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BACKGROUND: The outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal. METHODS: A multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments. RESULTS: A total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73.7) and 23.4 months (18.6-28.2) for patients who received ADT with or without first-generation anti-androgens and treatment intensification, respectively. The 2-year survival rate was 93.3%, and estimated median overall survival of was 74.9 months (95% CI, 68.7-81.0). Most patients (90%) underwent germline testing; the most frequent known alterations were found within the DNA repair group of genes. Somatic testing revealed pathogenic alterations of interest, notably TP53 (24%) and CDK12 (12%). CONCLUSION: In our cohort, Black men with mHSPC presented with a high proportion of de novo metastases and high-volume disease. Treatment outcomes were very favorable with ADT-based regimens. The genomic landscape suggests different molecular profile relative to White patients with potential therapeutic implications.
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Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Antagonistas de Andrógenos/uso terapéutico , Hormonas/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The stereoselective and divergent synthesis of two aza-nucleosides is reported. Starting from xylofuranose 9, aza-adenosine 2 was prepared in 13 steps and 7% overall yield, and aza-guanosine 3 was prepared in 13 steps and 7.8% overall yield. Compared to the original syntheses, some advantages of these new routes are significant yield improvement, overall step-count reduction, an optimized protecting group strategy, the development of a versatile platform for nitrogenous base incorporation, and the elimination of hazardous reagents (e.g., benzyl isocyanate, Et3N·HF).
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Adenosina , Nucleósidos , GuanosinaRESUMEN
A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than 16-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications.
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Proteínas de la Membrana , Indicadores y Reactivos , Proteínas de la Membrana/químicaRESUMEN
BACKGROUND: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations. METHODS: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed. RESULTS: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men. CONCLUSIONS: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.
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Proteína BRCA2/genética , Negro o Afroamericano/genética , Mutación de Línea Germinal , Metástasis de la Neoplasia/genética , Neoplasias de la Próstata/genética , Población Blanca/genética , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/patología , Neoplasias de la Próstata/patologíaRESUMEN
PURPOSE: Contemporary trends and racial disparities in prostate cancer screening and referral to urology for prostate cancer risk are not well characterized, despite consensus that Black men are at higher risk for poor prostate cancer outcomes. The objective of this study was to characterize current racial disparities in prostate cancer screening and referral from primary care to urology for prostate cancer concern within our large, integrated health care system. MATERIALS AND METHODS: This retrospective cohort study used data from Atrium Health's enterprise data warehouse, which includes patient information from more than 900 care locations across North Carolina, South Carolina and Georgia. We included all men seen in the ambulatory or outpatient setting between 2014 and 2019 who were ≥40 years old. Clinical and demographic data were collected for all men, including age and race. Racial outcomes were reported for all groups with >2% representation in the population. Between-group comparisons were determined using chi-squared analysis, Wilcoxon rank sum testing and multivariable logistic regression, with significance defined as p <0.05. RESULTS: We observed a significant decrease in prostate specific antigen testing across all age and racial groups in a cohort of 606,985 men at Atrium Health, including 87,189 Black men, with an overall relative decline of 56%. As compared to White men, Black men were more likely to undergo prostate specific antigen testing (adjusted OR 1.24, 95% CI 1.22-1.26) and be referred to urology for prostate cancer (adjusted OR 1.94, 95% CI 1.75-2.16). CONCLUSIONS: There was a continued significant decline in prostate cancer screening between 2014 and 2019. Despite having modestly elevated odds of being screened for prostate cancer compared to White men, Black men are relatively underscreened when considering that those who undergo prostate specific antigen screening are more likely to be referred by primary care to urology for additional prostate cancer diagnostic evaluation.
