Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 106
Filtrar
1.
ESMO Open ; 8(4): 101587, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37356358

RESUMO

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Consenso , Patologistas , Biomarcadores Tumorais , Reflexo
3.
Ann Oncol ; 34(4): 377-388, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36709038

RESUMO

BACKGROUND: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial. PATIENTS AND METHODS: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. RESULTS: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. CONCLUSION: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Estudos Retrospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/uso terapêutico , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
5.
Ann Oncol ; 33(5): 466-487, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35176458

RESUMO

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Consenso , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Oncologia
6.
ESMO Open ; 7(1): 100355, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34922299

RESUMO

BACKGROUND: Immunotherapy represents the standard of care in the first-line treatment of advanced non-small-cell lung cancer (NSCLC), either as monotherapy in high programmed death-ligand 1 (PD-L1)-positive tumors (≥50%) or in combination with platinum-based chemotherapy regardless of PD-L1 status. However, most pivotal clinical trials of immune checkpoint inhibitors (ICIs) did not include patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. Hence, a consensus is lacking on the safety and efficacy of ICIs in this specific subgroup of patients. MATERIALS AND METHODS: A virtual International Expert Panel took place in July 2021 with the aim of reviewing the available evidence on the use of ICIs in NSCLC patients with ECOG PS 2, both in clinical practice and in a research setting. RESULTS: All panelists expressed concern about the applicability of currently available PS scales to evaluate patients for ICI treatment. The panelists agreed that, though limited, the available data support the safety of single-agent immunotherapy in PS 2 NSCLC patients, whereas concern was raised on the safety of ICI combinations, mainly related to chemotherapy and/or anti-cytotoxic T-lymphocyte-associated antigen 4 toxicity. On the basis of reviewed data, ICI efficacy may be speculated in PS 2 NSCLC patients; however, PS 2 remains a negative prognostic category as compared to PS 0-1 in patients treated with ICI, as it is for chemotherapy. The panelists defined high, medium and low priorities in clinical research. High priority was attributed to the inclusion of PS 2 patients in prospective clinical trials and the specific evaluation of combined ICI treatments with attenuated chemotherapy doses. CONCLUSIONS: Based on the current evidence, the panelists outlined the major limitations affecting PS 2 patients with NSCLC and reached common considerations on the feasibility, safety and effectiveness of ICI monotherapy and ICI combinations in the first-line setting.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estudos Prospectivos
7.
ESMO Open ; 7(1): 100339, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34953404

RESUMO

The coronavirus disease-19 (COVID-19) pandemic promises to have lasting impacts on cancer clinical trials that could lead to faster patient access to new treatments. In this article, an international panel of oncology experts discusses the lasting impacts of the pandemic on oncology clinical trials and proposes solutions for clinical trial stakeholders, with the support of recent data on worldwide clinical trials collected by IQVIA. These lasting impacts and proposed solutions encompass three topic areas. Firstly, acceleration and implementation of new operational approaches to oncology trials with patient-centric, fully decentralized virtual approaches that include remote assessments via telemedicine and remote devices. Geographical differences in the uptake of remote technology, including telemedicine, are discussed in the article, focusing on the impact of the local adoption of new operational approaches. Secondly, innovative clinical trials. The pandemic has highlighted the need for new trial designs that accelerate research and limit risks and burden for patients while driving optimization of clinical trial objectives and endpoints, while testing is being minimized. Areas of considerations for clinical trial stakeholders are discussed in detail. In addition, the COVID-19 pandemic has exposed the underrepresentation of minority groups in clinical trials; the approach for oncology clinical trials to improve generalizability of efficacy and outcomes data is discussed. Thirdly, a new problem-focused collaborative framework between oncology trial stakeholders, including decision makers, to leverage and further accelerate the innovative approaches in clinical research developed during the COVID-19 pandemic. This could shorten timelines for patient access to new treatments by addressing the cultural and technological barriers to adopting new operational approaches and innovative clinical trials. The role of the different stakeholders is described, with the aim of making COVID-19 a catalyst for positive change in oncology clinical research and eventually in cancer care.


