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To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRß chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.
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Carcinoma de Pulmón de Células no Pequeñas/inmunología , Mapeo Epitopo/métodos , Epítopos de Linfocito T/genética , Neoplasias Pulmonares/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Linfocitos T/inmunología , Algoritmos , Presentación de Antígeno , Antígenos de Neoplasias/metabolismo , Células Cultivadas , Reacciones Cruzadas , Epítopos de Linfocito T/metabolismo , Antígeno HLA-A2/metabolismo , Humanos , Unión Proteica , Especificidad del Receptor de Antígeno de Linfocitos TRESUMEN
BACKGROUND: Bias pervades every aspect of healthcare including admissions, perpetuating the lack of diversity in the healthcare workforce. Admissions interviews may be a time when applicants to health profession education programs experience discrimination. METHODS: Between January and June 2021 we invited US and Canadian applicants to health profession education programs to complete a survey including the Everyday Discrimination Scale, adapted to ascertain experiences of discrimination during admissions interviews. We used chi-square tests and multivariable logistic regression to determine associations between identity factors and positive responses. RESULTS: Of 1115 respondents, 281 (25.2%) reported discrimination in the interview process. Individuals with lower socioeconomic status (OR: 1.78, 95% CI [1.26, 2.52], p = 0.001) and non-native English speakers (OR: 1.76, 95% CI [1.08, 2.87], p = 0.02) were significantly more likely to experience discrimination. Half of those experiencing discrimination (139, or 49.6%) did nothing in response, though 44 (15.7%) reported the incident anonymously and 10 (3.6%) reported directly to the institution where it happened. CONCLUSIONS: Reports of discrimination are common among HPE applicants. Reforms at the interviewer- (e.g. avoiding questions about family planning) and institution-level (e.g. presenting institutional efforts to promote health equity) are needed to decrease the incidence and mitigate the impact of such events.
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Promoción de la Salud , Internado y Residencia , Humanos , Canadá , Escuelas para Profesionales de Salud , Empleos en SaludRESUMEN
Cholesterol esters are a key ingredient of foamy cells in atherosclerotic lesions; their formation is catalyzed by two enzymes: acyl-CoA:cholesterol acyltransferases (ACATs; also called sterol O-acyltransferases, or SOATs) ACAT1 and ACAT2. ACAT1 is present in all body cells and is the major isoenzyme in macrophages. Whether blocking ACAT1 benefits atherosclerosis has been under debate for more than a decade. Previously, our laboratory developed a myeloid-specific Acat1 knockout (KO) mouse (Acat1-M/-M), devoid of ACAT1 only in macrophages, microglia, and neutrophils. In previous work using the ApoE KO (ApoE-/-) mouse model for early lesions, Acat1-M/-M significantly reduced lesion macrophage content and suppressed atherosclerosis progression. In advanced lesions, cholesterol crystals become a prominent feature. Here we evaluated the effects of Acat1-M/-M in the ApoE KO mouse model for more advanced lesions and found that mice lacking myeloid Acat1 had significantly reduced lesion cholesterol crystal contents. Acat1-M/-M also significantly reduced lesion size and macrophage content without increasing apoptotic cell death. Cell culture studies showed that inhibiting ACAT1 in macrophages caused cells to produce less proinflammatory responses upon cholesterol loading by acetyl low-density lipoprotein. In advanced lesions, Acat1-M/-M reduced but did not eliminate foamy cells. In advanced plaques isolated from ApoE-/- mice, immunostainings showed that both ACAT1 and ACAT2 are present. In cell culture, both enzymes are present in macrophages and smooth muscle cells and contribute to cholesterol ester biosynthesis. Overall, our results support the notion that targeting ACAT1 or targeting both ACAT1 and ACAT2 in macrophages is a novel strategy to treat advanced lesions.
