Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
2.
Lung Cancer ; 158: 146-150, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34217967

RESUMO

IMPORTANCE: Therapies targeting immune checkpoints, such as the programmed cell death 1 (PD-1) receptor, have become the standard-of-care for patients with non-small cell lung cancer (NSCLC), but people living with HIV (PLWH) were excluded from these studies. OBJECTIVE: To evaluate the efficacy and tolerability of nivolumab in PLWH with advanced NSCLC. DESIGN: The CHIVA2 study was a nonrandomized, open-label, phase 2 clinical trial in PLWH with previously treated advanced NSCLC. SETTING: National multicenter prospective study. PARTICIPANTS: patients had viral load of <200 copies/mL, regardless of their CD4+ T-cell count. INTERVENTION: Nivolumab was administered in second or third line, as monotherapy intravenously at 3 mg/kg every 2 weeks, until disease progression or limiting toxicity. MAIN OUTCOMES AND MEASURES: The primary endpoint was disease control rate, evaluated using the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Sixteen patients with advanced NSCLC were enrolled: 14 (88 %) were men, median age was 58 years (range: 44-71), and all were smokers. The median duration of nivolumab treatment was 3.5 months (range: 0.5-26.5). The median follow-up was 23.6 months. Disease control rate was 62.5 % for 15 evaluable patients at 8 weeks (2 with partial response, 8 with stable disease, and 5 with disease progression). Twelve (75 %) patients had treatment-related adverse events, which were mild or moderate, except for one patient experiencing severe pruritus, onycholysis, and pemphigoid. There were no opportunistic infections or unexpected immune-related events. HIV viral load was stable during treatment. An increase in proliferating CD8+ and CD4+ T-cells was observed after 3 nivolumab cycles in a subgroup of 9 patients. CONCLUSIONS AND RELEVANCE: Second/third-line nivolumab treatment was well-tolerated and beneficial in PLWH with NSCLC. Future trials should investigate immune checkpoint inhibitors in first-line settings. TRIAL REGISTRATION: EudraCT.ema.europa.eu registration number: 2016-003796-22.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Infecções por HIV , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Estudos Prospectivos
3.
J Pharm Biomed Anal ; 197: 113968, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33618135

RESUMO

Kinase inhibitors (KIs) and antiandrogen drugs (AAs) are oral anticancer drugs with narrow therapeutic index that exhibit high inter- and intra-individual variability. We describe here a UPLC-MS/MS method for the simultaneous quantification of nine KIs: cobimetinib, dasatinib, ibrutinib, imatinib, nilotinib, palbociclib, ruxolitinib, sorafenib and vemurafenib; two active metabolites of them: N-desmethyl imatinib, N-oxide sorafenib; and two AAs: abiraterone and enzalutamide; with short pre-treatment and run time in order to be easily used in clinical practice for their therapeutic drug monitoring (TDM) and facilitating pharmacokinetics and pharmacokinetics/pharmacodynamics studies. Plasma samples were prepared by a single-step protein precipitation. Analytes were separated on a Waters Acquity UPLC® T3 HSS C18 column by non-linear gradient elution; with subsequent detection by Xevo® TQD triple quadrupole tandem mass spectrometer in a positive ionization mode. Analysis time was 2.8 min per run, and all analytes eluted within 1.46-1.97 minutes. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, dilution integrity and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-500 ng/mL for abiraterone, dasatinib and ibrutinib; 5-500 ng/mL for cobimetinib and palbociclib; 10-5,000 ng/mL for imatinib, N-desmethyl imatinib, nilotinib, sorafenib, N-oxide sorafenib and ruxolitinib; 100-50,000 ng/mL for enzalutamide and 100-100,000 ng/mL for vemurafenib with coefficient of correlation above 0.995 for all analytes. This novel method was successfully applied to TDM in clinical practice.


