Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 182
Filtrar
2.
Artigo em Inglês | MEDLINE | ID: mdl-33611735

RESUMO

To illustrate methods for assessing environmental exposures associated with lung cancer risk, we investigated anthropogenic based air pollutant data in a major metropolitan area using United States-Environmental Protection Agency (US-EPA) Toxic Release Inventory (TRI) (1987-2017), and PM2.5 (1998-2016) and NO2 (1996-2012) concentrations from NASA satellite data. We studied chemicals reported according to the following five exposome features: (1) International Agency for Research on Cancer (IARC) cancer grouping; (2) priority EPA polycyclic aromatic hydrocarbons (PAHs); (3) component of diesel exhaust; (4) status as a volatile organic compound (VOC); and (5) evidence of lung carcinogenesis. Published articles from PubChem were tallied for occurrences of 10 key characteristics of cancer-causing agents on those chemicals. Zone Improvement Plan (ZIP) codes with higher exposures were identified in two ways: (1) combined mean exposure from all features, and (2) hazard index derived through a multi-step multi-criteria decision analysis (MMCDA) process. VOCs, IARC Group 1 carcinogens consisted 82.3% and 11.5% of the reported TRI emissions, respectively. ZIP codes along major highways tended to have greater exposure. The MMCDA approach yielded hazard indices based on imputed toxicity, occurrence, and persistence for risk assessment. Despite many studies describing environmental exposures and lung cancer risk, this study develops a method to integrate these exposures into population-based exposure estimates that could be incorporated into future lung cancer screening trials and benefit public health surveillance of lung cancer incidence. Our methodology may be applied to probe other hazardous exposures for other cancers.

3.
Clin Lung Cancer ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33279417

RESUMO

BACKGROUND: Patients with metastatic non-small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited. PATIENTS AND METHODS: We conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation. RESULTS: Between Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P = .671), PFS (mPFS 9.2 vs. 7.7 months; P = .609), or OS (mOS 18.0 vs. 18.7 months; P = .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy. CONCLUSIONS: Patients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy.

4.
Pulm Circ ; 10(4): 2045894020966889, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33282194

RESUMO

Readmissions for pulmonary hypertension are poorly understood and understudied. We sought to determine national estimates and risk factors for 30-day readmission after pulmonary hypertension-related hospitalizations. We utilized the Healthcare Cost and Utilization Project Nationwide Readmission Database, which has weighted estimates of roughly 35 million discharges in the US. Adult patients with primary International Classification of Disease, Ninth Revision, Clinical Modification diagnosis codes of 416.0 and 416.8 for primary and secondary pulmonary hypertension with an index admission between 2012 and 2014 and any readmission within 30 days of the index event were identified. Predictors of 30-day readmission were identified using multivariable logistic regression with adjustment for covariates. Results showed that the national estimate for Primary Pulmonary Hypertension vs Secondary Pulmonary Hypertension-related index events between 2012 and 2014 with 30-day readmission was 247 vs 2550 corresponding to a national readmission risk estimate of 17% vs 18.3%, respectively. The presence of fluid and electrolyte disorders, renal failure, and alcohol abuse were associated with increased risk of readmission in Primary Pulmonary Hypertension, while factors associated with Secondary Pulmonary Hypertension readmissions included anemia, congestive heart failure, lung disease, fluid and electrolyte disorders, renal failure, diabetes, and liver disease. The median cost of Primary Pulmonary Hypertension admissions and readmissions were $46,132 (IQR: $25,384-$85,647) and $41,604.50 (IQR: $22,481.50-$84,420.50), respectively. The median costs of Secondary Pulmonary Hypertension admissions and readmissions were $34,893 (IQR: $19,670-$66,143) and $36,279 (IQR: $19,059-$74,679), respectively. In conclusion, approximately 19% of Primary Pulmonary Hypertension and Secondary Pulmonary Hypertension hospitalizations result in 30-day readmission, with significant costs accrued during the index hospitalization and readmission. With evolving clinical terminology and diagnostic codes, future study will need to better clarify underlying factors associated with readmissions amongst pulmonary hypertension sub-types, and identify methods and procedures to minimize readmission risk.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33352953