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Aterosclerosis/enzimología , Aterosclerosis/prevención & control , Inflamación/patología , Macrófagos Peritoneales/enzimología , Células Mieloides/enzimología , Esterol O-Aciltransferasa/metabolismo , Animales , Apolipoproteínas E , Apoptosis , Aterosclerosis/patología , Colesterol/metabolismo , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Eliminación de Gen , Silenciador del Gen , Hidroxicolesteroles/metabolismo , Lipoproteínas LDL/metabolismo , Ratones , Ratones Noqueados , Músculo Liso Vascular/patología , Células Mieloides/patología , Miocitos del Músculo Liso/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7RESUMEN
Background Primary tumor maximum standardized uptake value is a prognostic marker for non-small cell lung cancer. In the setting of malignancy, bone marrow activity from fluorine 18-fluorodeoxyglucose (FDG) PET may be informative for clinical risk stratification. Purpose To determine whether integrating FDG PET radiomic features of the primary tumor, tumor penumbra, and bone marrow identifies lung cancer disease-free survival more accurately than clinical features alone. Materials and Methods Patients were retrospectively analyzed from two distinct cohorts collected between 2008 and 2016. Each tumor, its surrounding penumbra, and bone marrow from the L3-L5 vertebral bodies was contoured on pretreatment FDG PET/CT images. There were 156 bone marrow and 512 tumor and penumbra radiomic features computed from the PET series. Randomized sparse Cox regression by least absolute shrinkage and selection operator identified features that predicted disease-free survival in the training cohort. Cox proportional hazards models were built and locked in the training cohort, then evaluated in an independent cohort for temporal validation. Results There were 227 patients analyzed; 136 for training (mean age, 69 years ± 9 [standard deviation]; 101 men) and 91 for temporal validation (mean age, 72 years ± 10; 91 men). The top clinical model included stage; adding tumor region features alone improved outcome prediction (log likelihood, -158 vs -152; P = .007). Adding bone marrow features continued to improve performance (log likelihood, -158 vs -145; P = .001). The top model integrated stage, two bone marrow texture features, one tumor with penumbra texture feature, and two penumbra texture features (concordance, 0.78; 95% confidence interval: 0.70, 0.85; P < .001). This fully integrated model was a predictor of poor outcome in the independent cohort (concordance, 0.72; 95% confidence interval: 0.64, 0.80; P < .001) and a binary score stratified patients into high and low risk of poor outcome (P < .001). Conclusion A model that includes pretreatment fluorine 18-fluorodeoxyglucose PET texture features from the primary tumor, tumor penumbra, and bone marrow predicts disease-free survival of patients with non-small cell lung cancer more accurately than clinical features alone. © RSNA, 2019 Online supplemental material is available for this article.
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Médula Ósea/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Anciano , Médula Ósea/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Neoplasias Pulmonares/patología , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Radiofármacos , Estudios Retrospectivos , Medición de RiesgoRESUMEN
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an aggressive, often fatal soft tissue sarcoma that lacks an optimal salvage regimen. We retrospectively reviewed data from 29 pretreated DSRCT patients who received pazopanib at MD Anderson Cancer Center after failure of standard chemotherapies. SUBJECTS, MATERIALS, AND METHODS: Medical records of patients treated from January 2012 to December 2016 were reviewed and regression analyses were performed. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and differences in survival were assessed by a log-rank test. A landmark statistical analysis was used to assess OS at a predefined 12-week time point following pazopanib initiation. RESULTS: The mean age at pazopanib treatment was 27.5 years (range, 6.3-50.1 years). According to RECIST 1.1 criteria, 16 patients (55%) had stable disease, 1 patient (3%) had partial response, 1 patient (3%) had complete response, and 11 patients (38%) had progressive disease. Estimated median PFS was 5.63 months (95% confidence interval [CI]: 3.23-7.47). Median OS was 15.7 months (95% CI: 10.3-32.4). As of December 2016, 11 patients (38%) were still alive, with a median follow-up time of 16.8 (range 3.8-30.1) months. Doses between 400 and 800 mg were included. Pazopanib was well tolerated and 23 (79%) of the patients continued it until progression or death, 4 discontinued because of side effects, and 2 were still on pazopanib at the time of data analysis. CONCLUSION: In the largest study conducted to date in DSRCT, pazopanib was well tolerated and clinically active in heavily pretreated patients who otherwise lack good treatment options. IMPLICATIONS FOR PRACTICE: Desmoplastic small round cell tumor (DSRCT) is a rare, extremely aggressive soft tissue sarcoma subtype that most commonly occurs in adolescent and young adult males. No DSRCT-specific therapies exist, and for lack of a better treatment approach, current therapies have relied upon U.S. Food and Drug Administration-approved drugs like pazopanib that exhibit clinical activity in other sarcoma subtypes. This article describes the largest experience to date using pazopanib as salvage treatment in heavily pretreated DSRCT patients. Pazopanib was well tolerated and clinically active, surpassing predefined metrics proposed by the European Organization for Research and Treatment of Cancer indicative of "active" sarcoma drugs (5.63 months progression-free survival [PSF], with 62% of the study population achieving progression-free survival at 12 weeks).