Assuntos
Preparações Farmacêuticas , Espectrometria de Massas em Tandem , Antagonistas de Androgênios , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Monitoramento de Medicamentos , Humanos , Inibidores de Proteínas Quinases , Reprodutibilidade dos Testes
4.
Bull Cancer ; 107(1): 21-29, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31980144

RESUMO

The HIV infection remains a serious public health concern in France and around the world. Cancers are frequent among people living with HIV (PLWH) and have become the leading cause of mortality among this population in France. Certain non-AIDS-defining cancers are much more common among PLWH, such as anal carcinoma, Hodgkin lymphoma, hepatocellular carcinoma and lung cancer. The incidence of cancer among PLWH depending on various factors, virological control under combined antiretrovial therapies (cART), exposure prevention to oncogenic virus and toxics are of utmost importance, such as the implementation of specific screening programmes. Drug interactions between cART and oncologic treatments can lead to serious adverse effects or to a reduction in the therapeutic effects, therefore they require a close monitoring. The PLWH have been excluded from the oncologic clinical trials assessing the efficacy and toxicity profile of the immune checkpoints inhibitors (ICPi) because of an increased theoretical risk of inducing adverse events and a feared lack of efficacy in the immunocompromised population. However, the mostly retrospective clinical data reporting the use of ICPi among PLWH are somewhat reassuring with a safety and efficacy profile similar to what observed in HIV-negative patients. Regarding the "shock and kill" anti-HIV effects of ICPi, the preliminary clinical data available are still modest and relatively disappointing despite encouraging results obtained in vitro. HIV-associated cancers represent a particular care challenge due to the multiple comorbidities in the population and the high risk of drug interactions, thus the CANCERVIH national network is of particular interest within this context.


Assuntos
Infecções por HIV/complicações , Sobreviventes de Longo Prazo ao HIV , Neoplasias/diagnóstico , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Neoplasias do Ânus/diagnóstico , Neoplasias do Ânus/tratamento farmacológico , Interações Medicamentosas , França , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Neoplasias/imunologia
5.
AIDS ; 34(2): 167-175, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634190

RESUMO

: Immune checkpoint inhibitors (ICPi) have shown major therapeutic successes when used in various cancers. In the HIV field a double benefit of such ICPi should result from their dual ability to restore in-vitro HIV-specific CD8 T-cell functions and to enhance HIV production from reservoir cells, thus fulfilling the goals of the 'shock and kill' concept proposed as an HIV cure therapeutic strategy. We conducted a systematic review to identify studies reporting the tolerance profile of ICPi and their effects on HIV plasma loads (pVL), CD4 cell count, HIV reservoirs (cell-associated HIV-DNA) and/or HIV-specific CD8 T cells in PLWH. Thirty-one articles were included for a total 176 participants. Twelve percent of the participants experienced severe adverse events and 49% nonsevere adverse events. pVL remained stable in 91.9% participant, showed increases in 5.8% participant, and decreases in 2.3%. CD4 cell count remained stable in 60.7% participants, showed increases in 24.6%, and decreases in 14.7%. Regarding ICPi effects on HIV-DNA and HIV-specific immunity, we identified three distinct profiles: profile I, transient pVL increases followed by a boost in HIV-specific CD8 T cells concomitant to a decrease in HIV-DNA, reported in one participant. Profile II: increase in HIV-specific CD8 T cells without changes in pVL or HIV-DNA, reported in three participants. III: no effect, reported in five participants. In conclusion, the clinical, virological and immunological safety profiles of ICPi reported in about 200 PLWH appear to be favorable but there are still modest results in terms of HIV cure strategy.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Indução de Remissão , Resultado do Tratamento , Carga Viral
7.
Lung Cancer ; 132: 65-71, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31097096

