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Purpose: 18F-Flotufolastat (18F-rhPSMA-7.3) is a newly approved prostate-specific membrane antigen targeting radiopharmaceutical for diagnostic imaging of prostate cancer (PCa). SPOTLIGHT (National Clinical Trials 04186845) evaluated 18F-flotufolastat in men with suspected PCa recurrence. Here, we present results of predefined exploratory endpoints from SPOTLIGHT to evaluate the impact of clinical factors on 18F-flotufolastat detection rates (DR). Methods and Materials: The impact of baseline prostate-specific antigen (PSA), PSA doubling time (PSAdt), and International Society of Urologic Pathology Grade Group (GG) on 18F-flotufolastat DR was evaluated among all SPOTLIGHT patients with an evaluable scan, with DR stratified according to the patients' prior treatment (radical prostatectomy ± radiation therapy [RP] or radiation therapy only [RT]). The patients underwent positron emission tomography 50 to 70 minutes after receiving 18F-flotufolastat (296 MBq IV), and scans were read by 3 blinded central readers, with the majority read representing agreement between ≥2 readers. Results: In total, 389 men (median PSA: 1.10 ng/mL) were evaluable. By majority read, 18F-flotufolastat identified distant lesions in 39% and 43% of patients treated with prior RP or RT, respectively. The overall DR broadly increased with increasing PSA (<0.2 ng/mL: 33%; ≥10 ng/mL: 100%). Among patients with PSA <1 ng/mL, 68% had positive scans, and 27% had extrapelvic findings. PSAdt was available for 145/389 (37%) patients. PSAdt did not appear to influence 18F-flotufolastat DR (77%-90% across all PSAdt categories). Among patients with prior RP, DR ranged from 70% to 83% across PSAdt categories, and 100% DR was reported for all post-RT patients. In total, 362/389 (93%) patients had baseline GG data. Overall DRs were uniformly high (75%â95%) across all GG. When stratified by prior treatment, DRs across all GG were 69% to 89% in patients with prior RP and ≥96% in patients with prior RT. Conclusions: 18F-Flotufolastat-positron emission tomography enabled the accurate detection of recurrent PCa lesions across a wide range of PSA, PSAdt, and International Society of Urologic Pathology GG, thus supporting its clinical utility for a broad range of patients with recurrent PCa.
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BACKGROUND AND OBJECTIVE: The source of tissue for genomic profiling of metastatic castration-resistant prostate cancer (mCRPC) is often limited to osseous metastases. To guide patient management, metastatic site selection and the technique for targeted bone biopsies are critical for identifying deleterious gene mutations. Our objective was to identify key parameters associated with successful large-panel DNA sequencing. METHODS: We analyzed parameters for 243 men with progressing mCRPC who underwent 269 bone biopsies for genomic profiling between 2014 and 2018. Univariate and multivariate analyses were performed for clinical, imaging (bone scan; fluorodeoxyglucose [FDG] positron emission tomography [PET]; computed tomography [CT]; magnetic resonance imaging), and technical (biopsy site, number of samples, needle gauge) features associated with successful genomic profiling. KEY FINDINGS AND LIMITATIONS: Overall, 159 of 269 biopsies (59%) generated sufficient tumor material for a genomic profile. Seventy (26%) of the failures were histopathologically negative for mCRPC and 40 (15%) had insufficient tumor for genomic profiling. Of 199 mCRPC samples submitted for molecular testing, 159 (80%) yielded a genomic profile. On univariate analysis, PSA, serum acid phosphatase, number of biopsy samples, FDG PET positivity, CT attenuation, and CT morphology were significantly associated with genomic profiling success. On multivariate analysis, higher FDG maximum standardized uptake value (odds ratio [OR] 7.51, 95% confidence interval [CI] 3.01-18.78; p < 0.001), higher number of biopsy samples (OR 4.73, 95% CI 1.49-15.02; p = 0.008), and lower mean CT attenuation (OR 0.4, 95% CI 0.18-0.89; p = 0.025) were significantly associated with sequencing success. CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with mCRPC, bone biopsies from sites with metabolic activity and lower CT attenuation are associated with higher success rates for genomic profiling via a large-panel DNA sequencing platform. PATIENT SUMMARY: We identified factors associated with successful genetic testing of bone tissue for patients with metastatic prostate cancer. Our findings may help in guiding the right scan technique and biopsy site for personalized treatment planning.
