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1.
Immunotherapy ; 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35416048

RESUMO

Introduction: Aims of the study were to explore outcomes and toxicities of chemotherapy-immunotherapy (CT-IT) for patients (pts) with metastatic nonsquamous non-small-cell lung cancer (mNSCLC) in a real-world population. Materials & methods: Clinical data of 26 pts with mNSCLC treated with CT-IT at our institution from January 2020 to January 2021 were collected retrospectively. Results: Median follow-up time was 7.7 months. Median progression-free survival was 9.5 months. The most frequent immune-related adverse event was thyroid dysfunction (ThD): 30.7%. Conclusion: There was a higher rate of ThD in this study population compared with the literature, with a possible correlation with clinical outcomes.


Aims of the study were to explore outcomes and toxicities of chemotherapy-immunotherapy (CT-IT) for patients (pts) with metastatic nonsquamous NSCLC (mNSCLC) in a real practice experience, because practice experience not always could be the same of experimental experience. We collected clinical data of 26 pts with mNSCLC, treated with CT-IT at our Institution from January 2020 to January 2021. We observed efficacy and tolerability of treatment were similar to known data, except for thyroid disfunctions (ThD) that was more frequent in our experience. This collateral effect was not cause of treatment interruption, indeed the pts with this manifestation would seem responder better to this therapy. However, we need more time and kind of studies for confirm this observation.

2.
Cancers (Basel) ; 14(8)2022 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-35454926

RESUMO

INTRODUCTION: BRAF mutation involved 2-4% of lung adenocarcinoma. Differences in clinicopathologic features and patient outcome exist between V600E and non-V600E BRAF mutated NSCLC. Thus, we sought to assess the frequency and clinical relevance of BRAF mutations in a real-life population of advanced-NSCLC, investigating the potential prognostic significance of distinct genetic alterations. MATERIALS AND METHODS: The present multicenter Italian retrospective study involved advanced BRAF mutant NSCLC. Complete clinicopathologic data were evaluated for BRAF V600E and non-V600E patients. RESULTS: A total of 44 BRAFmut NSCLC patients were included (V600E, n = 23; non-V600E, n = 21). No significant differences in survival outcome and treatment response were documented, according to V600E vs. non-V600E mutations, although a trend towards prolonged PFS was observed in the V600E subgroup (median PFS = 11.3 vs. 6.0 months in non-V600E). In the overall population, ECOG PS and age significantly impacted on OS, while bone lesions were associated with shorter PFS. Compared to immunotherapy, first-line chemotherapy was associated with longer OS in the overall population, and especially in the BRAF V600E subtype. CONCLUSIONS: Here, we report on real-life data from a retrospective cohort of advanced-NSCLC harboring BRAF alterations. Our study offers relevant clues on survival outcome, therapeutic response, and clinicopathologic correlations of BRAF-mutant NSCLC.

3.
Cancers (Basel) ; 14(4)2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35205721

RESUMO

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs' self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/ß-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.

4.
Int J Mol Sci ; 22(23)2021 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-34884672

RESUMO

ROS proto-oncogene 1 (ROS1) rearrangements are reported in about 1-2% of non-squamous non-small-cell lung cancer (NSCLC). After efficacy of crizotinib was demonstrated, identification of ROS1 translocations in advanced disease became fundamental to give patients the chance of specific and effective treatment. Different methods are available for detection of rearrangements, and probably the real prevalence of ROS1 rearrangements is higher than that reported in literature, as our capacity to detect gene rearrangements is improving. In particular, with next generation sequencing (NGS) techniques, we are currently able to assess multiple genes simultaneously with increasing sensitivity. This is leading to overcome the "single oncogenic driver" paradigm, and in the very near future, the co-existence of multiple drivers will probably emerge more frequently and represent a therapeutic issue. Since recently, crizotinib has been the only available therapy, but today, many other tyrosine kinase inhibitors (TKI) are emerging and seem promising both in first and subsequent lines of treatment. Indeed, novel inhibitors are also able to overcome resistance mutations to crizotinib, hypothesizing a possible sequential strategy also in ROS1-rearranged disease. In this review, we will focus on ROS1 rearrangements, dealing with diagnostic aspects, new therapeutic options, resistance issues and the coexistence of ROS1 translocations with other molecular alterations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Rearranjo Gênico , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Int J Mol Sci ; 22(22)2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34830058