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Antineoplásicos/uso terapéutico , Tumor Desmoplásico de Células Pequeñas Redondas/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adolescente , Adulto , Antineoplásicos/efectos adversos , Niño , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Femenino , Humanos , Indazoles , Masculino , Persona de Mediana Edad , Pirimidinas/efectos adversos , Estudios Retrospectivos , Terapia Recuperativa , Sulfonamidas/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To explore how gender and low-income status independently influence general health care access in patients with hearing loss. STUDY DESIGN: Cross-sectional study. SETTING: National database. METHODS: Patients with a diagnosis of sensorineural hearing loss from the National Institutes of Health All of Us database were included. Data entered from May 2018 to November 2022 was analyzed. Patient demographics such as age, gender, educational level, and insurance status were assessed. Multivariate logistic regressions were performed for statistical evaluation. RESULTS: A subset of 8875 patients (48.3% male, mean age 69) were evaluated. After multivariate analysis, female participants were more likely than male participants to report difficulty affording prescribed medications (odds ratio [OR]: 1.7, p < .0005) and specialists (OR: 1.4, p < 0.005). Female patients were also more likely to delay care due to elder care responsibilities (OR: 2.6, p < .0005), employment obligations (OR: 1.7, p < .0005), and feelings of apprehension in seeing a provider (OR: 1.7, p < .0005). Finally, female participants reported feeling less likely to be involved in their own medical care compared to males (OR: 1.2, p < .005). Low-income (<$25,000) participants reported less likely to feel respected (OR: 3.2, p < .0005) and delivered understandable health information (OR: 2.3, p < .0005) by providers compared to participants of higher income. CONCLUSION: This work suggests that patients with hearing loss, female gender, and lower socioeconomic status independently introduce barriers to health care access and utilization. These factors should be considered in efforts to promote equity in the care of patients with hearing loss.
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Sordera , Pérdida Auditiva , Salud Poblacional , Humanos , Masculino , Femenino , Anciano , Estudios Transversales , Pérdida Auditiva/terapia , Accesibilidad a los Servicios de Salud , Factores SocioeconómicosRESUMEN
OBJECTIVE: The survival rate of patients with trisomy 13 and trisomy 18 has increased dramatically over the past two decades. We sought to comprehensively describe the otolaryngologic clinical characteristics and procedures required for these patients at our institution. METHODS: We performed algorithmic identification of patients with a diagnosis of trisomy 13 and trisomy 18 for whom the otolaryngology service provided inpatient or outpatient care at our institution between the dates of February 1997 and March 2021. RESULTS: Of the 47 patients studied, 18 patients had a diagnosis of trisomy 13, and 29 had a diagnosis of trisomy 18. Complete trisomy was present in 44% (8/18) of trisomy 13 patients and 55% (16/29) of trisomy 18 patients. 81% of patients were living at the time of the study. About 94% (44/47) of patients required consultation with another specialty in addition to Otolaryngology. Overall, the most common diagnoses among this cohort were gastroesophageal reflux disease (47%), dysphagia (40%), otitis media (38%), and obstructive sleep apnea (34%). Nearly three-quarters (74%) of patients studied required an otolaryngologic procedure. The most common surgical procedure was tonsillectomy and/or adenoidectomy. Patients with trisomy 18 were significantly more likely to have external auditory canal stenosis and obstructive sleep apnea whereas patients with trisomy 13 were more likely to have cleft lip and palate. CONCLUSIONS: Patients with a diagnosis of trisomy 13 or 18 often require multidisciplinary management and the range of required care spans the breadth of otolaryngology. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1501-1506, 2023.