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Allergic bronchopulmonary aspergillosis (ABPA) results from complex hypersensitivity reactions to Aspergillus fumigatus, which often occur in patients with asthma, cystic fibrosis (CF), or CF transmembrane conductance regulator (CFTR)-related disorders. Genetic predisposition, particularly variants of the CFTR gene, probably plays a significant role in the development of ABPA. We present the case of a 20-year-old male with ABPA and bronchiectasis that was initially misdiagnosed as a result of normal sweat chloride values and negative first-level genetic testing results. Comprehensive CFTR gene sequencing revealed 2 pathogenic variants, R347H and D1152H, which together with the clinical phenotype and functional tests, supported the diagnosis of CF. Treatment with elexacaftor/tezacaftor/ivacaftor resulted in significant clinical and functional improvement, including a marked decrease in total IgE levels, suggesting a potential role for CFTR modulators in controlling ABPA. This case illustrates the evolving understanding of CF as a spectrum of disorders in which CFTR dysfunction may manifest subtly and variably, necessitating a high index of suspicion and a comprehensive diagnostic approach to ensure timely treatment in the era of highly effective CFTR modulators.
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INTRODUCTION: Asthma is the most common diagnosis in military personnel who endorse chronic dyspnea. Service members have unique occupational risk factors, and there is concern that airborne exposures in the deployed environment as well as other occupational exposures may contribute to the development of asthma or exacerbate pre-existing disease. Asthma phenotyping with clinical biomarkers such as serum immunoglobulin E (IgE) levels and eosinophil (EOS) counts is useful in defining treatment strategies for the management of asthma. This study sought to characterize the phenotype of medically separated military personnel with career-limiting asthma to define potential management strategies and guide future research evaluating the unexplained prevalence of asthma in this population. MATERIALS AND METHODS: A retrospective chart review of active duty service members (ADSM) who underwent fitness for duty evaluation via medical evaluation board between 2005 and 2016 and were separated with a minimum 30% conditional disability rating for asthma was performed. Only ADSM who were diagnosed with asthma by a pulmonologist and had spirometry data available were included in the analysis. Demographics, spirometry data, and laboratory data to include IgE levels, radioallergosorbent panels, and EOS counts were analyzed from the DoD electronic medical record. RESULTS: A total of 141 service members were evaluated with a mean age of 42 ± 6.8 years, mean serum EOS count of 300 ± 358 cells/µL, and mean IgE level of 305 ± 363 IU/mL. The patients were further categorized into 4 subgroups based on serum EOS count and IgE level: group A with IgE < 100 IU/mL and EOS < 300 cells/µL (n = 45; 33%), group B with IgE > 100 IU/mL and EOS < 300 cells/µL (n = 44; 32%), group C with IgE < 100 IU/mL and EOS > 300 cells/µL (n = 6; 1%), and group D with IgE > 100 IU/mL, EOS > 300 cells/µL (n = 46; 34%). Among the cohorts, there were no statistically significant differences in demographics, body mass index, spirometry, smoking history, or disability rating. CONCLUSION: The majority of ADSM with a defined asthma history do not have concordant elevations in serum IgE and blood EOS suggestive of a Th2-high phenotype. Asthma in this population is heterogeneous, and phenotyping using clinical biomarkers may be useful to define optimal treatment strategies.