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Negro o Afroamericano/estadística & datos numéricos , Detección Precoz del Cáncer , Disparidades en Atención de Salud , Antígeno Prostático Específico/análisis , Derivación y Consulta/estadística & datos numéricos , Población Blanca/estadística & datos numéricos , Adulto , Anciano , Estudios de Cohortes , Prestación Integrada de Atención de Salud , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estados UnidosRESUMEN
OBJECTIVES: In response to the dearth of consumer health information for patients with gastrointestinal cancers, this study examined the informational needs of these patients to build a plan for future resource development. Although studies have examined informational needs of some such cancers, no published literature has investigated the comprehensive informational needs across all sites of gastrointestinal cancer. METHODS: A cross-sectional needs assessment comprising a self-administered questionnaire was conducted at an ambulatory gastrointestinal oncology clinic in Toronto, Canada. Patient informational needs were measured, including importance of information, amount desired and preferred mode of delivery. Informational needs were grouped into six domains: medical, practical, physical, emotional, social and spiritual. RESULTS: Eighty-two surveys were analysed. The majority of the respondents were male (53.8%), over the age of 50 (77.8%), and born outside of Canada (51.9%). While many did not speak English as a child (46.3%), and do not speak English at home (22.2%), nearly all indicated comfort with receiving health information in English (97.5%). The majority of respondents were college educated (79.3%) and married (73%). Multiple cancer types were reported; the most common being colorectal (39%), followed by pancreatic (12%) and cancers of the gallbladder or bile duct (12%). Overall, respondents placed highest importance on medical information (P < 0.001). Preferred education modalities were pamphlets, websites and one-on-one discussions with health-care professionals. CONCLUSIONS: This study highlights the principal informational needs of patients with gastrointestinal malignancies, along with preferred modality for information delivery. This information will guide the development of educational resources for future patients.
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Información de Salud al Consumidor , Neoplasias Gastrointestinales , Evaluación de Necesidades , Educación del Paciente como Asunto , Adulto , Anciano , Anciano de 80 o más Años , Canadá , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Apoyo Social , Encuestas y CuestionariosRESUMEN
Quality improvement measures are uniformly applied to all oncology providers, regardless of their roles. Little is known about differences in adherence to these measures between oncology fellows, advance practice providers (APP), and attending physicians. We investigated conformance across Quality Oncology Practice Initiative (QOPI) measures for oncology fellows, advance practice providers, and attending physicians at the Durham Veterans Affairs Medical Center (DVAMC). Using data collected from the Spring 2012 and 2013 QOPI cycles, we abstracted charts of patients and separated them based on their primary provider. Descriptive statistics and the chi-square test were calculated for each QOPI measure between fellows, advanced practice providers (APPs), and attending physicians. A total of 169 patients were reviewed. Of these, 31 patients had a fellow, 39 had an APP, and 99 had an attending as their primary oncology provider. Fellows and attending physicians performed similarly on 90 of 94 QOPI metrics. High-performing metrics included several core QOPI measures including documenting consent for chemotherapy, recommending adjuvant chemotherapy when appropriate, and prescribing serotonin antagonists when prescribing emetogenic chemotherapies. Low-performing metrics included documentation of treatment summary and taking action to address problems with emotional well-being by the second office visit. Attendings documented the plan for oral chemotherapy more often (92 vs. 63%, P=0.049). However, after the chart audit, we found that fellows actually documented the plan for oral chemotherapy 88% of the time (p=0.73). APPs and attendings performed similarly on 88 of 90 QOPI measures. The quality of oncology care tends to be similar between attendings and fellows overall; some of the significant differences do not remain significant after a second manual chart review, highlighting that the use of manual data collection for QOPI analysis is an imperfect system, and there may be significant inter-observer variability.