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2-4 years from the time of diagnosis. Although IPF has unknown aetiology by definition, there have been identified several risks factors increasing the probability of the onset and progression of the disease in IPF patients such as cigarette smoking and environmental risk factors associated with domestic and occupational exposure. Among them, cigarette smoking together with concomitant emphysema might predispose IPF patients to lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer development. To this purpose, IPF and LC share several cellular and molecular processes driving the progression of both pathologies such as fibroblast transition proliferation and activation, endoplasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose IPF patients to LC development. Nintedanib, a tyrosine-kinase inhibitor, was firstly developed as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target molecular pathway. In this review our aim is to describe the updated studies on common cellular and molecular mechanisms between IPF and lung cancer, knowledge of which might help to find novel therapeutic targets for this disease combination.


Assuntos
Fibrose Pulmonar Idiopática/genética , Neoplasias Pulmonares/genética , Animais , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Mecanotransdução Celular , Miofibroblastos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
6.
Immunotherapy ; 13(18): 1501-1519, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34670403

RESUMO

Background: Immunotherapy changed the landscape of non-small-cell lung cancer (NSCLC). Efforts were made to implement its action. This study aims to describe body composition, nutritional and inflammatory status in NSCLC patients treated by first-line immunotherapy, their correlation, variation and impact. Patients and methods: We retrospectively analyzed 44 consecutive patients who received pembrolizumab treatment. Results: During the therapy, inflammation and visceral fat increased, whereas muscle and subcutaneous fat decreased. Parameters related to inflammation had an interesting prognostic impact. High numbers of white blood cells remained significantly correlated with a high risk of death in multivariate model. Conclusion: For the best treatment choice, a combination of clinical and biological factors will be most likely be necessary. Prospective and larger studies with a multidimensional approach are needed.


Lay abstract Inflammation and malnutrition in cancer patients may affect the immune system and response to therapy. We noticed an increase in inflammation and visceral fat and a decrease in muscle and subcutaneous fat during therapy. No variation showed a significant correlation with survival. Muscle mass, adipose tissue and body mass index do not confirm any prognostic impact or relationship with response to therapy. More interesting results were observed with parameters related to inflammation. Probably, for the best treatment choice, a combination of clinical and biological factors will be necessary. Further studies with a multidimensional approach are needed to propose the best treatment and the best support to everyone.


Assuntos
Composição Corporal , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Inflamação/etiologia , Inflamação/imunologia , Inflamação/terapia , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
7.
Transl Lung Cancer Res ; 10(6): 2890-2916, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34295687

RESUMO

BACKGROUND: Treatment of oncogene-addicted non-small cell lung cancer (NSCLC) has been changed by the advent of tyrosine kinase inhibitors (TKIs). Albeit great benefits are achieved with target therapies, resistance invariably occurs and recourse to alternative treatments is unavoidable. Immune checkpoint inhibitors (ICIs) role and the best setting of immunotherapy administration in oncogene-driven NSCLC are matter of debate. METHODS: We performed a systematic literature review through PubMed, in order to gather all the available information regarding ICI activity and efficacy in oncogene-addicted NSCLC, from both prospective trials and retrospective series. A meta-analysis of objective response rate in different molecular subgroups was provided. Combinatorial strategies including ICIs and related toxicities were also recorded. RESULTS: Eighty-seven studies were included in the qualitative analysis. EGFR mutation may be a biomarker of poor response to single-agent ICIs (7% of EGFR-mutant NSCLC patients achieved disease response in prospective trials), while encouraging results have been shown with combination strategies. KRAS-mutated disease (response rate, RR, 22%) has different clinical and pathological characteristics, and the co-existence of additional mutations (e.g., STK11 or TP53) influence tumor microenvironment and response to immunotherapy. Other molecular alterations have been marginally considered prospectively, and data from clinical practice are variegated, given poor effectiveness of ICIs in ALK-rearranged disease (RR 9.5%, pooling the data of retrospective studies) or some encouraging results in BRAF-(RR 25%, retrospective data) or MET-driven one (with estimations conditioned by the presence of both exon 14 skipping mutations and gene amplification in reported series). CONCLUSIONS: In oncogene-addicted NSCLC (with the exception of KRAS-mutated), ICIs are usually administered at the failure of other treatment options, but administering single-agent immunotherapy in later disease phases may limit its efficacy. With the progressive administration of TKIs and ICIs in early-stage disease, molecular characterization will become fundamental in this setting.