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Asma , Inmunoglobulina E , Personal Militar , Fenotipo , Humanos , Personal Militar/estadística & datos numéricos , Asma/sangre , Asma/epidemiología , Asma/diagnóstico , Asma/fisiopatología , Masculino , Adulto , Femenino , Estudios Retrospectivos , Inmunoglobulina E/sangre , Inmunoglobulina E/análisis , Persona de Mediana Edad , Eosinófilos , Biomarcadores/sangre , Biomarcadores/análisis , Espirometría/métodos , Factores de Riesgo , PrevalenciaRESUMEN
Background Lutetium 177 [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) is a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC). Quantitative PSMA PET/CT analysis could provide information on 177Lu-PSMA-617 treatment benefits. Purpose To explore the association between quantitative baseline gallium 68 [68Ga]Ga-PSMA-11 (68Ga-PSMA-11) PET/CT parameters and treatment response and outcomes in the VISION trial. Materials and Methods This was an exploratory secondary analysis of the VISION trial. Eligible participants were randomized (June 2018 to October 2019) in a 2:1 ratio to 177Lu-PSMA-617 therapy (7.4 GBq every 6 weeks for up to six cycles) plus standard of care (SOC) or to SOC only. Baseline 68Ga-PSMA-11 PET parameters, including the mean and maximum standardized uptake value (SUVmean and SUVmax), PSMA-positive tumor volume, and tumor load, were extracted from five anatomic regions and the whole body. Associations of quantitative PET parameters with radiographic progression-free survival (rPFS), overall survival (OS), objective response rate, and prostate-specific antigen response were investigated using univariable and multivariable analyses (with treatment as the only other covariate). Outcomes were assessed in subgroups based on SUVmean quartiles. Results Quantitative PET parameters were well balanced between study arms for the 826 participants included. The median whole-body tumor SUVmean was 7.6 (IQR, 5.8-9.9). Whole-body tumor SUVmean was the best predictor of 177Lu-PSMA-617 efficacy, with a hazard ratio (HR) range of 0.86-1.43 for all outcomes (all P < .001). A 1-unit whole-body tumor SUVmean increase was associated with a 12% and 10% decrease in risk of an rPFS event and death, respectively. 177Lu-PSMA-617 plus SOC prolonged rPFS and OS in all SUVmean quartiles versus SOC only, with no identifiable optimum among participants receiving 177Lu-PSMA-617. Higher baseline PSMA-positive tumor volume and tumor load were associated with worse rPFS (HR range, 1.44-1.53 [P < .05] and 1.02-1.03 [P < .001], respectively) and OS (HR range, 1.36-2.12 [P < .006] and 1.04 [P < .001], respectively). Conclusion Baseline 68Ga-PSMA-11 PET/CT whole-body tumor SUVmean was the best predictor of 177Lu-PSMA-617 efficacy in participants in the VISION trial. Improvements in rPFS and OS with 177Lu-PSMA-617 plus SOC were greater among participants with higher whole-body tumor SUVmean, with evidence for benefit at all SUVmean levels. ClinicalTrials.gov identifier: NCT03511664 Published under a CC BY 4.0 license. Supplemental material is available for this article.
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Dipéptidos , Isótopos de Galio , Radioisótopos de Galio , Compuestos Heterocíclicos con 1 Anillo , Lutecio , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata Resistentes a la Castración , Radiofármacos , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Neoplasias de la Próstata Resistentes a la Castración/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Lutecio/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Anciano , Dipéptidos/uso terapéutico , Radiofármacos/uso terapéutico , Persona de Mediana Edad , Resultado del Tratamiento , Radioisótopos/uso terapéutico , Ácido Edético/análogos & derivados , Ácido Edético/uso terapéutico , Antígeno Prostático EspecíficoRESUMEN
Cardiac electrophysiology involves the diagnosis and management of arrhythmias. CT and MRI play an increasingly important role in cardiac electrophysiology, primarily in preprocedural planning of ablation procedures but also in procedural guidance and postprocedural follow-up. The most common applications include ablation for atrial fibrillation (AF), ablation for ventricular tachycardia (VT), and for planning cardiac resynchronization therapy (CRT). For AF ablation, preprocedural evaluation includes anatomic evaluation and planning using CT or MRI as well as evaluation for left atrial fibrosis using MRI, a marker of poor outcomes following ablation. Procedural guidance during AF ablation is achieved by fusing anatomic data from CT or MRI with electroanatomic mapping to guide the procedure. Postprocedural imaging with CT following AF ablation is commonly used to evaluate for complications such as pulmonary vein stenosis and atrioesophageal fistula. For VT ablation, both MRI and CT are used to identify scar, representing the arrhythmogenic substrate targeted for ablation, and to plan the optimal approach for ablation. CT or MR images may be fused with electroanatomic maps for intraprocedural guidance during VT ablation and may also be used to assess for complications following ablation. Finally, functional information from MRI may be used to identify patients who may benefit from CRT, and cardiac vein mapping with CT or MRI may assist in planning access. ©RSNA, 2024 Supplemental material is available for this article.