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Labio Leporino , Fisura del Paladar , Otolaringología , Apnea Obstructiva del Sueño , Tonsilectomía , Niño , Humanos , Síndrome de la Trisomía 13/complicaciones , Síndrome de la Trisomía 13/diagnóstico , Síndrome de la Trisomía 13/cirugía , Síndrome de la Trisomía 18/complicaciones , Síndrome de la Trisomía 18/diagnóstico , Síndrome de la Trisomía 18/cirugía , Labio Leporino/cirugía , Fisura del Paladar/cirugía , Tonsilectomía/métodos , Adenoidectomía/métodos , Apnea Obstructiva del Sueño/cirugía , Estudios RetrospectivosRESUMEN
Malignant pleural effusions (MPEs) can be utilized as liquid biopsy for phenotyping malignant cells and for precision immunotherapy, yet MPEs are inadequately studied at the single-cell proteomic level. Here we leverage mass cytometry to interrogate immune and epithelial cellular profiles of primary tumors and pleural effusions (PEs) from early and late-stage non-small cell lung cancer (NSCLC) patients, with the goal of assessing epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in patient specimens. By using the EMT-MET reference map PHENOSTAMP, we observe a variety of EMT states in cytokeratin positive (CK+) cells, and report for the first time MET-enriched CK+ cells in MPEs. We show that these states may be relevant to disease stage and therapy response. Furthermore, we found that the fraction of CD33+ myeloid cells in PEs was positively correlated to the fraction of CK+ cells. Longitudinal analysis of MPEs drawn 2 months apart from a patient undergoing therapy, revealed that CK+ cells acquired heterogeneous EMT features during treatment. We present this work as a feasibility study that justifies deeper characterization of EMT and MET states in malignant cells found in PEs as a promising clinical platform to better evaluate disease progression and treatment response at a personalized level.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Derrame Pleural Maligno , Derrame Pleural , Humanos , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteómica , Transición Epitelial-Mesenquimal/fisiología , Derrame Pleural Maligno/tratamiento farmacológico , Biopsia LíquidaRESUMEN
We sought to develop and evaluate a personalized multimedia education (ME) tool for preoperative patient education to improve patient health knowledge, quality of life and satisfaction with care in thoracic surgery. The ME tool was developed and deployed in outpatient clinic during preoperative teaching for patients undergoing surgical resection for lung cancer for quality improvement. Patients were given an electronic survey prior to preoperative teaching and at initial postoperative visit to assess teaching effectiveness and care satisfaction. Sequential patients received either standard preoperative teaching or teaching using the ME tool. Pre- and postoperative survey responses were compared using independent sample paired t test and multivariable linear regression modeling for adjustment. The final ME tool was an iPad application that incorporated real-time annotations of 3-dimensional, interactive anatomic diagrams. The tool featured video tours of operations, and radiology image import for annotation by the surgeon. Forty-eight patients were included in this pilot study (standard education nâ¯=â¯26; ME, nâ¯=â¯22). ME patients had significantly higher satisfaction scores compared to SE patients with respect to length of education materials, clarity of content, supportiveness of content and willingness to recommend materials to others. There was no difference in length of clinic visit between groups. Both patient and provider input can be used to create an innovative electronic preoperative educational tool that prepares and empowers patients in shared decision-making before surgery. Improvements in health literacy and self-efficacy may be more difficult to achieve but remain important as multimedia teaching tools are further developed.