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Adhesión a Directriz , Oncología Médica/organización & administración , Oncología Médica/normas , Cuerpo Médico de Hospitales , Neoplasias/prevención & control , Pautas de la Práctica en Medicina/normas , Garantía de la Calidad de Atención de Salud , Calidad de la Atención de Salud/normas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mejoramiento de la CalidadRESUMEN
Rechargeability in zinc (Zn) batteries is limited by anode irreversibility. The practical lean electrolytes exacerbate the issue, compromising the cost benefits of zinc batteries for large-scale energy storage. In this study, a zinc-coordinated interphase is developed to avoid chemical corrosion and stabilize zinc anodes. The interphase promotes Zn2+ ions to selectively bind with histidine and carboxylate ligands, creating a coordination environment with high affinity and fast diffusion due to thermodynamic stability and kinetic lability. Experiments and simulations indicate that interphase regulates dendrite-free electrodeposition and reduces side reactions. Implementing such labile coordination interphase results in increased cycling at 20 mA cm-2 and high reversibility of dendrite-free zinc plating/stripping for over 200 hours. A Zn||LiMn2 O4 cell with 74.7 mWh g-1 energy density and 99.7% Coulombic efficiency after 500 cycles realized enhanced reversibility using the labile coordination interphase. A lean-electrolyte full cell using only 10 µL mAh-1 electrolyte is also demonstrated with an elongated lifespan of 100 cycles, five times longer than bare Zn anodes. The cell offers a higher energy density than most existing aqueous batteries. This study presents a proof-of-concept design for low-electrolyte, high-energy-density batteries by modulating coordination interphases on Zn anodes.
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The development of potent pseudocapacitive charge storage materials has emerged as an effective solution for closing the gap between high-energy density batteries and high-power density and long-lasting electrical double-layer capacitors. Sulfonyl compounds are ideal candidates owing to their rapid and reversible redox reactions. However, structural instability and low electrical conductivity hinder their practical application as electrode materials. This work addresses these challenges using a fast and clean laser process to interconnect sulfonated carbon nanodots into functionalized porous carbon frameworks. In this bottom-up approach, the resulting laser-converted three-dimensional (3D) turbostratic carbon foams serve as high-surface-area, conductive scaffolds for redox-active sulfonyl groups. This design enables efficient faradaic processes using pendant sulfonyl groups, leading to a high specific capacitance of 157.6 F g-1 due to the fast reversible redox reactions of sulfonyl moieties. Even at 20 A g-1, the capacitance remained at 78.4% due to the uniform distribution of redox-active sites on the graphitic domains. Additionally, the 3D-tsSC300 electrode showed remarkable cycling stability of >15 000 cycles. The dominant capacitive processes and kinetics were analysed using extensive electrochemical characterizations. Furthermore, we successfully used 3D-tsSC300 in flexible solid-state supercapacitors, achieving a high specific capacitance of up to 17.4 mF cm-2 and retaining 91.6% of the initial capacitance after 20 000 cycles of charge and discharge coupled with 90° bending tests. Additionally, an as-assembled flexible all-solid-state symmetric supercapacitor exhibits a high energy density of 12.6 mW h cm-3 at a high power density of 766.2 W cm-3, both normalized by the volumes of the full device, which is comparable or better than state-of-the-art commercial pseudocapacitors and hybrid capacitors. The integrated supercapacitor provides a wide potential window of 2.0 V using a serial circuit, showing great promise for metal-free energy storage devices.
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There has been increasing recognition of vaccine access challenges in middle-income countries and the need for increased action, particularly in countries that are not eligible for or have transitioned out of Gavi, the Vaccine Alliance support. These countries' immunization systems are more vulnerable than ever as the COVID-19 pandemic exacerbates existing programme challenges, increasing the risk of delayed vaccine introductions, backsliding immunization coverage rates, and increased coverage inequity. The potential health and equity impact of improving immunization outcomes in middle-income countries is substantial. Modelling suggests that the introduction of pneumococcal conjugate vaccine and vaccines for rotavirus and human papillomavirus in this set of Gavi-transitioned and non-Gavieligible middle-income countries in 2020 could have saved an estimated 70,000 lives if 90 % coverage had been reached. Further, increasing coverage for already-introduced vaccines to 90 % could have saved an additional estimated 16,000 lives. Over the past decade, stakeholders have made considerable efforts to identify immunization challenges in middle-income countries as documented in the 2015 SAGE-endorsed Shared Partner Middle-Income Country Strategy. In the coming decade, new global platforms like Gavi 5.0 and the Immunization Agenda 2030 provide opportunities to align on MIC strategies and provide coordinated global support to middle-income countries. The international COVID-19 pandemic response has the potential to lay the foundation for long term support beyond the scope of COVID-19 to non-Gavi eligible middle-income countries. Meanwhile regional mechanisms to address immunization barriers in middle-income countries have grown in number and strength, offering sustainable platforms for cross-country collaboration and the provision of tailored technical support. To ensure that these opportunities are successfully acted upon and that middle-income countries achieve the Immunization Agenda 2030 goals, comprehensive, multi-stakeholder consultations were conducted to identify areas of action with the greatest potential to accelerate immunization progress. Stakeholders should work together to put these findings, highlighted in this paper, into action, adapting their approaches to specific country contexts and learning from and building on existing efforts.