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Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Humanos , Tomografía Computarizada por Rayos X/métodos , Imagen por Resonancia Magnética/métodos , Ablación por Catéter/métodos , Taquicardia Ventricular/diagnóstico por imagen , Fibrilación Atrial/diagnóstico por imagen , Fibrilación Atrial/cirugía , Técnicas Electrofisiológicas Cardíacas/métodos , Arritmias Cardíacas/diagnóstico por imagenRESUMEN
PURPOSE: Accurate diagnosis and staging of prostate cancer are crucial to improving patient care. Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography with computed tomography (PET/CT) imaging has demonstrated superiority for initial staging and restaging in patients with prostate cancer. Referring physicians and PET/CT readers must agree on a consistent communication method and application of information derived from this imaging modality. While several guidelines have been published, a single PSMA PET/CT reporting template has yet to be widely adopted. Based on the consensus from community and academic physicians, we developed a standardized PSMA PET/CT reporting template for radiologists and nuclear medicine physicians to report and relay key imaging findings to referring physicians. The aim was to improve the quality, clarity, and utility of imaging results reporting to facilitate patient management decisions. METHODS: Based on community and expert consensus, we developed a standardized PSMA PET/CT reporting template to deliver key imaging findings to referring clinicians. RESULTS: Core category components proposed include a summary of any prior treatment history; presence, location, and degree of PSMA radiopharmaceutical uptake in primary and/or metastatic tumor(s), lesions with no uptake, and incidentally found lesions with positive uptake on PET/CT. CONCLUSIONS: This article provides recommendations on best practices for standardized reporting of PSMA PET/CT imaging. The generated reporting template is a proposed supplement designed to educate and improve data communication between imaging experts and referring physicians.
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BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.
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Péptidos y Proteínas de Señalización Intracelular , Neoplasias Pulmonares , Proteínas de la Membrana , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Radioisótopos , Circonio , Humanos , Masculino , Persona de Mediana Edad , Anciano , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/inmunología , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/inmunología , Tumores Neuroendocrinos/tratamiento farmacológico , Femenino , Deferoxamina/química , Inmunoconjugados/farmacocinética , Clasificación del Tumor , Radiofármacos , Adulto , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/administración & dosificación , Anciano de 80 o más Años , Benzodiazepinonas , Anticuerpos Monoclonales HumanizadosRESUMEN
The use of cardiac CT and MRI is rapidly expanding based on strong evidence from large international trials. The number of physicians competent to interpret cardiac CT and MRI may be unable to keep pace with the increasing demand. Societies and organizations have prescribed training requirements for interpreting cardiac CT and MRI, with recent updates focusing on the increased breadth of competency that is now required due to ongoing imaging advances. In this AJR Expert Panel Narrative Review, we discuss several aspects of cardiac CT and MRI training, focusing on topics that are uncertain or not addressed in existing society statements and guidelines, including determination of competency in different practice types in real-world settings and the impact of artificial intelligence on training and education. The article is intended to guide updates in professional society training requirements and also inform institutional verification processes.
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BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression-free survival (rPFS) versus SOC in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health-related quality of life (HRQOL). METHODS: Post hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu-PSMA-617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and 5-level EQ-5D [EQ-5D-5L]). Correlation analyses used an iterative multiple imputation copula-based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong). RESULTS: In the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT-P total score and emotional and physical well-being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time-to-worsening EQ-5D-5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms. CONCLUSIONS: In this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation.
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Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.
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Análisis de la Célula Individual , Masculino , Humanos , Análisis de la Célula Individual/métodos , Animales , Ratones , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Antígenos de Superficie/metabolismo , Antígenos de Superficie/genética , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/tratamiento farmacológico , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológicoRESUMEN
PURPOSE: Patients with microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI (TMB-H/MSS). METHODS: We sequenced 3,244 tumors from 2,257 prostate cancer patients. MSI-H/dMMR prostate cancer was defined as MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival (OS) and radiographic progression-free survival (rPFS) were compared using log rank test. RESULTS: 63 (2.8%) men had MSI-H/dMMR and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel and neoantigen burden compared with TMB-H/MSS. 27 patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored POLE mutations. 45% of MSI-H/dMMR patients had a RECIST response and 65% had a PSA50 response. No TMB-H/MSS patient had a RECIST response and 50% had a PSA50 response. rPFS tended to be longer in MSI-H/dMMR patients than in TMB-H/MSS patients who received immunotherapy. Pronounced differences in genomics, TMB or MSIsensor score were not detected between MSI-H/dMMR responders and non-responders. CONCLUSIONS: MSI-H/dMMR prostate cancers have greater TMB, indel and neoantigen burden compared with TMB-H/MSS prostate cancers, and these differences may contribute to more profound and durable responses to ICB.