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Neoplasias Pulmonares , Multimedia , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Proyectos Piloto , Calidad de Vida , Resultado del TratamientoRESUMEN
Background: Both primary lung adenocarcinoma and benign processes can have a ground-glass opacity (GGO) appearance on imaging. This study evaluated the incidence of and risk factors for malignancy in a diverse cohort of patients who underwent resection of a GGO suspicious for lung cancer. Methods: All patients who underwent resection of a pulmonary nodule with a GGO component and suspected to be primary lung cancer at a single institution from 2001-2017 were retrospectively reviewed. Risk factors for malignancy were evaluated using multivariable logistic regression analysis that included nodule size, age, sex, and race as potential predictors. Results: The incidence of pulmonary adenocarcinoma in the 243 patients who met inclusion criteria was 86% (n=208). The most common pathologic findings in 35 patients with a benign pathology was granulomatous inflammation (n=14, 40%). Risk factors for adenocarcinoma in multivariable logistic regression were age [odds ratio (OR) 1.06, P=0.003], GGO size (OR 2.76, P<0.001), female sex (OR 4.47, P=0.002), and Asian race (OR 8.35, P=0.002). In this cohort, adenocarcinoma was found in 100% (44/44) of Asian females, 86% (25/29) of Asian males, 84% (98/117) of non-Asian females, and 77% (41/53) of non-Asian males. Conclusions: The likelihood of adenocarcinoma in lung nodules with a ground-glass component is influenced by sex and race. Asian females with a GGO have a much higher likelihood of having adenocarcinoma than men and non-Asians. This data can be used when deciding whether to pursue nodule resection or surveillance in a patient with a GGO.
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The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that cross-talk between tumor and stromal cells within the tumor microenvironment results in activation of key biological pathways depending on their position in the tumor (edge vs. core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts from the tumor core, established from human lung adenocarcinomas. A multiomics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize cross-talk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential posttranslational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 (CDK4) and phosphorylated retinoblastoma protein axis in the stroma and indirectly modulates proinvasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor-stroma cross-talk and a potential avenue to improve the anticancer efficacy of CDK4 inhibitors. SIGNIFICANCE: A multiomics analysis of spatially distinct fibroblasts establishes the importance of the stromal O-glycoproteome in tumor-stroma interactions at the leading edge and provides potential strategies to improve cancer treatment. See related commentary by De Wever, p. 537.
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Fibroblastos Asociados al Cáncer/metabolismo , Quinasa 4 Dependiente de la Ciclina/genética , Genómica/métodos , Neoplasias/genética , Proteómica/métodos , Proteína de Retinoblastoma/genética , Células del Estroma/metabolismo , Células A549 , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Glicosilación , Humanos , Invasividad Neoplásica , Neoplasias/metabolismo , Neoplasias/patología , Fosforilación , Proteína de Retinoblastoma/metabolismo , Transducción de Señal/genética , Transcriptoma/genéticaRESUMEN
Genomic profiling of bronchoalveolar lavage (BAL) samples may be useful for tumor profiling and diagnosis in the clinic. Here, we compared tumor-derived mutations detected in BAL samples from subjects with non-small cell lung cancer (NSCLC) to those detected in matched plasma samples. Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) was used to genotype DNA purified from BAL, plasma, and tumor samples from patients with NSCLC. The characteristics of cell-free DNA (cfDNA) isolated from BAL fluid were first characterized to optimize the technical approach. Somatic mutations identified in tumor were then compared with those identified in BAL and plasma, and the potential of BAL cfDNA analysis to distinguish lung cancer patients from risk-matched controls was explored. In total, 200 biofluid and tumor samples from 38 cases and 21 controls undergoing BAL for lung cancer evaluation were profiled. More tumor variants were identified in BAL cfDNA than plasma cfDNA in all stages (P < 0.001) and in stage I to II disease only. Four of 21 controls harbored low levels of cancer-associated driver mutations in BAL cfDNA [mean variant allele frequency (VAF) = 0.5%], suggesting the presence of somatic mutations in nonmalignant airway cells. Finally, using a Random Forest model with leave-one-out cross-validation, an exploratory BAL genomic classifier identified lung cancer with 69% sensitivity and 100% specificity in this cohort and detected more cancers than BAL cytology. Detecting tumor-derived mutations by targeted sequencing of BAL cfDNA is technically feasible and appears to be more sensitive than plasma profiling. Further studies are required to define optimal diagnostic applications and clinical utility. SIGNIFICANCE: Hybrid-capture, targeted deep sequencing of lung cancer mutational burden in cell-free BAL fluid identifies more tumor-derived mutations with increased allele frequencies compared with plasma cell-free DNA. See related commentary by Rolfo et al., p. 2826.