8.
Clin Nutr ESPEN ; 43: 64-75, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34024567

RESUMO

BACKGROUND AND AIMS: Body composition and balance of nutritional and inflammatory status are important for the immune system. Alterations of these aspects may impact on response, outcome and toxicities of immunotherapy. In this review we try to clarify some definitions and tools used for the assessment of the different aspects of nutritional disorders, body composition and inflammatory status with a focus on lung cancer. METHODS: We primary investigate the definitions of malnutrition, cachexia, sarcopenia and overweight. Secondary, tools used to measure body composition, nutritional and inflammatory status, mainly in lung cancer are reviewed. RESULTS: All these features, in the time of precision medicine may improve assessment and selection of patients, incorporating also early palliative care in standard therapy. CONCLUSIONS: A multimodal approach based on nutrition assessment and physical exercise should be evaluated to improve aspects of the immune response against cancer and to propose the best treatment to every patient.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Composição Corporal , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Imunoterapia , Neoplasias Pulmonares/terapia , Estado Nutricional
9.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34016723

RESUMO

BACKGROUND: Until now, no robust data supported the efficacy, safety and recommendation for influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs). METHODS: The prospective multicenter observational INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors (INVIDIa-2) study investigated the clinical effectiveness of influenza vaccination in patients with advanced cancer receiving ICIs, enrolled in 82 Italian centers from October 2019 to January 2020. The primary endpoint was the time-adjusted incidence of influenza-like illness (ILI) until April 30, 2020. Secondary endpoints regarded ILI severity and vaccine safety. RESULTS: The study enrolled 1279 patients; 1188 patients were evaluable for the primary endpoint analysis. Of them, 48.9% (581) received influenza vaccination. The overall ILI incidence was 8.2% (98 patients). Vaccinated patients were significantly more frequently elderly (p<0.0001), males (p=0.004), with poor European Cooperative Oncology Group performance status (p=0.009), affected by lung cancer (p=0.01), and by other non-cancer comorbidities (p<0.0001) when compared with unvaccinated. ILI incidence was not different basing on influenza vaccination: the time-to-ILI was similar in vaccinated and unvaccinated patients (p=0.62). ILI complications were significantly less frequent for patients receiving the vaccination (11.8% vs 38.3% in unvaccinated, p=0.002). ILI-related intravenous therapies were significantly less frequent in vaccinated patients than in unvaccinated (11.8% vs 29.8%, p=0.027). ILI lethality was, respectively, 0% in vaccinated and 4.3% in unvaccinated patients. Vaccine-related adverse events were rare and mild (1.5%, grades 1-2). CONCLUSION: The INVIDIa-2 study results support a positive recommendation for influenza vaccination in patients with advanced cancer receiving immunotherapy.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Neoplasias/tratamento farmacológico , Vacinação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Incidência , Vacinas contra Influenza/efeitos adversos , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/imunologia , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Vacinação/efeitos adversos , Adulto Jovem
10.
Eur J Cancer ; 150: 224-231, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33934059

RESUMO

BACKGROUND: We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This 'drug score' was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1-2 and poor risk with score 3-4. METHODS: Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non-small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy). RESULTS: Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts. CONCLUSION: Our 'drug score' showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients.


Assuntos
Corticosteroides/uso terapêutico , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Técnicas de Apoio para a Decisão , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Corticosteroides/efeitos adversos , Idoso , Antibacterianos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Tomada de Decisão Clínica , Interações Medicamentosas , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Itália , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Seleção de Pacientes , Polimedicação , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
11.
J Immunother Cancer ; 9(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33827906

RESUMO

BACKGROUND: Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate. METHODS: We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses. RESULTS: 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, ß-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate. CONCLUSION: In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.


