (ICIs) has greatly improved the overall survival of advanced RCC, and now the ICI-based doublet (dual ICI-ICI doublet; or ICI in combination with a vascular endothelial growth factor tyrosine kinase inhibitor, ICI-TKI doublet) has become the standard frontline therapy. Based on unprecedented outcomes in the metastatic with ICIs, they are also being explored in the neoadjuvant and adjuvant setting for patients with high-risk disease. Adjuvant pembrolizumab has proven efficacy to reduce the risk of RCC recurrence after nephrectomy. Historically considered a radioresistant tumor, SBRT occupies an expanding role to treat RCC with oligometastasis or oligoprogression in combination with systemic therapy. Furthermore, SBRT is being investigated in combination with ICI-doublet in the advanced disease setting. Lastly, given the treatment paradigm is shifting to adopt ICIs at earlier disease course, the prospective studies guiding treatment sequencing in the post-ICI setting is maturing. The effort is ongoing in search of predictive biomarkers to guide optimal treatment option in RCC.

Geometrical optimization and electronic structure of chlorophenols were researched by DFT (B3LYP) utilizing a 3-21G basis set. We have likewise researched the aggregate electronic properties, Highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO) and energy gap. The calculated HOMO and LUMO energies demonstrate that charge transfer occurs within the molecule.

A myriad of organ-specific complications have been observed with COVID-19. While racial/ethnic minorities have been disproportionately burdened by this disease, our understanding of the unique risk factors for complications among a diverse population of cancer patients remains limited. This is a multi-institutional, multi-ethnic cohort study evaluating COVID-19 complications among cancer patients. Patients with an invasive cancer diagnosis and confirmed SARS-CoV-2 infection were identified from March to November 2020. Demographic and clinical data were obtained and a multivariate logistic regression was employed to evaluate the impact of demographic and clinical factors on COVID-19 complications. The study endpoints were evaluated independently and included any complication, sepsis, pulmonary complications and cardiac complications. A total of 303 patients were evaluated, of whom 48% were male, 79% had solid tumors, and 42% were Hispanic/Latinx (Hispanic). Malignant hematologic cancers were associated with a higher risk of sepsis (OR 3.93 (95% CI 1.58-9.81)). Male patients had a higher risk of sepsis (OR 4.42 (95% CI 1.63-11.96)) and cardiac complications (OR 2.02 (95% CI 1.05-3.89)). Hispanic patients had a higher odds of any complication (OR 2.31 (95% CI 1.18-4.51)) and other race was associated with a higher odds of cardiac complications (OR 2.41 (95% CI 1.01-5.73)). Clinically, fever, cough, and ≥2 co-morbidities were independently significantly associated with any complication. This analysis evaluated covariates that can significantly predict a myriad of complications among a multi-ethnic cohort of cancer patients. The conclusions drawn from this analysis elucidate a mechanistic understanding of differential illness severity from COVID-19.

Aims: The aim of this study was to evaluate the effect of the natural denture cleanser saturated salt solution on disinfection of C. albicans for the maxillary complete denture (An in vivo study). Mate-rials and Methods: An in vivo study testing anti fungal efficiency of the natural denture cleanser satu-rated salt solution on disinfection of C. albicans for 60 patient wearing maxillary complete denture by using light microscope with camera and connected to computer. The swab was taken from the fitting surface of the denture of about 2.5 cm following the median line starting from incisive papilla. This study compared the effect of disinfection between before and after immersion in distilled water (Con-trol), saturated salt solution (Iraq), and protefix(Germany). Results: The results demonstrated that there were significant differences between salt solution and distilled water, that there were no signifi-cant differences between salt solution and protefix at p=0.05. Conclusions: saturated salt solution was very efficient for disinfection of C. albicans for acrylic denture base material.

The unique glia located in the olfactory system, called olfactory ensheathing cells (OECs), are implicated as an attractive choice for transplantation therapy following spinal cord injury because of their pro-regenerative characteristics. Adult OECs are thought to improve functional recovery and regeneration after injury by secreting neurotrophic factors and making cell-to-cell contacts with regenerating processes, but the mechanisms are not well understood. We show first that α7 integrin, a laminin receptor, is highly expressed at the protein level by OECs throughout the olfactory system, i.e., in the olfactory mucosa, olfactory nerve, and olfactory nerve layer of the olfactory bulb. Then we asked if OECs use the α7 integrin receptor directly to promote neurite outgrowth on permissive and neutral substrates, in vitro. We co-cultured α7+/+ and α7lacZ/lacZ postnatal cerebral cortical neurons with α7+/+ or α7lacZ/lacZ OECs and found that genotype did not effect the ability of OECs to enhance neurite outgrowth by direct contact. Loss of α7 integrin did however significantly decrease the motility of adult OECs in transwell experiments. Twice as many α7+/+ OECs migrated through laminin-coated transwells compared to α7+/+ OECs on poly-L-lysine (PLL). This is in contrast to α7lacZ/lacZ OECs, which showed no migratory preference for laminin substrate over PLL. These results demonstrate that OECs express α7 integrin, and that laminin and its α7 integrin receptor contribute to adult OEC migration in vitro and perhaps also in vivo.

Aims: The study aims to evaluate the antifungal action of some natural oils (sun flower oil, sesame oil, nigella sativa, flax oil and ginger oil) in relation to nystatin suspension on acrylic resin denture base materials. Materials and method: The total number of specimens were seventy, they were (10×10×2mm). Half of the specimens were prepared from heat cured acrylic resin and the other half prepared from cold cured acrylic resin denture base materials, for each group they were immersed for 8hr in these oils after they had been infected with Candida albicans and incubated for 48hr. This study compared antifungal efficiency of sun flower oil, sesame oil, nigella sativa, flax oil and ginger oil. The statistical tests used were one way analysis of variance test, Dunnett t-test. Results: There were signifi-cant differences between all tested oils and distilled water in relation to antifungal action at (P=0.05). Conclusions: All the tested natural oils were effective antifungal agent.