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ABSTRACT: Cytotoxic T lymphocytes (CTLs) destroy virally infected cells and are critical for the elimination of viral infections such as those caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Delayed and dysfunctional adaptive immune responses to SARS-CoV-2 are associated with poor outcomes. Treatment with allogeneic SARS-CoV-2-specific CTLs may enhance cellular immunity in high-risk patients providing a safe, direct mechanism of treatment. Thirty high-risk ambulatory patients with COVID-19 were enrolled in a phase 1 trial assessing the safety of third party, SARS-CoV-2-specific CTLs. Twelve interventional patients, 6 of whom were immunocompromised, matched the HLA-A∗02:01 restriction of the CTLs and received a single infusion of 1 of 4 escalating doses of a product containing 68.5% SARS-CoV-2-specific CD8+ CTLs/total cells. Symptom improvement and resolution in these patients was compared with an observational group of 18 patients lacking HLA-A∗02:01 who could receive standard of care. No dose-limiting toxicities were observed at any dosing level. Nasal swab polymerase chain reaction testing showed ≥88% and >99% viral elimination from baseline in all patients at 4 and 14 days after infusion, respectively. The CTLs did not interfere with the development of endogenous anti-SARS-CoV-2 humoral or cellular responses. T-cell receptor ß analysis showed persistence of donor-derived SARS-CoV-2-specific CTLs through the end of the 6-month follow-up period. Interventional patients consistently reported symptomatic improvement 2 to 3 days after infusion, whereas improvement was more variable in observational patients. SARS-CoV-2-specific CTLs are a potentially feasible cellular therapy for COVID-19 illness. This trial was registered at www.clinicaltrials.gov as #NCT04765449.
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COVID-19 , SARS-CoV-2 , Linfocitos T Citotóxicos , Humanos , COVID-19/inmunología , COVID-19/terapia , Linfocitos T Citotóxicos/inmunología , Persona de Mediana Edad , Masculino , SARS-CoV-2/inmunología , Femenino , Anciano , Adulto , Estudios de Factibilidad , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Resultado del Tratamiento , Antígeno HLA-A2/inmunologíaRESUMEN
The COVID-19 pandemic placed a spotlight on the potential to dramatically increase the use of telehealth across the cancer care continuum, but whether and how telehealth can be implemented in practice in ways that reduce, rather than exacerbate, inequities are largely unknown. To help fill this critical gap in research and practice, we developed the Framework for Integrating Telehealth Equitably (FITE), a process and evaluation model designed to help guide equitable integration of telehealth into practice. In this manuscript, we present FITE and showcase how investigators across the National Cancer Institute's Telehealth Research Centers of Excellence are applying the framework in different ways to advance digital and health equity. By highlighting multilevel determinants of digital equity that span further than access alone, FITE highlights the complex and differential ways structural determinants restrict or enable digital equity at the individual and community level. As such, achieving digital equity will require strategies designed to not only support individual behavior but also change the broader context to ensure all patients and communities have the choice, opportunity, and resources to use telehealth across the cancer care continuum.
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COVID-19 , Continuidad de la Atención al Paciente , Neoplasias , Telemedicina , Humanos , Neoplasias/terapia , Neoplasias/epidemiología , COVID-19/epidemiología , Continuidad de la Atención al Paciente/organización & administración , Estados Unidos , SARS-CoV-2 , Equidad en Salud , Disparidades en Atención de Salud , Accesibilidad a los Servicios de Salud , PandemiasRESUMEN
Modern cancer care is costly and logistically burdensome for patients and their families despite an expansion of technology and medical advances that create the opportunity for novel approaches to care. Therefore, there is a growing appreciation for the need to leverage these innovations to make cancer care more patient centered and convenient. The Memorial Sloan Kettering Making Telehealth Delivery of Cancer Care at Home Efficient and Safe Telehealth Research Center is a National Cancer Institute-designated and funded Telehealth Research Center of Excellence poised to generate the evidence necessary to inform the appropriate use of telehealth as a strategy to improve access to cancer services that are convenient for patients. The center will evaluate telehealth as a strategy to personalize cancer care delivery to ensure that it is not only safe and effective but also convenient and efficient. In this article, we outline this new center's research strategy, as well as highlight challenges that exist in further integrating telehealth into standard oncology practice based on early experiences.