Assuntos
Antibacterianos/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Corticosteroides/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Europa (Continente) , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Polimedicação , Intervalo Livre de Progressão , Inibidores da Bomba de Prótons/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo
12.
Immunotherapy ; 13(4): 277-281, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33249929

RESUMO

Immune checkpoint inhibitors (ICIs) changed management of non-small-cell lung cancer, but resistance usually develops. Today, at ICIs failure, chemotherapy is the treatment of choice, but the chance of immunotherapy rechallenge is appealing. Another challenging issue is whether it is safe to treat HIV-positive patients with ICIs: safety and efficacy of immunotherapy have been marginally considered in this subgroup. We report the case of a non-small-cell lung cancer patient treated by PD-1 inhibitors rechallenge despite his HIV-positivity, achieving good partial response with significant clinical benefit and without toxicities. Our experience underlines that HIV-positive patients can be treated similarly to HIV-negative individuals. HIV-positivity should be considered similar to other comorbidities, and not as a sufficient reason to preclude them the best available treatments.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Infecções por HIV/complicações , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imunoterapia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Masculino , Nivolumabe/uso terapêutico , Retratamento
13.
J Immunother Cancer ; 8(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33077515

RESUMO

BACKGROUND: The association between obesity and outcomes in patients receiving programmed death-1/programmed death ligand-1 (PD-L1) checkpoint inhibitors has already been confirmed in pre-treated non-small cell lung cancer (NSCLC) patients, regardless of PD-L1 tumor expression. METHODS: We present the outcomes analysis according to baseline body mass index (BMI) and BMI variation in a large cohort of metastatic NSCLC patients with a PD-L1 expression ≥50%, receiving first line pembrolizumab. We also evaluated a control cohort of metastatic NSCLC patients treated with first line platinum-based chemotherapy. Normal weight was set as control group. RESULTS: 962 patients and 426 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Obese patients had a significantly higher objective response rate (ORR) (OR=1.61 (95% CI: 1.04-2.50)) in the pembrolizumab cohort, while overweight patients had a significantly lower ORR (OR=0.59 (95% CI: 0.37-0.92)) within the chemotherapy cohort. Obese patients had a significantly longer progression-free survival (PFS) (HR=0.61 (95% CI: 0.45-0.82)) in the pembrolizumab cohort. Conversely, they had a significantly shorter PFS in the chemotherapy cohort (HR=1.27 (95% CI: 1.01-1.60)). Obese patients had a significantly longer overall survival (OS) within the pembrolizumab cohort (HR=0.70 (95% CI: 0.49-0.99)), while no significant differences according to baseline BMI were found in the chemotherapy cohort. BMI variation significantly affected ORR, PFS and OS in both the pembrolizumab and the chemotherapy cohorts. CONCLUSIONS: Baseline obesity is associated to significantly improved ORR, PFS and OS in metastatic NSCLC patients with a PD-L1 expression of ≥50%, receiving first line pembrolizumab, but not among patients treated with chemotherapy. BMI variation is also significantly related to clinical outcomes.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Índice de Massa Corporal , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Obesidade/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Clin Lung Cancer ; 21(5): e464-e473, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32276870

RESUMO

BACKGROUND: In advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients whose disease has progressed during treatment with first- and second-generation tyrosine kinase inhibitors (TKIs), liquid biopsy (LB) is routinely used to evaluate the presence of EGFR T790M as an acquired resistance mechanism. The objective of this study was to assess a real-life picture of EGFR T790M detection in LB. MATERIALS AND METHODS: Liquid biopsies performed between June 2016 and October 2018 for advanced EGFR-mutated NSCLC at disease progression during treatment with first- and second-generation TKIs were retrospectively evaluated in 5 Italian centers. Circulating tumor DNA was extracted from plasma and tested with different commercial kits. The detection rate in LBs and the patients' characteristics were correlated. RESULTS: We enrolled 120 consecutive patients. The overall T790M detection rate observed using LB was 25.8%. Fifty-four of 89 (60.7%) patients with negative LB results underwent tissue rebiopsy, and 56% were positive for T790M. The overall rate of T790M positivity in the study cohort was 49.2%. LB performed before formal tumor progression according to Response Evaluation Criteria In Solid Tumors criteria was negative for T790M in all patients (n = 21; P = .012). T790M positivity was statistically significantly higher in cases of disease progression at extrathoracic metastatic sites (P = .008) and, specifically, in the case of worsening bone disease (P = .003). CONCLUSION: Our study shows that the detection of T790M-positive patients whose disease progressed during treatment with first- and second-generation TKIs in real life was according to the literature. However, this result was obtained with a specific clinical course (repeat LBs and tissue rebiopsy), thus implying the necessity for multidisciplinary management.