RESUMO

This study investigated the geographic variation and the clustering of lung cancer incidence rates in Philadelphia and the surrounding areas using addresses at the time of diagnosis. Using 60,844 cases from Pennsylvania Cancer Registry, we calculated and mapped the age-adjusted incidence rates for five Pennsylvania (PA) counties near Philadelphia between 1998-2007 and 2008-2017. We identified ZIP codes with significantly higher incidence rates than the state rates and examined their demographic and exposure characteristics. Further, we tested for spatial autocorrelation and identified spatial clusters using Moran's I statistic. Our results showed that approximately one in four ZIP codes had an incidence rate that was significantly higher than the PA state rate in each period studied. Clusters of higher incidences were detected in the southeastern part of PA bordering New Jersey. These areas tended to be more populated, of lower socioeconomic status, and closer to manufacturing facilities and major highways. Possibly driven by the community and environmental factors, the observed differences in disease incidence suggest the importance of including residential location in risk assessment tools for lung cancer.


Assuntos
Neoplasias Pulmonares , Análise por Conglomerados , Humanos , Incidência , Neoplasias Pulmonares/epidemiologia , New Jersey/epidemiologia , Philadelphia/epidemiologia
6.
Mol Ther ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33186691

RESUMO

MazF is an Escherichia coli-derived endoribonuclease that selectively cleaves ACA sequences of mRNA prevalent in HIV. We administered a single infusion of autologous CD4 T lymphocytes modified to express a Tat-dependent MazF transgene to 10 HIV-infected individuals (six remaining on antiretroviral therapy [ART]; four undergoing treatment interruption post-infusion) in order to provide a population of HIV-resistant immune cells. In participants who remained on ART, increases in CD4 and CD8 T cell counts of ~200 cells/mm3 each occurred within 2 weeks of infusion and persisted for at least 6 months. Modified cells were detectable for several months in the blood and trafficked to gastrointestinal lymph tissue. HIV-1 Tat introduced ex vivo to the modified CD4+ T cells induced MazF expression in both pre- and post-infusion samples, and MazF expression was detected in vivo post-viral-rebound during ATI. One participant experienced mild cytokine release syndrome. In sum, this study of a single infusion of MazF-modified CD4 T lymphocytes demonstrated safety of these cells, distribution to lymph tissue and maintenance of Tat-inducible MazF endoribonuclease activity, as well as sustained elevation of blood CD4 and CD8 T cell counts. Future studies to assess effects on viremia and latent proviral reservoir are warranted.

7.
J Immunother Cancer ; 8(2)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33028693

RESUMO

BACKGROUND: Limited data exist on the role of alterations in HLA Class I antigen processing and presentation machinery in mediating response to immune checkpoint blockade (ICB). METHODS: This retrospective cohort study analyzed transcriptional profiles from pre-treatment tumor samples of 51 chemotherapy-refractory advanced non-small cell lung cancer (NSCLC) patients and two independent melanoma cohorts treated with ICB. An antigen processing machinery (APM) score was generated utilizing eight genes associated with APM (B2M, CALR, NLRC5, PSMB9, PSME1, PSME3, RFX5, and HSP90AB1). Associations were made for therapeutic response, progression-free survival (PFS) and overall survival (OS). RESULTS: In NSCLC, the APM score was significantly higher in responders compared with non-responders (p=0.0001). An APM score above the median value for the cohort was associated with improved PFS (HR 0.34 (0.18 to 0.64), p=0.001) and OS (HR 0.44 (0.23 to 0.83), p=0.006). The APM score was correlated with an inflammation score based on the established T-cell-inflamed resistance gene expression profile (Pearson's r=0.58, p<0.0001). However, the APM score better predicted response to ICB relative to the inflammation score with area under a receiving operating characteristics curve of 0.84 and 0.70 for PFS and OS, respectively. In a cohort of 14 high-risk resectable stage III/IV melanoma patients treated with neoadjuvant anti-PD1 ICB, a higher APM score was associated with improved disease-free survival (HR: 0.08 (0.01 to 0.50), p=0.0065). In an additional independent melanoma cohort of 27 metastatic patients treated with ICB, a higher APM score was associated with improved OS (HR 0.29 (0.09 to 0.89), p=0.044). CONCLUSION: Our data demonstrate that defects in antigen presentation may be an important feature in predicting outcomes to ICB in both lung cancer and melanoma.