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Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Biomarcadores de Tumor/genética , Líquido del Lavado Bronquioalveolar , ADN de Neoplasias/genética , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/patología , MutaciónRESUMEN
BACKGROUND: Well-differentiated lung neuroendocrine tumors (NETs), also known as typical and atypical carcinoids, have a decreased incidence of lymph node (LN) and distant metastases compared to poorly differentiated lung NETs. We aimed to (i) examine the clinicopathologic features associated with LN involvement in lung carcinoids and (ii) describe the postoperative management of patients with LN metastases. METHODS: We identified 98 patients who underwent surgical resection and lymph node sampling at Stanford University. We assessed the following and used AJCC staging version 7: clinical features (age, sex, race, prior malignancy, smoking history), tumor features (functional syndrome, histology, size, location, laterality), pre-operative workup performed (imaging and suspicion of LN metastases), surgery (nodes and stations sampled, margin status, surgical approach, and type of surgery), and recurrence outcome. These features were examined between patients with and without LN metastases using the Wilcoxon test (continuous variables) and Fisher's exact test (categorical variables). RESULTS: 87 patients (89%) had typical carcinoid and 11 patients (11%) had atypical carcinoid. 17 patients were found to have at least one positive lymph node, with 11 having N1 disease and 6 having N2 disease. In the univariable analysis, patients with lymph node disease were more likely to have recurrence of lung carcinoid (29% vs. 6%, p=0.01). In the multivariable logistic regression, there was a trend towards performance of preoperative SSTR imaging and lymph node involvement (OR = 3.06, p=0.07). No patients received adjuvant therapy. CONCLUSION: We found a trend for the performance of SSTR imaging and association of lymph node metastases in both univariable and multivariable analysis. A large proportion (41%) of patients with lymph node positive disease had < 2 cm tumors. This suggests the potential importance of incorporating SSTR imaging into routine practice and not restricting the use of this staging modality in patients with small tumors.
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Tumor Carcinoide , Neoplasias Pulmonares , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/patología , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Ganglios Linfáticos/patología , Metástasis Linfática , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Extended thymectomy has been proven to improve the course of myasthenia gravis. Retrospective studies demonstrate that several techniques for thymectomy achieve overlapping remission rates. We therefore compared perioperative outcomes and costs among 3 approaches to thymectomy: sternotomy, video and/or robot assisted, and transcervical. METHODS: To ensure similar study groups, we excluded patients with >4 cm or invasive tumors and those who underwent less than an extended thymectomy or concurrent procedures. Hospital costs were collected and analyzed by blinded finance personnel. RESULTS: The final study group consisted of 25 transcervical, 23 video/robot-assisted, and 14 sternotomy subjects. There was a higher incidence of myasthenia gravis in the transcervical and sternotomy groups (P < 0.001) and of thymoma in the video/robot-assisted and sternotomy groups (P = .002). Mean modified Charlson comorbidity score was higher for sternotomy (2.7 ± 2.1, mean ± SD) than transcervical (1.00 ± 0.58; P < .001) and video/robot-assisted (1.13 ± 0.97; P = .001) procedures. There was no difference in complication rates between approaches (P = 0.828). The cost of transcervical thymectomy was 45% of the cost of sternotomy (P < .001), and was 58% of the cost of video/robot-assisted (P = .018) approaches; these differences remained highly significant on multivariate analysis. Transcervical thymectomy had a shorter mean length of stay (1.2 ± 0.5 days) than median sternotomy (4.4 ± 3.5; P < .001), and video/robot-assisted thymectomy (2.4 ± 0.95; P = .045) and "bed cost" were major contributors to the cost difference between the groups. CONCLUSIONS: Transcervical thymectomy, which provides overlapping myasthenia gravis remission rates versus more invasive approaches, is equally safe and far less costly than sternotomy and video/robot-assisted approaches.