Assuntos
Adenocarcinoma de Pulmão/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/secundário , Biópsia Líquida/métodos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Receptores ErbB/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
15.
Eur J Cancer ; 130: 155-167, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32220780

RESUMO

BACKGROUND: Pembrolizumab is the first-line standard of care for advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumour proportion score (TPS) ≥ 50%. Eastern Cooperative Oncology Group performance status (PS) 2 patients may receive pembrolizumab, despite the absence of sustaining evidence. PATIENTS AND METHODS: GOIRC-2018-01 is a multicentre, retrospective, observational study. PS 2 NSCLC patients with a PD-L1 TPS ≥50% receiving first-line pembrolizumab from June 2017 to December 2018 at 21 Italian institutions were included. Clinical-pathological characteristics were correlated with disease response and survival outcomes; adverse events were recorded. The primary objective was 6-months progression-free rate (6-months PFR). RESULTS: One hundred fifty-three patients (median age 70 years) were enrolled. At a median follow-up of 18.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.4 (95% confidence interval, 95% CI, 1.6-2.5) and 3.0 months (95% CI 2.4-3.5), respectively. 6-months PFR was 27% (95% CI 21-35%). Patients with a PS 2 determined by comorbidities (n = 41) had significantly better outcomes compared with disease burden-induced PS 2 (n = 112). Indeed, 6-months PFR was 49% versus 19%, median PFS 5.6 versus 1.8 months and OS 11.8 versus 2.8 months, respectively. Additional potential prognostic factors (radiotherapy, antibiotics, steroids received before pembrolizumab) correlated with clinical outcomes. The determinant of PS 2 resulted the only factor independently impacting on both PFS and OS. No toxicity issues emerged. CONCLUSIONS: Outcomes of PS 2 NSCLC patients with PD-L1 TPS ≥50% receiving first-line pembrolizumab were globally dismal but strongly dependent on the reason conditioning the poor PS itself.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Humanos , Masculino , Estudos Retrospectivos
16.
Crit Rev Oncol Hematol ; 145: 102836, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31918216

RESUMO

Immunotherapy has widely changed the management of different malignancies. However, efficacy and safety of immune checkpoint inhibitors (ICIs) are not well established in people living with HIV (PLWH). Population of HIV-positive patients has deeply changed after the introduction of modern antiretroviral therapy (ART) and available data of immunotherapy in this subgroup are inadequate considering that cancer has become a leading cause of death and morbidity in this population. Moreover, there are many similarities between cancer and infectious antigen stimulation so that ICIs are even under evaluation as specific HIV treatment. Most of literature on this topic is based on small case series that suggest that immunotherapy for PLWH seems to be as effective as in HIV-negative population with a good safety profile. In this article we review literature on HIV and immunotherapy and we collect many case series available in different malignancies, with a brief focus on lung cancer.


Assuntos
Infecções por HIV , Imunoterapia , Neoplasias Pulmonares , Infecções por HIV/complicações , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/virologia
17.
Int J Oncol ; 55(5): 1157-1164, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545419

RESUMO

The tumor immune microenvironment (TME) and immune checkpoints have been reported to serve a role in the pathogenesis of malignant mesothelioma (MM) and treatment outcome. Additionally, mismatch Repair (MMR) deficiency appears to enhance the response to checkpoints blockade in several tumors. The aim of the present study was to analyze programmed death­1 ligand 1 (PD­L1) expression in MM and to characterize the TME. This could help to understand the immune response, and evaluate its prognostic and predictive values. We also investigated MMR protein expression. We retrospectively analyzed 55 mesotheliomas to determine PD­L1, CD4+, CD8+, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2, mismatch repair system component (PMS2) expression. We used an immunoscore (1+, 2+ and 3+) to evaluate tumor­infiltrating lymphocytes (TILs). TILs were observed in all but two samples (53/55); the majority had an immunoscore 1+ (30/53), while 2+/3+ was reported for 23/53 samples. A predominance of CD8+ was highlighted in 8 cases (15%). PD­L1 expression of ≥1% on tumor cells was displayed in 40 cases; in 9 of these, ≥50% expression was reported. Of note, alterations in MMR staining was not observed. In addition, survival analysis revealed that epithelioid subtype was associated with better prognosis. We observed a trend towards poorer prognosis for ≥50% PD­L1 expression on tumor cells, lower immunoscore (1+) and CD8+ TIL predominance. The present study highlighted the importance of exploring the TME and the standardization of PD­L1 assessment guidelines to apply in the field of immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Mesotelioma/patologia , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Enzimas Reparadoras do DNA/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Masculino , Mesotelioma/imunologia , Mesotelioma/metabolismo , Mesotelioma Maligno , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
18.
Crit Rev Oncol Hematol ; 138: 112-119, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31092366