8.
Int J Radiat Oncol Biol Phys ; 108(4): 856-863, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32668279

RESUMO

PURPOSE: Black physicians remain disproportionately underrepresented in certain medical specialties, yet comprehensive assessments in radiation oncology (RO) are lacking. Our purpose was to report current and historical representation trends for Black physicians in the US RO workforce. METHODS AND MATERIALS: Public registries were used to assess significant differences in 2016 representation for US vs RO Black academic full-time faculty, residents, and applicants. Historical changes from 1970 to 2016 were reported descriptively. Linear regression was used to assess significant changes for Black residents and faculty from 1995 to 2016. RESULTS: In 2016, Black people represented 3.2% vs 1.5% (P < .001), 5.6% vs 3.2% (P = .005), and 6.5% vs 5.4% (P = .352) of US vs RO faculty, residents, and applicants, respectively. Although RO residents nearly doubled from 374 (1974) to 720 (2016), Black residents peaked at 31 in 1984 (5.9%; 31 of 522) and fell to 23 (3.2%; 23 of 720) in 2016 across 91 accredited programs; Black US graduate medical education trainees nearly doubled over the same period: 3506 (1984) to 6905 (2016). From 1995 to 2016, Black US resident representation significantly increased by 0.03%/y, but decreased significantly in RO by -0.20%/y before 2006 and did not change significantly thereafter. Over the same period, Black US faculty representation significantly increased by 0.02%/y, whereas Black RO faculty significantly increased by 0.07%/y before 2006, then decreased significantly by -0.16%/y thereafter. The number of Black RO faculty peaked at 37 in 2006 (3.1%; 37 of 1203) and was 27 (1.5%; 27 of 1769) in 2016, despite the nearly 1.5-fold increase in the number of both RO faculty and Black US faculty overall (4169 in 2006 and 6047 in 2016) during that period. CONCLUSIONS: Black physicians remain disproportionately underrepresented in RO despite an increasing available pipeline in the US physician workforce. Deliberate efforts to understand barriers to specialty training and inclusion, along with evidence-based targeted interventions to overcome them, are needed to ensure diversification of the RO physician workforce.

9.
Acad Psychiatry ; 44(5): 523-530, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32705570

RESUMO

OBJECTIVE: This study assessed the distribution of race, ethnicity, and sex within the US psychiatry physician workforce and trends from 1987 to 2016. METHODS: The authors used physician workforce data to assess differences in race, ethnicity, and sex among psychiatric practicing physicians, faculty, fellows, residents, residency applicants, and medical graduate cohorts. Binomial tests were used for comparison between individual cohorts and to US population statistics. A simple linear regression model was used to assess trends among psychiatric residents and faculty over years 1987-2016. RESULTS: Within psychiatry, historically underrepresented minorities in medicine (URMs) had less representation as residents (16.2%), faculty (8.7%), and practicing physicians (10.4%) compared with the US population (32.6%), Ps < 0.0001. Females were underrepresented as psychiatric practicing physicians (38.5%, P < .0001). There was greater URM representation among residents (16.2%) compared with that of Psychiatry faculty and practicing physicians (Ps < .0001). Racial/ethnic representation did not differ significantly compared with subspecialty fellows; however, the addiction subspecialty contained the least URM and female diversity. Historical trends indicated the proportion of female faculty (0.9%/yr) increased nearly 1.5 times faster than that of female trainees (0.6%/year). Conversely, the proportion of URM residents (0.26%/year) increased over 4 times faster than that of URM faculty (0.06%/year), with black faculty actually decreasing in proportion. CONCLUSIONS: Female and URM representation within the psychiatry physician workforce is significantly lower than US population demographics; however, trends indicate diminishing underrepresentation. While psychiatry residency remains more diverse than other specialties, specific trends identify poor minority representation among psychiatry faculty and fellows as areas needing attention.