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Análisis Costo-Beneficio , Miastenia Gravis/cirugía , Timectomía/economía , Timectomía/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cuello , Procedimientos Quirúrgicos Robotizados , Esternotomía , Resultado del Tratamiento , Cirugía Asistida por VideoRESUMEN
BACKGROUND: Asian and Caucasian patients with lung cancer have been compared in several database studies, with conflicting findings regarding survival. However, these studies did not include proportion of ground-glass opacity or mutational status in their analyses. Asian patients commonly develop sub-solid lung adenocarcinomas that harbor EGFR mutations, which have a better prognosis. We hypothesized that among patients undergoing surgery for sub-solid lung adenocarcinomas, Asian patients have better survival compared to Caucasian patients. METHODS: We identified Asian and Caucasian patients who underwent surgical resection for a sub-solid lung adenocarcinoma from 2002 to 2015 at our institution. Sub-solid was defined as ≥10% ground-glass opacity on preoperative CT scan or ≥10% lepidic component on surgical pathology. Time-to-event multivariable analysis was performed to determine which characteristics were associated with recurrence and survival. RESULTS: Two hundred twenty-four patients were included with median follow up 48 months. Asian patients were more likely to be never smokers (76.3% vs. 29.0%, P<0.01) and have an EGFR mutation (69.4% vs. 25.6% of those tested, P<0.01), while Caucasian patients were more likely to have a KRAS mutation (23.5% vs. 4.9% of those tested, P<0.01). There was a trend towards Asian patients having a higher proportion of ground-glass opacity (38.8% vs. 30.5%, P=0.11). Time-to-event multivariable analysis showed that higher proportion of ground-glass opacity was significantly associated with better recurrence-free survival (HR 0.76 per 20% increase, P=0.02). However, mutational status and race did not have a significant impact on recurrence-free or overall survival. CONCLUSIONS: Asian and Caucasian patients with sub-solid lung adenocarcinoma have different tumor biology, but recurrence-free and overall survival after surgical resection is similar.
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Elucidating the spectrum of epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in clinical samples promises insights on cancer progression and drug resistance. Using mass cytometry time-course analysis, we resolve lung cancer EMT states through TGFß-treatment and identify, through TGFß-withdrawal, a distinct MET state. We demonstrate significant differences between EMT and MET trajectories using a computational tool (TRACER) for reconstructing trajectories between cell states. In addition, we construct a lung cancer reference map of EMT and MET states referred to as the EMT-MET PHENOtypic STAte MaP (PHENOSTAMP). Using a neural net algorithm, we project clinical samples onto the EMT-MET PHENOSTAMP to characterize their phenotypic profile with single-cell resolution in terms of our in vitro EMT-MET analysis. In summary, we provide a framework to phenotypically characterize clinical samples in the context of in vitro EMT-MET findings which could help assess clinical relevance of EMT in cancer in future studies.
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Transición Epitelial-Mesenquimal/fisiología , Neoplasias Pulmonares/patología , Algoritmos , Línea Celular Tumoral , Biología Computacional , Citofotometría/métodos , Células Epiteliales/patología , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Fenotipo , Biología de Sistemas , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVE: To determine whether surgeon selection of instrumentation and other supplies during video-assisted thoracoscopic lobectomy (VATSL) can safely reduce intraoperative costs. METHODS: In this retrospective, cost-focused review of all video-assisted thoracoscopic surgery anatomic lung resections performed by 2 surgeons at a single institution between 2010 and 2014, we compared VATSL hospital costs and perioperative outcomes between the surgeons, as well as costs of VATSL compared with thoracotomy lobectomy (THORL). RESULTS: A total of 100 VATSLs were performed by surgeon A, and 70 were performed by surgeon B. The preoperative risk factors did not differ significantly between the 2 groups of surgeries. Mean VATSL total hospital costs per case were 24% percent greater for surgeon A compared with surgeon B (P = .0026). Intraoperative supply costs accounted for most of this cost difference and were 85% greater for surgeon A compared with surgeon B (P < .0001). The use of nonstapler supplies, including energy devices, sealants, and disposables, drove intraoperative costs, accounting for 55% of the difference in intraoperative supply costs between the surgeons. Operative time was 25% longer for surgeon A compared with surgeon B (P < .0001), but this accounted for only 11% of the difference in total cost. Surgeon A's overall VATSL costs per case were similar to those of THORLs (n = 100) performed over the same time period, whereas surgeon B's VATSL costs per case were 24% less than those of THORLs. On adjusted analysis, there was no difference in VATSL perioperative outcomes between the 2 surgeons. CONCLUSIONS: The costs of VATSL differ substantially among surgeons and are heavily influenced by the use of disposable equipment/devices. Surgeons can substantially reduce the costs of VATSL to far lower than those of THORL without compromising surgical outcomes through prudent use of costly instruments and technologies.