Assuntos
COVID-19 , Neoplasias , Telemedicina , Ensaios Clínicos como Assunto , Humanos , Neoplasias/epidemiologia , Neoplasias/terapia , Pandemias , SARS-CoV-2
8.
Ann Oncol ; 32(12): 1597-1607, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34487855

RESUMO

Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1 , Estudos Prospectivos
9.
Ultrasound Obstet Gynecol ; 57(5): 798-803, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32770786

RESUMO

OBJECTIVES: To evaluate the accuracy of an automated three-dimensional (3D) ultrasound technique for fetal intracranial measurements compared with manual acquisition. METHODS: This was a prospective observational study of patients presenting for routine anatomical survey between 18 + 0 and 22 + 6 weeks' gestation. After providing informed consent, each patient underwent two consecutive ultrasound examinations of the fetal head, one by a sonographer and one by a physician. Each operator obtained manual measurements of the biparietal diameter (BPD), head circumference (HC), transcerebellar diameter (TCD), cisterna magna (CM) and posterior horn of the lateral ventricle (Vp), followed by automated measurements of these structures using an artificial intelligence-based tool, SonoCNS® Fetal Brain. Both operators repeated the automated approach until all five measurements were obtained in a single sweep, up to a maximum of three attempts. The accuracy of automated measurements was compared with that of manual measurements using intraclass correlation coefficients (ICC) by operator type, accounting for patient and ultrasound characteristics. RESULTS: One hundred and forty-three women were enrolled in the study. Median body mass index was 24.0 kg/m2 (interquartile range (IQR), 22.5-26.8 kg/m2 ) and median subcutaneous thickness was 1.6 cm (IQR, 1.3-2.0 cm). Fifteen (10%) patients had at least one prior Cesarean delivery, 17 (12%) had other abdominal surgery and 78 (55%) had an anterior placenta. Successful acquisition of the automated measurements was achieved on the first, second and third attempts in 70%, 22% and 3% of patients, respectively, by sonographers and in 76%, 16% and 3% of cases, respectively, by physicians. The automated algorithm was not able to identify and measure all five structures correctly in six (4%) and seven (5%) patients scanned by the sonographers and physicians, respectively. The ICCs reflected good reliability (0.80-0.88) of the automated compared with the manual approach for BPD and HC and poor to moderate reliability (0.23-0.50) for TCD, CM and Vp. Fetal lie, head position, placental location, maternal subcutaneous thickness and prior Cesarean section were not associated with the success or accuracy of the automated technique. CONCLUSIONS: Automated 3D ultrasound imaging of the fetal head using SonoCNS reliably identified and measured BPD and HC but was less consistent in accurately identifying and measuring TCD, CM and Vp. While these results are encouraging, further optimization of the automated technology is necessary prior to incorporation of the technique into routine sonographic protocols. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.


Assuntos
Biometria/métodos , Feto/diagnóstico por imagem , Cabeça/diagnóstico por imagem , Imageamento Tridimensional/métodos , Ultrassonografia Pré-Natal/métodos , Adulto , Inteligência Artificial , Feminino , Feto/embriologia , Idade Gestacional , Cabeça/embriologia , Humanos , Gravidez , Estudos Prospectivos , Reprodutibilidade dos Testes
10.
Ann Oncol ; 31(11): 1536-1544, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32861806

RESUMO

BACKGROUND: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. PATIENTS AND METHODS: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. RESULTS: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. CONCLUSIONS: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Adulto , Compostos de Anilina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Pemetrexede/uso terapêutico , Platina/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Análise de Sobrevida
11.
Ann Oncol ; 31(8): 1056-1064, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32418886

RESUMO

BACKGROUND: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). PATIENTS AND METHODS: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. RESULTS: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32-0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46-0.98). The 5-year OS rate was 62.5% (95% CI 54.3-70.8) with alectinib and 45.5% (95% CI 33.6-57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34-1.00)] and those without [HR 0.76 (95% CI 0.45-1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. CONCLUSIONS: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. CLINICAL TRIALS NUMBER: NCT02075840.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Crizotinibe , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico
13.
Ann Oncol ; 31(4): 517-524, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32151507

RESUMO

BACKGROUND: Adenosquamous carcinoma (ASC) of the lung is a heterogeneous disease that is composed of both adenocarcinoma components (ACC) and squamous cell carcinoma components (SCCC). Their genomic profile, genetic origin, and clinical management remain controversial. PATIENTS AND METHODS: Resected ASC and metastatic tumor in regional lymph nodes (LNs) were collected. The ACC and SCCC were separated by microdissection of primary tumor. The 1021 cancer-related genes were evaluated by next-generation sequencing independently in ACC and SCCC and LNs. Shared and private alterations in the two components were investigated. In addition, genomic profiles of independent cohorts of adenocarcinomas and squamous cell carcinomas were examined for comparison. We have also carried out a retrospective study of ASCs with known EGFR mutation status from 11 hospitals in China for their clinical outcomes. RESULTS: The most frequent alterations in 28 surgically resected ASCs include EGFR (79%), TP53 (68%), MAP3K1 (14%) mutations, EGFR amplifications (32%), and MDM2 amplifications (18%). Twenty-seven patients (96%) had shared variations between ACC and SCCC, and pure SCCC metastases were not found in metastatic LNs among these patients. Only one patient with geographically separated ACC and SCCC had no shared mutations. Inter-component heterogeneity was a common genetic event of ACC and SCCC. The genomic profile of ASC was similar to that of 170 adenocarcinomas, but different from that of 62 squamous cell carcinomas. The incidence of EGFR mutations in the retrospective analysis of 517 ASCs was 51.8%. Among the 129 EGFR-positive patients who received EGFR-TKIs, the objective response rate was 56.6% and the median progression-free survival was 10.1 months (95% confidence interval: 9.0-11.2). CONCLUSIONS: The ACC and SCCC share a monoclonal origin, a majority with genetically inter-component heterogeneity. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR TKI.