11.
J Clin Oncol ; 38(25): 2862-2871, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298202

RESUMO

PURPOSE: To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS: Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS: At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups (P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not (P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR (P < .0001). Toxicity was comparable in both dose groups. CONCLUSION: In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.

12.
Reprod Toxicol ; 94: 75-83, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32335222

RESUMO

Many reports describe an association between preconceptional paternal exposure to environmental chemicals, including the persistent organic pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with an increased number of female offspring. We chronically treated wild-type C57BL/6 male mice with TCDD to investigate a role for the aryl hydrocarbon receptor (AHR) transcription factor. These mice had a 14 % lower male:female sex ratio than control mice, which was not observed in TCDD-treated Ahr knock out mice. AHR target genes Cyp1a1 and Ahrr were upregulated in the liver and testis of WT mice and Ahr expression was higher in the epididymis (2-fold) and liver (18-fold) than in whole testis tissue. The AHR protein was localized to round spermatids, elongating spermatids, and Leydig cells in the testis of WT mice. These studies demonstrate AHR involvement in the sex ratio distortion of TCDD-exposed males and the need for evaluating the molecular and genetic mechanism of this process.

13.
Environ Sci Pollut Res Int ; 27(13): 14883-14902, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32060827

RESUMO

Road dust was investigated within Philadelphia, a major United States city with a long history of industrial activities, in order to determine pollution levels. Almost all of the investigated minor elements were enriched relative to the continental crust. Furthermore, mean concentrations of Cr, Co, Cu, and Pb were high compared with those reported in cities in other countries. Lead pollution should be investigated further in Philadelphia, where 8 of the 30 sample sites, including those heavily trafficked by civilians, were at or above the EPA's child safety threshold for Pb in bare soil. High Spearman correlations between Zn and Cu, Zn and Cr, Cu and Cr, and Sn and V, as well as factor analysis of minor elements suggests that the primary sources of these elements were anthropogenic. Potential sources included the breakdown of alloys, non-exhaust traffic emissions, paint, smelting, and industry. We found that higher organic content in road dust may be related to higher traffic densities, which could be due to tire-wear particles. Additionally, higher mean concentrations of Fe, Cr, Cu, and Zn were found at sites with elevated traffic densities. Land use impacted some of the elements not influenced by traffic density, including Co, Sn, and Pb. Bulk mineral content was similar across different land uses and traffic densities and, thus, did not appear to be influenced by these factors. Our research emphasized the complexity of road dust and utilized a more comprehensive approach than many previous studies. This study established fundamental groundwork for future risk assessment in Philadelphia, as it identified several key pollutants in the city. Overall, this assessment serves as an informative reference point for other formerly heavily industrialized cities in the USA and abroad.


Assuntos
Poeira/análise , Metais Pesados/análise , Criança , Cidades , Monitoramento Ambiental , Poluição Ambiental/análise , Humanos , Philadelphia , Gravidez , Medição de Risco , Estados Unidos
14.
Oncologist ; 25(2): e381-e385, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32043765

RESUMO

Management of melanoma has been revolutionized by the use of immune checkpoint inhibitors. Immune system changes associated with aging may affect the efficacy of immune-based therapies. Using the National Cancer Database, we evaluated the impact of age on the receipt and efficacy of modern immunotherapies in patients with metastatic melanoma. We identified 11,944 patients from 2011-2015, of whom 25% received immunotherapy. Older (≥60 years), compared with younger, patients were less likely to receive immunotherapy (odds ratio, 0.69; 95% confidence interval [CI], 0.61-0.78; p < .001). Immunotherapy was associated with a survival benefit in both younger and older patients (<60 years: hazard ratio [HR], 0.64; 95% CI, 0.57-0.72; p < .001; ≥60 years: HR, 0.55; 95% CI, 0.50-0.60; p < .001). Importantly, there was a statistically significant interaction between age and survival with immunotherapy, where a greater benefit was observed for older patients (pinteraction = 0.013). Further work studying the age-related response to immunotherapy is warranted.