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PURPOSE: Homologous recombination deficiency (HRD) is a well-described phenotype of some prostate cancers; however, current biomarkers for HRD are imperfect and rely on detection of single gene alterations in the homologous recombination repair (HRR) pathway, which may not capture the complexity of HRD biology. RNA signature-based methods of HRD identification present a potentially dynamic assessment of the HRD phenotype; however, its relationship with HRR gene alterations is not well characterized in prostate cancer. METHODS: A HRD assay on the basis of an RNA signature associated with biallelic BRCA1/2 loss was applied to a retrospective cohort study of 985 men with prostate cancer analyzed on the Tempus xT platform. HRD status was defined by a binary threshold on a continuous scale. RESULTS: In this cohort, of the 126 (13%) patients found to be HRD+ by RNA signature (HRD-RNA+), 100 (79%) had no coexisting HRR gene alteration. Among samples with biallelic BRCA1/2 loss, 78% (7/9) were classified as HRD-RNA+, while 8% (2/25) of samples with BRCA1/2 monoallelic loss were HRD-RNA+. Biallelic and monoallelic ATM loss exhibited HRD-RNA+ at a lower prevalence: 6.7% (1/15) and 7.1% (1/14), respectively, compared with HRD-RNA+ prevalence among samples without any HRR gene loss (13%; 100/782). HRD-RNA+ was associated with a significantly higher prevalence of TP53 and AR gene alterations relative to HRD-RNA- after correction for multiple comparisons, 59% versus 39% (q = 0.003) and 23% versus 12% (q = 0.024), respectively. CONCLUSION: Use of an RNA-based HRD signature significantly expands the fraction of patients with prostate cancer who may derive benefit from poly (ADP-ribose) polymerase inhibitors (PARPis) compared with using HRR gene mutations alone. Further studies are needed to evaluate functional HRD significance and inform future usage as a predictive biomarker for PARPi selection.
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Proteína BRCA1 , Neoplasias de la Próstata , Masculino , Humanos , Proteína BRCA1/genética , Reparación del ADN por Recombinación/genética , Recombinación Homóloga/genética , Estudios Retrospectivos , Proteína BRCA2/genética , Neoplasias de la Próstata/genética , Inhibidores de Poli(ADP-Ribosa) PolimerasasRESUMEN
Background: Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are carbohydrate binding proteins with a wide range of biological activity, including regulation of cellular adhesion, proliferation, and apoptosis in solid tumors. Prior small studies have reported that Gal-3 expression is associated with progression of disease in urothelial carcinoma (UC), from non-muscle invasive UC progression to muscle invasive UC. We assessed Gal-1 and Gal-3 protein expression H-score utilizing a tissue microarray (TMA) created from 301 cystectomy specimens. Methods: Immunohistochemistry for Gal-1 and Gal-3 was performed on TMA generated from tumor blocks from chemotherapy naïve cystectomy specimens. The variable of interest, H-score, was defined as the product of the percentage of cells staining positive (0-100) and intensity score (0-3) scored by a single pathologist. Survival end points were analyzed using Kaplan-Meier and Cox Proportional Hazards methods. Clinical data including Charlson Comorbidity Index (CCI), pathologic tumor (T) stage, tumor size, node stage, and surgical margins, were included in multivariable analysis. Results: We found that Gal-1 and Gal-3 expression correlated with intratumoral T stage (median Gal-1 H-score was 0 across non-invasive tissue types and 200 in invasive, P<0.01 and median Gal-3 score was 270 across non-invasive tissue types and 70 in invasive, P<0.01). However, the highest intratumoral H-score per cystectomy core did not independently predict for recurrence-free survival (RFS) (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.65) or OS (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.72) in this cohort. Significant intratumoral heterogeneity was present for both Gal-1 and Gal-3, with an average difference between the highest and lowest H score was 95 for Gal-1 and 109 for Gal-3 for cystectomy specimens with more than one biopsy. Conclusions: Gal-1 and Gal-3 H-score per bladder did not independently predict for RFS or OS. Intra-tumoral Gal-1/Gal-3 heterogeneity complicates the use of Gal-1 and Gal-3 expression as a prognostic biomarker. Future studies should consider the evaluation of serum and urinary galectins as an approach to mitigate tumor heterogeneity.