Assuntos
Carcinoma Adenoescamoso , Neoplasias Pulmonares , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/genética , China , Receptores ErbB/genética , Genômica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases , Estudos Retrospectivos
14.
Clin Oncol (R Coll Radiol) ; 32(1): e1-e9, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31375307

RESUMO

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highlight the recent developments in the management of advanced-stage non-small cell lung cancer and to compare the differences in clinical practice between Eastern and Western countries.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Qualidade de Vida/psicologia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Análise de Sobrevida
15.
Mol Psychiatry ; 25(12): 3399-3412, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-30279455

RESUMO

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.


Assuntos
Demência , Sequenciamento de Nucleotídeos em Larga Escala , Idoso , Demência/genética , Genômica , Humanos , Mutação/genética , Encaminhamento e Consulta
16.
Ann Oncol ; 30(6): 884-896, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30912805

RESUMO

Antibodies that target programmed death 1 (PD-1) or its ligand [programmed death ligand 1 (PD-L1)] have become a mainstay of first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC) without targetable genetic alterations. In this review, we summarize results from recent clinical trials that have evaluated the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies atezolizumab and durvalumab as first-line treatment as monotherapy and in combination with chemotherapy, other immunotherapies, and antiangiogenesis agents. We discuss factors that may influence treatment selection, including patient baseline clinical and demographic characteristics, tumor histology, and biomarkers such as PD-L1 expression and tumor mutation burden. While immunotherapy has become a central component of first-line treatment of most patients with advanced NSCLC, important questions remain about how treatment should be managed for individual patients.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Seleção de Pacientes , Prognóstico
17.
Integr Cancer Ther ; 18: 1534735419836501, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30905173

RESUMO

PURPOSE: Chemotherapy-induced peripheral neuropathy is a complex side effect with few available treatment options. The aim of the study was to test the effectiveness of an 8-week course of acupuncture in the management of chemotherapy-induced peripheral neuropathy in cancer patients who were receiving or had received neurotoxic chemotherapy. METHODS: Randomized assessor-blinded controlled trial with 2 arms; one arm received acupuncture twice weekly for 8 weeks, while the other arm was a wait-list control group receiving only standard care. Primary outcome was pain intensity and interference over the past week using the Brief Pain Inventory at the end of the intervention. Secondary outcomes included clinical assessment (CTCAE [Common Toxicity Criteria for Adverse Events] grading and Total Neuropathy Score-Clinical Version) and nerve conduction studies; and patient-reported outcome measures (Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity Quality of Life scale and Symptom Distress Scale) assessed at baseline, end of treatment (8 weeks), week 14, and week 20 from the beginning of treatment. RESULTS: Eighty-seven patients were randomized to the experimental arm (n = 44) and to the standard care wait-list control arm (n = 43). Significant changes at 8 weeks were detected in relation to primary outcome (pain), the clinical neurological assessment, quality of life domains, and symptom distress (all P < .05). Improvements in pain interference, neurotoxicity-related symptoms, and functional aspects of quality of life were sustained in the 14-week assessment ( P < .05), as were physical and functional well-being at the 20-week assessment ( P < .05). CONCLUSIONS: Acupuncture is an effective intervention for treating chemotherapy-induced peripheral neuropathy and improving patients' quality of life and experience with neurotoxicity-related symptoms with longer term effects evident.


Assuntos
Antineoplásicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Acupuntura/métodos , Terapia por Acupuntura/métodos , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Qualidade de Vida , Inquéritos e Questionários
19.
Ann Oncol ; 29(Suppl 4): iv192-iv237, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30285222
20.
Ann Oncol ; 29(11): 2214-2222, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30215676

RESUMO

Background: The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods: Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results: In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Conclusion: Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration: ClinicalTrials.gov NCT02075840.


Assuntos
Quinase do Linfoma Anaplásico/genética , Neoplasias Encefálicas/terapia , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/terapia , Piperidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/efeitos da radiação , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Carbazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Quimiorradioterapia/métodos , Crizotinibe/farmacologia , Progressão da Doença , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Pulmão/efeitos da radiação , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Piperidinas/farmacologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...