15.
Science ; 367(6481)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32029687

RESUMO

CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRß (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.


Assuntos
Transferência Adotiva , Sistemas CRISPR-Cas , Edição de Genes , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/imunologia , Linfócitos T/transplante , Idoso , Proteína 9 Associada à CRISPR , Engenharia Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Transgenes
16.
Biochim Biophys Acta Gen Subj ; 1864(7): 129548, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32035161

RESUMO

BACKGROUND: Radiation exposure of tissues is associated with inflammatory cell influx. Myeloperoxidase (MPO) is an enzyme expressed in granulocytes, such as neutrophils (PMN) and macrophages, responsible for active chlorine species (ACS) generation. The present study aimed to: 1) determine whether exposure to γ-irradiation induces MPO-dependent ACS generation in murine PMN; 2) elucidate the mechanism of radiation-induced ACS generation; and 3) evaluate the effect of the synthetic lignan LGM2605, known for ACS scavenging properties. METHODS: MPO-dependent ACS generation was determined by using hypochlorite-specific 3'-(p-aminophenyl) fluorescein (APF) and a highly potent MPO inhibitor, 4-aminobenzoic acid hydrazide (ABAH), and confirmed in PMN derived from MPO-/- mice. Radiation-induced MPO activation was determined by EPR spectroscopy and computational analysis identified tyrosine, serine, and threonine residues near MPO's active site. RESULTS: γ-radiation increased MPO-dependent ACS generation dose-dependently in human MPO and in wild-type murine PMN, but not in PMN from MPO-/- mice. LGM2605 decreased radiation-induced, MPO-dependent ACS. Protein tyrosine phosphatase (PTP) and protein serine/threonine phosphatase (PSTP) inhibitors decreased the radiation-induced increase in ACS. Peroxidase cycle results demonstrate that tyrosine phosphorylation blocks MPO Compound I formation by preventing catalysis on H2O2 in the active site of MPO. EPR data demonstrate that γ-radiation increased tyrosyl radical species formation in a dose-dependent manner. CONCLUSIONS: We demonstrate that γ-radiation induces MPO-dependent generation of ACS, which is dependent, at least in part, by protein tyrosine and Ser/Thr dephosphorylation and is reduced by LGM2605. This study identified for the first time a novel protein dephosphorylation-dependent mechanism of radiation-induced MPO activation.

17.
Clin Cancer Res ; 26(10): 2354-2361, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32102950

RESUMO

PURPOSE: The role of plasma-based tumor mutation burden (pTMB) in predicting response to pembrolizumab-based first-line standard-of-care therapy for metastatic non-small cell lung cancer (mNSCLC) has not been explored. EXPERIMENTAL DESIGN: A 500-gene next-generation sequencing panel was used to assess pTMB. Sixty-six patients with newly diagnosed mNSCLC starting first-line pembrolizumab-based therapy, either alone or in combination with chemotherapy, were enrolled (Clinicaltrial.gov identifier: NCT03047616). Response was assessed using RECIST 1.1. Associations were made for patient characteristics, 6-month durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 66 patients, 52 (78.8%) were pTMB-evaluable. Median pTMB was 16.8 mutations per megabase (mut/Mb; range, 1.9-52.5) and was significantly higher for patients achieving DCB compared with no durable benefit (21.3 mut/Mb vs. 12.4 mut/Mb, P = 0.003). For patients with pTMB ≥ 16 mut/Mb, median PFS was 14.1 versus 4.7 months for patients with pTMB < 16 mut/Mb [HR, 0.30 (0.16-0.60); P < 0.001]. Median OS for patients with pTMB ≥ 16 was not reached versus 8.8 months for patients with pTMB < 16 mut/Mb [HR, 0.48 (0.22-1.03); P = 0.061]. Mutations in ERBB2 exon 20, STK11, KEAP1, or PTEN were more common in patients with no DCB. A combination of pTMB ≥ 16 and absence of negative predictor mutations was associated with PFS [HR, 0.24 (0.11-0.49); P < 0.001] and OS [HR, 0.31 (0.13-0.74); P = 0.009]. CONCLUSIONS: pTMB ≥ 16 mut/Mb is associated with improved PFS after first-line standard-of-care pembrolizumab-based therapy in mNSCLC. STK11/KEAP1/PTEN and ERBB2 mutations may help identify pTMB-high patients unlikely to respond. These results should be validated in larger prospective studies.