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Fully implantable wireless systems for the recording and modulation of neural circuits that do not require physical tethers or batteries allow for studies that demand the use of unconstrained and freely behaving animals in isolation or in social groups. Moreover, feedback-control algorithms that can be executed within such devices without the need for remote computing eliminate virtual tethers and any associated latencies. Here we report a wireless and battery-less technology of this type, implanted subdermally along the back of freely moving small animals, for the autonomous recording of electroencephalograms, electromyograms and body temperature, and for closed-loop neuromodulation via optogenetics and pharmacology. The device incorporates a system-on-a-chip with Bluetooth Low Energy for data transmission and a compressed deep-learning module for autonomous operation, that offers neurorecording capabilities matching those of gold-standard wired systems. We also show the use of the implant in studies of sleep-wake regulation and for the programmable closed-loop pharmacological suppression of epileptic seizures via feedback from electroencephalography. The technology can support a broader range of applications in neuroscience and in biomedical research with small animals.
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Measurements of the thermal properties of the skin can serve as the basis for a noninvasive, quantitative characterization of dermatological health and physiological status. Applications range from the detection of subtle spatiotemporal changes in skin temperature associated with thermoregulatory processes, to the evaluation of depth-dependent compositional properties and hydration levels, to the assessment of various features of microvascular/macrovascular blood flow. Examples of recent advances for performing such measurements include thin, skin-interfaced systems that enable continuous, real-time monitoring of the intrinsic thermal properties of the skin beyond its superficial layers, with a path to reliable, inexpensive instruments that offer potential for widespread use as diagnostic tools in clinical settings or in the home. This paper reviews the foundational aspects of the latest thermal sensing techniques with applicability to the skin, summarizes the various devices that exploit these concepts, and provides an overview of specific areas of application in the context of skin health. A concluding section presents an outlook on the challenges and prospects for research in this field.
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Biomarkers are needed in muscle-invasive bladder cancer (MIBC). We previously reported that high tumor aurora kinase (AURK) A expression identifies patients with MIBC with poor prognosis. Aberrant p53 expression has also been associated with poor outcomes in MIBC, though to the best of our knowledge, co-expression rates of p53 and aurora kinases have not been previously described in MIBC. As aurora kinase and p53 family members may co-regulate each other, the present study investigated whether tumor p53 or p63 protein expression influenced the prognostic value of AURKA in a pilot study of 50 patients with MIBC treated with curative intent. Immunohistochemistry for AURKA, AURKB, p53 and p63 were performed on archival pre-treatment tumor specimens and correlated with clinical outcomes in patients with MIBC who received neoadjuvant chemotherapy (NAC) prior to cystectomy. Baseline p53 [hazard ratio (HR) 1.46; 95% confidence interval (CI)=0.55-3.9; P=0.448) and p63 (HR 2.02; 95% CI=0.51-8.1; P=0.313) protein expression did not predict for overall survival (OS). Low p53 protein expression did not correlate with high AURKA (φ=0.190) or AURKB (φ=0.075) expression. However, in tumors with low p53 expression (n=17), the presence of either high AURKA or AURKB expression levels predicted an increased risk for relapse (HR 27.1; 95% CI=2.7-270.1; P=0.005) and mortality (HR 14.9; 95% CI=2.3-95.6; P=0.004) compared to tumors with both low AURKA and AURKB levels. The relationship between p63 and AURKA/B expression levels was not tested due to the prevalence (80%) of high p63 expression in the present cohort. In tumors with low AURKA expression, p53 status did not predict for OS (HR 0.62; 95% CI 0.2-3.2; P=0.572). In multivariable analysis, only high baseline AURKA expression predicted for inferior OS (HR 4.9; 95% CI 1.7-14.1; P=0.003). To the best of our knowledge, the present study was the first to report co-expression of p53 and aurora kinase family members in MIBC, and although wild-type p53 may regulate the aurora kinases in preclinical models, the adverse prognostic value of tumor AURKA overexpression was independent from baseline tumor p53 protein expression in the present cohort. AURKA remains an important prognostic biomarker in patients with MIBC and warrants further evaluation in prospective studies to validate whether baseline AURKA can identify patients that are unlikely to benefit from standard of care with NAC.