BackgroundLimited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations.MethodsThis is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity.Results1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status.ConclusionsUsing one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients.FundingThis study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication.Clinical trial numberCCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

The purpose of this paper is to describe the technique of making casts using alginate compound for negative and dental stone plaster for positive impressions. With certain modifications a cast could be made of any part of the body and one can make a museum of interesting cases. Casts serve as useful teaching material especially in cleft lip and palate patients to study the effect of surgery on growth and development of the cleft lip-palate-nose complex in relation to the remaining face. It also helps in planning reconstruction in cases of facial defects, recording serial changes in multistage surgery, pre-operative and post-operative comparison as in rhinoplasty, ear reconstruction, hand etc; for comparing results before and after treatment in keloid and hypertrophic scars, fabrication of implants and preparation of prosthesis. In spite of newer modalities like 3-D imaging and stereolithography, the usefulness of this old technique in certain interesting cases can not be denied.

BackgroundEarly progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC.Patients and methodsWe performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors.ResultsWe included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months.ConclusionAmong patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.

BACKGROUND. Metastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis. METHODS. We analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites. RESULTS. We included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC. CONCLUSION. We demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies., Introduction Renal cell carcinoma (RCC) is one of the most common cancers in the United States, affecting close to 80,000 patients annually (1). While most patients present with localized disease, [...]

Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real- world patient cohort, including ccRCC and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers ([PD- L1.sup.+]/[TMB.sup.hi]/[MSI.sup.hi]). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC., Introduction Renal cell carcinoma (RCC) is a common cancer among men and women in the United States, with an estimated 81,800 new cases and 14,890 deaths expected in 2023 (1). [...]

ObjectivesTo compare clinical outcomes with programmed-death ligand-1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation therapy (RT) prior to developing metastatic disease.Patients and methodsWe performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate [ORR], progression-free survival [PFS], overall survival [OS]) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first-line and second-line or greater [second-plus line]). Logistic regression was used to compare ORR, while Kaplan-Meier analysis and Cox regression were used for PFS and OS. Multivariable models were adjusted for known prognostic factors.ResultsWe included 562 patients (first-line: 342 and second-plus line: 220). There was no difference in outcomes based on prior locoregional treatment among those treated with first-line ICIs. In the second-plus-line setting, prior RS was associated with higher ORR (adjusted odds ratio 2.61, 95% confidence interval [CI]1.19-5.74]), longer OS (adjusted hazard ratio [aHR] 0.61, 95% CI 0.42-0.88) and PFS (aHR 0.63, 95% CI 0.45-0.89) vs no prior RS. This association remained significant when type of prior locoregional treatment (RS and RT) was modelled separately.ConclusionPrior RS before developing advanced disease was associated with better outcomes in patients with aUC treated with ICIs in the second-plus-line but not in the first-line setting. While further validation is needed, our findings could have implications for prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include the study's retrospective nature, lack of randomization, and possible selection and confounding biases.

BackgroundSites of metastasis have prognostic significance in advanced urothelial carcinoma (aUC), but more information is needed regarding outcomes based on metastatic sites in patients treated with immune checkpoint inhibitors (ICI). We hypothesized that presence of liver/bone metastases would be associated with worse outcomes with ICI.MethodsWe identified a retrospective cohort of patients with aUC across 26 institutions, collecting demographics, clinicopathological, treatment, and outcomes information. Outcomes were compared with logistic (observed response rate; ORR) and Cox (progression-free survival; PFS, overall survival; OS) regression between patients with/without metastasis beyond lymph nodes (LN) and those with/without bone/liver/lung metastasis. Analysis was stratified by 1st or 2nd+ line.ResultsWe identified 917 ICI-treated patients: in the 1st line, bone/liver metastases were associated with shorter PFS (Hazard ratio; HR: 1.65 and 2.54), OS (HR: 1.60 and 2.35, respectively) and lower ORR (OR: 0.48 and 0.31). In the 2nd+ line, bone/liver metastases were associated with shorter PFS (HR: 1.71 and 1.62), OS (HR: 1.76 and 1.56) and, for bone-only metastases, lower ORR (OR: 0.29). In the 1st line, LN-confined metastasis was associated with longer PFS (HR: 0.53), OS (HR:0.49) and higher ORR (OR: 2.97). In the 2nd+ line, LN-confined metastasis was associated with longer PFS (HR: 0.47), OS (HR: 0.54), and higher ORR (OR: 2.79); all associations were significant.ConclusionBone and/or liver metastases were associated with worse, while LN-confined metastases were associated with better outcomes in patients with aUC receiving ICI. These findings in a large population treated outside clinical trials corroborate data from trial subset analyses.

Germline testing is becoming increasingly relevant in prostate cancer (PCa) screening, prognosis, and management. A subset of patients with PCa harbor pathogenic/likely pathogenic variants (P/LPVs) in genes mediating DNA-repair processes, and these P/LPVs have implications for cancer screening, treatment, and cascade testing. As a result, it is recommended that all men with high-risk localized and metastatic PCa undergo routine germline testing. As more PCa patients undergo germline testing, it is important that clinicians and genetics experts recognize current disparities in germline testing rates among racial/ethnic minorities in the United States. The reasons for these disparities are multiple and require similarly manifold consideration to close the germline testing gap and reduce inequities in PCa screening, management, and treatment.