RESUMO

Immune checkpoint inhibitors have changed history and management of different tumor types, including non-small cell lung cancer (NSCLC). Response patterns may be more heterogeneous than those seen with cytotoxic chemotherapy. Besides atypical response patterns, new types of outcome should be taken into account such as pseudo-progression (PP) and hyper-progressive disease (HPD). PP is described as initial tumor increase or appearance of new lesions followed by their shrinkage during immunotherapy treatment while HPD is a rapid and severe pattern of progression with a not yet univocal definition. Physiopathology and underlying mechanism of these phenomena are not completely understood and in absence of reliable clinical and biological markers of response to immunotherapy, radiological evaluation remains a key point in clinicians' decision-making process but further efforts would be useful to identify a unique system of evaluation.In this review we summarize the main radiological criteria available in the evaluation of response to checkpoint inhibitors and we describe peculiar response patterns such PP and HPD with a focus on lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Progressão da Doença , Humanos , Resultado do Tratamento
19.
Breast Cancer ; 26(4): 520-523, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30564995

RESUMO

Post-surgical pyoderma gangrenosum (PSPG) of the breast is a rare dermatosis that worsens surgical manipulation, with a chronical relapsing course. Diagnosis is mostly clinical and made by exclusion after the failure of antibiotic therapies and surgical debridement, while the mainstay of therapy is corticosteroid-based. Here we report a case of PSPG of the breast in a young woman with breast cancer, to emphasize the needs of an early and accurate diagnosis, to guarantee the most efficacious treatment and to avoid life-threatening complications.


Assuntos
Doenças Mamárias/diagnóstico , Doenças Mamárias/etiologia , Mastectomia Segmentar/efeitos adversos , Pioderma Gangrenoso/diagnóstico , Pioderma Gangrenoso/etiologia , Doenças Mamárias/tratamento farmacológico , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mamoplastia/efeitos adversos , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Pioderma Gangrenoso/tratamento farmacológico
20.
Cancer Biol Ther ; 19(10): 879-886, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30067438

RESUMO

BACKGROUND: HER2+ metastatic breast cancer (MBC) is a poor prognosis disease, unusually curable. To date, no predictive factors have been clearly correlated with long-term response to anti-HER2 agents. METHODS: 54 HER2+ MBC patients treated with HER2 targeted therapy as first line treatment were analysed: 40 with a time to progression longer than 3 years in Long Responders (LR) group and 14 with a progression disease within one year of anti-HER2 therapy in a control group named Early Progressors (EP). The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer pathway panel performed on FFPE BC tissues. RESULTS: Considering baseline patients and tumor characteristics, EP women had more CNS spread and more metastatic burden of disease compared to LR (p > 0.05). Gene expression analysis identified 30 genes with significantly different expression in the two cohorts; five were driver genes (BRCA1, PDGFRA, AR, PHF6 and MSH2). The majority of these genes were over-expressed, mainly in LR patients, and encoded growth factors, pro- or anti-inflammatory interleukins and DNA repair factors. Only four genes were down regulated, all in EP group (TNFSF10, CACNG1, IL20RB and BRCA1). Most of these genes were involved in MAPK and PI3K pathways. MAPK pathway was differently expressed between LR and EP (p = 0.05). PI3K was the only pathway overexpressed in EP patients. CONCLUSIONS: Whole genome expression analysis comparing LR vs. EP identified a group of genes that may predict more favourable long-term outcomes. Up-regulation of MAPK and down-regulation of PI3K pathway could be a positive predictive factors. Further clinical implications are warranted. ABBREVIATIONS: BC: breast cancer; MBC: metastatic breast cancer; LR: long responder; EP: early progressor; FFPE: formalin-fixed paraffin-embedded; CNS: central nervous system; PFS: progression free survival; OS: overall survival.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Receptor ErbB-2/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Transdução de Sinais , Resultado do Tratamento
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