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OBJECTIVE: To evaluate whether racial disparities in MRI-Bx usage persisted after correction for socioeconomic, demographic, and clinical factors. METHODS: This is a retrospective cohort study of patients who received either MRI-Bx or systematic biopsy (SB) within a single academic medical center between January 2018 - June 2020. For each patient, socioeconomic variables including household income, education, percent below poverty, and unemployment were estimated using 2015 American Community Survey census-tract level data. Chi-square analysis was used to examine differences in clinical and demographic characteristics between the two groups. The Benjamini-Hochberg procedure was used to control false discovery rate (FDR) for multiple testing. RESULTS: Eighteen percent of Black men (53/295) received MRI-Bx while 41% (228/561) of white men received MRI-Bx. Patients coming from highly impoverished areas were less likely to receive MRI-Bx, 25% vs 75%, respectively. In multivariate analysis, race remained significantly different across MRI-Bx and SB groups. Clinical factors including family history, DRE, BMI, and prostate volume were not significantly different between patients receiving MRI-Bx and SB. CONCLUSION: Black men are less likely to receive MRI-Bx than white men, even after adjusting for clinical and socioeconomic characteristics. Further work is necessary to identify and study methods to increase equity in PCa diagnostic testing.
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Biopsia Guiada por Imagen , Neoplasias de la Próstata , Humanos , Biopsia Guiada por Imagen/métodos , Imagen por Resonancia Magnética , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Factores SocioeconómicosRESUMEN
Our current understanding of human physiology and activities is largely derived from sparse and discrete individual clinical measurements. To achieve precise, proactive, and effective health management of an individual, longitudinal, and dense tracking of personal physiomes and activities is required, which is only feasible by utilizing wearable biosensors. As a pilot study, we implemented a cloud computing infrastructure to integrate wearable sensors, mobile computing, digital signal processing, and machine learning to improve early detection of seizure onsets in children. We recruited 99 children diagnosed with epilepsy and longitudinally tracked them at single-second resolution using a wearable wristband, and prospectively acquired more than one billion data points. This unique dataset offered us an opportunity to quantify physiological dynamics (e.g., heart rate, stress response) across age groups and to identify physiological irregularities upon epilepsy onset. The high-dimensional personal physiome and activity profiles displayed a clustering pattern anchored by patient age groups. These signatory patterns included strong age and sex-specific effects on varying circadian rhythms and stress responses across major childhood developmental stages. For each patient, we further compared the physiological and activity profiles associated with seizure onsets with the personal baseline and developed a machine learning framework to accurately capture these onset moments. The performance of this framework was further replicated in another independent patient cohort. We next referenced our predictions with the electroencephalogram (EEG) signals on selected patients and demonstrated that our approach could detect subtle seizures not recognized by humans and could detect seizures prior to clinical onset. Our work demonstrated the feasibility of a real-time mobile infrastructure in a clinical setting, which has the potential to be valuable in caring for epileptic patients. Extension of such a system has the potential to be leveraged as a health management device or longitudinal phenotyping tool in clinical cohort studies.