RESUMO

INTRODUCTION: Tumor mutational burden (TMB) correlates with response to immune checkpoint inhibitors (ICI) in advanced non-small-cell lung cancer (aNSCLC). We hypothesized that TP53 mutations could reflect TMB and be associated with ICI benefit. METHODS: TP53 mutations were assessed by next-generation sequencing in aNSCLC patients treated with programmed death-1 (PD-1) blockers. Clinical data, tumor programmed death ligand-1 (PD-L1) expression, and KRAS mutational status were collected. The primary endpoint was overall survival (OS). RESULTS: In total, 72 patients (median [interquartile range] age: 61 [33-83] years) were included; 52 (72%) were male; 39 (54%) had performance status 0-1; 53 (74%) had adenocarcinoma; 20 (28%) received first-line ICI, 52 (72%) second line or more. In 65 patients with available data, 36 (55%) expressed PD-L1 in ≥50% of tumor cells, 20 (31%) in 1-49% of cells, and nine (14%) were PD-L1-negative. Non-synonymous TP53 mutations were observed in 41 (57%) and 25 (35%) harbored KRAS-mutated tumors. After a median follow-up of 15.2 months (95% confidence interval [CI] 10.3-17.4 m), the median OS in the TP53-mutated group was 18.1 months (95% CI 6.6-not reached), vs. 8.1 months (95% CI 2.2-14.5, hazard ratio [HR] = 0.48; 95% CI 0.25-0.95, p = 0.04) in the TP53-wild-type group. Median progression-free survival was significantly longer in TP53-mutated patients (4.5 months, 95% CI 2.8-18.1 versus 1.4, 95% CI 1.1-3.5; p = 0.03), although TP53 mutation status failed to significantly influence PFS in the multivariate analysis (p = 0.32). Objective response rate (ORR) was higher in patients with TP53 mutation (51.2% vs. 20.7%; p = 0.01). In multivariate analysis, TP53 mutations independently associated with longer OS (HR = 0.35, 95% CI 0.16-0.77, p = 0.009). CONCLUSIONS: TP53-mutated status correlated with immunotherapy OS benefit in aNSCLC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Imunoterapia/métodos , Neoplasias Pulmonares/genética , Mutação/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos , Análise de Sobrevida
9.
Ann Intensive Care ; 7(1): 26, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28265980

RESUMO

BACKGROUND: As the population ages and cancer therapies improve, there is an increased call for elderly cancer patients to be admitted to the intensive care unit (ICU). This study aimed to assess short-term survival and prognostic factors in critically ill patients with solid tumors aged ≥65 years. METHODS: We conducted a retrospective study. The primary endpoint was ICU mortality. Resumption of anticancer therapy in patients who survived the ICU stay and 90-day mortality were secondary endpoints. All patients aged ≥65 years admitted to the ICU of Georges Pompidou Hospital (Paris, France) between 2009 and 2014 were eligible. RESULTS: Of 2327 eligible elderly patients (EP), 262 (75.0 ± 6.7 years) with solid tumors were analyzed. These patients were extremely critically ill (SAPS 2 61.9 ± 22.5), and 60.3% had metastatic disease. Gastrointestinal, lung and genitourinary cancers were the most common types of tumors. Mechanical ventilation was required in 51.5% of patients, inotropes in 48.1% and dialysis in 12.6%. Most patients (66.7%) were admitted for reasons unrelated to cancer, including sepsis (30.5%), acute respiratory failure (28.2%) and neurological problems (8.0%). ICU mortality in patients with cancer was 33.6 versus 32.6% among patients without cancer (p = 0.75). Among the cancer EP, the 90-day mortality was 51.9% (n = 136). In multivariate analysis, increased SAPS 2 score and primary tumor site were associated with 90-day death, whereas previous anticancer therapies and poor performance status were not. Among survivor patients from ICU with anti-tumoral treatment indication, 77 (52.7%) had resumption of anticancer treatment. CONCLUSIONS: Elderly solid tumor patients admitted to the ICU had a mortality rate similar to EP without cancer. Prognostic factors for 90-day mortality were more related to severity of clinical status at admission than the presence or stage of cancer, suggesting that early admission of EP with cancer to the ICU is appropriate.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...