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Neoplasias , Atención Dirigida al Paciente , Telemedicina , Humanos , Neoplasias/terapia , Estados Unidos , Oncología Médica/métodos , Accesibilidad a los Servicios de Salud , National Cancer Institute (U.S.)RESUMEN
Purpose To examine the clinical effect of lead length and lead orientation in patients with cardiac implantable electronic devices (CIEDs) and lead fragments or abandoned leads undergoing 1.5-T MRI. Materials and Methods This Health Insurance Portability and Accountability Act-compliant retrospective study included patients with CIEDs and abandoned leads or lead fragments undergoing 1.5-T MRI from March 2014 through July 2020. CIED settings before and after MRI were reviewed, with clinically significant variations defined as a composite of the change in capture threshold of at least 50%, in sensing of at least 40%, or in lead impedance of at least 30% between before MRI and after MRI interrogation. Adverse clinical events were assessed at MRI and up to 30 days after. Univariable and multivariable analysis was performed. Results Eighty patients with 126 abandoned CIED leads or lead fragments underwent 107 1.5-T MRI examinations. Sixty-seven patients (median age, 74 years; IQR, 66-78 years; 44 male patients, 23 female patients) had abandoned leads, and 13 (median age, 66 years; IQR, 52-74 years; nine male patients, four female patients) had lead fragments. There were no reported deaths, clinically significant arrhythmias, or adverse clinical events within 30 days of MRI. Three patients with abandoned leads had a significant change in the composite of capture threshold, sensing, or lead impedance. In a multivariable generalized estimating equation analysis, lead orientation, lead length, MRI type, and MRI duration were not associated with a significant change in the composite outcome. Conclusion Use of 1.5-T MRI in patients with abandoned CIED leads or lead fragments of varying length and orientation was not associated with adverse clinical events. Keywords: Cardiac Assist Devices, MRI, Cardiac Implantable Electronic Device Supplemental material is available for this article. © RSNA, 2024.
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Desfibriladores Implantables , Falla de Equipo , Imagen por Resonancia Magnética , Marcapaso Artificial , Humanos , Masculino , Femenino , Anciano , Desfibriladores Implantables/efectos adversos , Estudios Retrospectivos , Marcapaso Artificial/efectos adversos , Persona de Mediana Edad , Falla de Equipo/estadística & datos numéricosRESUMEN
Pleural effusions are categorized as transudative or exudative, with transudative effusions usually reflecting the sequala of a systemic etiology and exudative effusions usually resulting from a process localized to the pleura. Common causes of transudative pleural effusions include congestive heart failure, cirrhosis, and renal failure, whereas exudative effusions are typically due to infection, malignancy, or autoimmune disorders. This document summarizes appropriateness guidelines for imaging in four common clinical scenarios in patients with known or suspected pleural effusion or pleural disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.
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Medicina Basada en la Evidencia , Derrame Pleural , Sociedades Médicas , Humanos , Derrame Pleural/diagnóstico por imagen , Estados Unidos , Enfermedades Pleurales/diagnóstico por imagen , Diagnóstico por Imagen/métodos , Diagnóstico por Imagen/normas , Diagnóstico DiferencialRESUMEN
Despite the inclusion of multiple agents within the prostate cancer treatment landscape, new treatment options are needed to address the unmet need for patients with metastatic castration-resistant prostate cancer (mCRPC). Although prostate-specific membrane antigen is the only cell-surface target to yield clinical benefit in men with advanced prostate cancer, additional targets may further advance targeted immune, cytotoxic, radiopharmaceutical, and other tumor-directed therapies for these patients. Human kallikrein 2 (hK2) is a novel prostate-specific target with little to no expression in nonprostate tissues. This first-in-human phase 0 trial uses an 111In-radiolabeled anti-hK2 monoclonal antibody, [111In]-DOTA-h11B6, to credential hK2 as a potential target for prostate cancer treatment. Methods: Participants with progressive mCRPC received a single infusion of 2 mg of [111In]-DOTA-h11B6 (185 MBq of 111In), with or without 8 mg of unlabeled h11B6 to assess antibody mass effects. Sequential imaging and serial blood samples were collected to determine [111In]-DOTA-h11B6 biodistribution, dosimetry, serum radioactivity, and pharmacokinetics. Safety was assessed within a 2-wk follow-up period from the time of [111In]-DOTA-h11B6 administration. Results: Twenty-two participants received [111In]-DOTA-h11B6 and are included in this analysis. Within 6-8 d of administration, [111In]-DOTA-h11B6 visibly accumulated in known mCRPC lesions, with limited uptake in other organs. Two treatment-emergent adverse events unrelated to treatment occurred, including tumor-related bleeding in 1 patient, which led to early study discontinuation. Serum clearance, biodistribution, and tumor targeting were independent of total antibody mass (2 or 10 mg). Conclusion: This first-in-human study demonstrates that tumor-associated hK2 can be identified and targeted using h11B6 as a platform as the h11B6 antibody selectively accumulated in mCRPC metastases with mass-independent clearance kinetics. These data support the feasibility of hK2 as a target for imaging and hK2-directed agents as potential therapies in patients with mCRPC.