Asunto(s)
Costos de Hospital , Neoplasias Pulmonares/economía , Neoplasias Pulmonares/cirugía , Evaluación de Procesos y Resultados en Atención de Salud/economía , Neumonectomía/economía , Cirugía Torácica Asistida por Video/economía , Toracotomía/economía , Anciano , Ahorro de Costo , Análisis Costo-Beneficio , Equipos Desechables/economía , Equipo Reutilizado/economía , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tempo Operativo , Neumonectomía/instrumentación , Neumonectomía/métodos , Estudios Retrospectivos , Instrumentos Quirúrgicos/economía , Cirugía Torácica Asistida por Video/instrumentación , Cirugía Torácica Asistida por Video/métodos , Toracotomía/instrumentación , Toracotomía/métodos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare sarcoma tumor of adolescence and young adulthood, which harbors a recurrent chromosomal translocation between the Ewing's sarcoma gene (EWSR1) and the Wilms' tumor suppressor gene (WT1). Patients usually develop multiple abdominal tumors with liver and lymph node metastasis developing later. Survival is poor using a multimodal therapy that includes chemotherapy, radiation and surgical resection, new therapies are needed for better management of DSRCT. Triggering cell apoptosis is the scientific rationale of many cancer therapies. Here, we characterized for the first time the expression of pro-apoptotic receptors, tumor necrosis-related apoptosis-inducing ligand receptors (TRAILR1-4) within an established human DSRCT cell line and clinical samples. The molecular induction of TRAIL-mediated apoptosis using agonistic small molecule, ONC201 in vitro cell-based proliferation assay and in vivo novel orthotopic xenograft animal models of DSRCT, was able to inhibit cell proliferation that was associated with caspase activation, and tumor growth, indicating that a cell-based delivery of an apoptosis-inducing factor could be relevant therapeutic agent to control DSRCT.
Asunto(s)
Tumor Desmoplásico de Células Pequeñas Redondas/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Tumor Desmoplásico de Células Pequeñas Redondas/metabolismo , Humanos , Imidazoles , Masculino , Ratones , Piridinas , Pirimidinas , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Sarcoma/tratamiento farmacológico , Sarcoma/metabolismo , Proteínas WT1/genéticaRESUMEN
Medical image biomarkers of cancer promise improvements in patient care through advances in precision medicine. Compared to genomic biomarkers, image biomarkers provide the advantages of being non-invasive, and characterizing a heterogeneous tumor in its entirety, as opposed to limited tissue available via biopsy. We developed a unique radiogenomic dataset from a Non-Small Cell Lung Cancer (NSCLC) cohort of 211 subjects. The dataset comprises Computed Tomography (CT), Positron Emission Tomography (PET)/CT images, semantic annotations of the tumors as observed on the medical images using a controlled vocabulary, and segmentation maps of tumors in the CT scans. Imaging data are also paired with results of gene mutation analyses, gene expression microarrays and RNA sequencing data from samples of surgically excised tumor tissue, and clinical data, including survival outcomes. This dataset was created to facilitate the discovery of the underlying relationship between tumor molecular and medical image features, as well as the development and evaluation of prognostic medical image biomarkers.