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OBJECTIVES: Small cell bladder carcinoma (SCBC) represents a rare histologic variant with a poor prognosis and for which no routine biomarkers exist. Limited reports of genomic sequencing in SCBC have demonstrated a high prevalence of TP53 and RB1 gene mutations, though the prognostic value of these and other gene variants in SCBC remains undefined. In this study, we performed targeted genomic sequencing on a cohort of SCBC patients and correlated genomic findings with clinical outcomes to identify potential novel biomarkers. MATERIALS AND METHODS: Thirty-one patients with SCBC and available treatment-naïve tumor specimens were identified from an institutional database (23 limited stage [LS], 8 extensive stage [ES]). Small cell carcinoma specimens were microdissected and subjected to tumor next-generation whole-exon sequencing with a 592 gene panel. Kaplan-Meier techniques and Cox proportional hazards models were used to evaluate genomic aberration association with relapse-free survival (RFS) and overall survival (OS) in the limited stage cohort. RESULTS: The most common pathogenic gene variants included ARID1A (48%), TP53 (48%) and RB1 (48%). Mutations in genes with potential therapeutic targets not routinely evaluated in SCBC included BRCA1/2 (16%), POLE (13%), JAK2 (13%), PDGFB (13%) and FGFR3 (3%). Multiple novel biomarker candidates showed trends for improvements in OS in the LS subset including ERCC2 (HR 0.322, Pâ¯=â¯0.122) and RB1 (HR 0.481, Pâ¯=â¯0.182), while LS patients with TP53 mutations (HR 2.730, Pâ¯=â¯0.056), and MCL1 gene amplification (HR 4.183, Pâ¯=â¯0.018) suggested inferior OS. Additionally, gene or copy number variants with potential prognostic benefit included UBR5 and DAXX (Pâ¯=â¯0.02, [hazard ratios nonestimable due to zero events in biomarker positive groups]). CONCLUSIONS: These results support the role for tumor genomic profiling in SCBC and identify multiple potential novel biomarkers and therapeutic targets in this rare disease. Efforts to validate these findings should lead to improved decision-making and treatment outcomes in SCBC.
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Carcinoma , Neoplasias de la Vejiga Urinaria , Biomarcadores de Tumor/genética , Genómica , Humanos , Mutación , Recurrencia Local de Neoplasia/genética , Pronóstico , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Proteína de la Xerodermia Pigmentosa del Grupo D/genéticaRESUMEN
BACKGROUND: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy. METHODS: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. RESULTS: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS. CONCLUSION: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Antígeno B7-H1/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Antígeno CTLA-4/uso terapéutico , Factores de Transcripción Forkhead , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/farmacología , Ipilimumab/uso terapéutico , Neoplasias Renales/patología , Nivolumab/farmacología , Nivolumab/uso terapéutico , Estudios Retrospectivos , Microambiente TumoralRESUMEN
Human epidermal growth factor receptor 2 (HER2) overexpression occurs in 5-10% of primary urothelial carcinomas (UCs) but has not reliably predicted benefit from HER2-targeted agents in the metastatic setting. HER2 testing of primary tumors may not reflect the HER2 status of distant metastases. We assessed the concordance of HER2 expression in paired primary and distant metastatic UC lesions. Specimens from 149 patients with metastatic UC underwent immunohistochemical staining for HER2, including 79 paired primary and distant metastatic tumors. HER2 status was defined using 2018 ASCO/CAP guidelines. HER2 intratumoral heterogeneity (ITH) was defined as HER2 3+ expression in 5-50% of tumor cells. The HER2-positive, -equivocal, and -negative rates observed were 10.6%, 24.7%, and 64.7% for primary tumors and 9.8%, 12.6%, and 77.6% for metastatic tumors, respectively. HER2 ITH occurred in 44% of HER2-positive primary tumors. Low agreement of HER2-positive status between primary and metastatic tumors was observed (к = 0.193, P = 0.079). Loss of HER2 overexpression in the metastatic lesion was observed in 55% (5 of 9 cases) of HER2-positive primary cases and was associated with the presence of HER2 ITH in the primary tumor (Fisher's exact P = 0.048). Change from negative primary to positive metastasis was seen in 2% (1 of 50) of cases. No differences in metastasis-free survival or overall survival were observed in accordance with HER2 status defined by either the primary or metastatic lesion. These findings are likely to impact patient selection for HER2 targeted therapies in UC. Confirmation and evaluation of the clinical significance of HER2 discordance is warranted, preferably in the context of a clinical trial.