18.
Pediatr Blood Cancer ; 67(2): e28051, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31724814

RESUMO

PURPOSE: Family psychosocial risk in pediatric oncology can be assessed using the Psychosocial Assessment Tool (PAT), a brief parent report screener based on the Pediatric Psychosocial Preventative Health Model (PPPHM; universal, targeted, and clinical). However, little is known about risk over the course of treatment and its association with medical and psychosocial healthcare utilization. METHODS: Primary caregivers of children with cancer participated in this prospective multisite investigation, completing the PAT at diagnosis (T1; n = 396) and 6 months later (T2; n = 304). Healthcare utilization data were extracted from electronic health records. RESULTS: The distribution of PPPHM risk levels at T1 and T2 was highly consistent for the samples. Two-thirds of families remained at the same level of risk, 18% decreased and 16% increased risk level. Risk was not related to sociodemographic or treatment variables. The PAT risk score correlated with psychosocial contacts over the 6-month period. CONCLUSIONS: Although the majority of families reported universal (low) risk on the PAT and were stable in their risk level over 6 months, reassessing risk is helpful in identifying those families who report higher level of risk during treatment than at diagnosis. PAT scores were related to psychosocial services that are provided to most but not all families and could be tailored more specifically to match risk and delivery of evidence-based care.


Assuntos
Cuidadores/psicologia , Família/psicologia , Neoplasias/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Psicometria/estatística & dados numéricos , Estresse Psicológico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Prospectivos , Inquéritos e Questionários , Adulto Jovem
19.
Lung Cancer ; 139: 1-8, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683225

RESUMO

OBJECTIVES: Treatment of non-small cell lung cancer (NSCLC) with immune checkpoint blockade (ICB) has resulted in striking clinical responses, but only in a subset of patients. The goal of this study was to evaluate transcriptional signatures previously reported in the literature in an independent cohort of NSCLC patients receiving ICB. MATERIALS AND METHODS: This retrospective study analyzed transcriptional profiles from pre-treatment tumor samples of 52 chemotherapy-refractory advanced NSCLC patients treated with anti-PD1/PD-L1 therapy. Gene signatures based on published reports were created and examined for their association with response to therapy and progression-free and overall survival (PFS, OS). RESULTS: Two signatures predicting response and outcomes were identified. One reflected the degree of immune infiltration and upregulation of interferon-gamma-induced genes. A second reflected the EMT status. Compared to those not responding to therapy, patients whose tumors responded to ICB had higher scores in an inflammatory gene signature (6.0 ±â€¯2.9 vs -5.5 ±â€¯3.4, p = 0.014) or a more epithelial phenotype (-1.7 ±â€¯1.0 vs 2.1 ±â€¯1.2, p = 0.016). Both signatures demonstrated a satisfactory predictive accuracy for response: AUC of 0.69 (95% CI: 0.54, 0.84) for the inflammatory and 0.70 (95% CI: 0.55, 0.85) for EMT signatures, respectively. A weighted score combining EMT and inflammatory signatures showed increased predictive value with AUC of 0.92 (95% CI: 0.85, 0.99). Kaplan-Meier curves for patients above and below the median combined score showed a significant separation for PFS and OS (all p < 0.01, log rank test). CONCLUSIONS: The EMT/Inflammation signature score may be useful in directing checkpoint inhibitor therapy in lung cancer and suggests that reversal of EMT might augment efficacy of ICB.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...