RESUMO
Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.
Assuntos
Antagonistas de Receptores de Andrógenos , Melanoma , Quinases de Proteína Quinase Ativadas por Mitógeno , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas B-raf , Receptores Androgênicos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Receptores Androgênicos/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Análise de SobrevidaRESUMO
BACKGROUND: Patients with advanced type B3 thymoma and thymic carcinoma resistant to chemotherapy have few treatment options. We report the efficacy and safety results of the combination of the anti-PD-L1 inhibitor avelumab with the anti-angiogenesis drug axitinib in patients with advanced type B3 thymoma and thymic carcinoma. METHODS: CAVEATT was a single-arm, multicentre, phase 2 trial, conducted in two Italian centres (the European Instituteof Oncology and the Humanitas Institute, Milan) in patients with histologically confirmed type B3 thymoma or thymic carcinoma, with advanced stage of disease who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis drug was allowed but not with immune checkpoint inhibitors. Other inclusion criteria were age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, progressive disease, and presence of measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Patients received avelumab 10 mg/kg intravenously every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was the centrally assessed overall response rate according to RECIST version 1.1. Patients who received at least one cycle of treatment and had at least one CT scan after treatment start at scheduled time point by protocol were judged assessable for response and were included in efficacy and safety analyses. This study is registered with EUDRACT, 2017-004048-38; enrolment is completed and follow-up is ongoing. FINDINGS: Between April 22, 2019, and June 30, 2021, 32 patients were enrolled. 27 patients had a thymic carcinoma, three a type B3 thymoma, and two a mixed type B3 thymoma and thymic carcinoma. 29 (91%) of 32 patients had stage IVB disease and 13 (41%) of 32 had been pretreated with an anti-angiogenesis drug. 11 of 32 patients had an overall response; thus the overall response rate was 34% (90% CI 21-50); no patients had a complete response, 11 (34%) had a partial response, 18 (56%) had stable disease, and in two patients (6%) progressive disease was the best response. The most common grade 3 or 4 adverse event was hypertension (grade 3 in six [19%] of 32 patients). Four (12%) of 32 patients developed serious adverse events that were new-onset immune-related adverse events, including one grade 3 interstitial pneumonitis, one grade 4 polymyositis, and two grade 3 polymyositis. There were no treatment-related deaths. INTERPRETATION: Avelumab combined with axitinib has promising anti-tumour activity and acceptable toxicity in patients with advanced type B3 thymoma and thymic carcinoma progressing after chemotherapy, and could emerge as a new standard treatment option in this setting. FUNDING: Pfizer.
Assuntos
Polimiosite , Timoma , Neoplasias do Timo , Adolescente , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe/efeitos adversos , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Polimiosite/induzido quimicamente , Polimiosite/tratamento farmacológico , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/patologiaRESUMO
PURPOSE: Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters. METHODS: We synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction. RESULTS: We found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion. CONCLUSIONS: The rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.
Assuntos
Cardiotônicos/farmacologia , Malonatos/farmacologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Cardiotônicos/síntese química , Cardiotônicos/química , Linhagem Celular , Modelos Animais de Doenças , Ésteres/química , Feminino , Humanos , Masculino , Malonatos/síntese química , Malonatos/química , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Pró-Fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Ácido Succínico/metabolismoRESUMO
BACKGROUND AND AIMS: Type 2 Diabetes mellitus (T2DM) is associated with a higher risk of Heart Failure; Left Ventricular (LV) diastolic dysfunction is often considered the first marker of Diabetic cardiomyopathy; however, early preclinical LV systolic dysfunction has also been observed by means of echocardiographic measurement of strain. This study is aimed at assessing determinants of impaired strain and diastolic ventricular dysfunction in patients with T2DM. METHODS AND RESULTS: Cross-sectional study, performed on a consecutive series of patients with T2DM aged 30-80 years, BMI<40 kg/m2, free of cardiovascular disease, assessing metabolic control, microvascular complications, echocardiographic measures. Out of 206 patients, 19.6% had GLS lower than 18. GLS showed a significant inverse correlation with HBA1c, (p = 0.016), BMI (p = 0.002), waist (p < 0.0001), and mean L:H Ratio (p = 0.019). In a multivariate regression for LV GLS including HbA1c, age, sex, BMI and mean RR SDNN index, only HbA1c retained statistical significance: (B = -0.050 [-0.091; -0.009], p = 0.01. Among markers of LV diastolic function, only the E/E' ratio was associated with HbA1c at a univariate analysis, and it retained statistical significance in a multivariate regression including HbA1c, age, sex and disease duration (B = 0.038 [0.03; -0.073], p = 0.032). No significant difference in any parameter of systolic or diastolic function was observed between patients with or without microalbuminuria or diabetic retinopathy. CONCLUSION: In patients with T2DM, a reduced left ventricular global longitudinal strain appears to be independently associated with impaired glucose control and autonomic neuropathy, regardless of microvascular complications.
Assuntos
Diabetes Mellitus Tipo 2 , Disfunção Ventricular Esquerda , Biomarcadores , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Hemoglobinas Glicadas/metabolismo , Controle Glicêmico , Humanos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Função Ventricular EsquerdaRESUMO
OBJECTIVE: The aim of the present study was to assess the extent and severity of periodontal disease among type 1 diabetic patients (T1DM) and to investigate the possible association with systemic markers of glucose control and variability. MATERIAL AND METHODS: Patients were consecutively enrolled in a Diabetic Unit. A full-mouth periodontal evaluation was performed, and data on systemic markers of diabetes were collected. Descriptive statistics and logistic and linear models were performed. RESULTS: A total of 136 T1DM patients (mean age: 45.5 ± 14.6 years) were examined. Periodontitis was detected in 62% of cases (mean CAL: 3.0 ± 0.9 mm): stage III periodontitis was diagnosed in 32% of patients while stage IV in 8%. Mean level of glycated hemoglobin (HbA1c) was 7.5% ± 1.4. Among the investigated factors, mean CAL (p=0.040) was associated with HbA1c ≥ 7%; 93% of patients with mean CAL > 6 mm showed HbA1c ≥ 7%. Mean CAL (p=0.004), mean PPD (p=0.005), mean FMPS (p=0.030), and stage III/IV periodontitis (p=0.018) predict glucose coefficient of variation (CV). CONCLUSIONS: Periodontitis showed a relevant prevalence in the present, well-controlled T1DM population and predicts poor glycemic control (HbA1c ≥7%) and higher glucose variability. The present findings suggest that periodontal infection may have systemic effects also in T1DM patients. CLINICAL RELEVANCE: The extent and severity of periodontitis and its possible systemic effects in T1DM patients could be underestimated.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Periodontite , Adulto , Glicemia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Glucose , Hemoglobinas Glicadas/análise , Humanos , Pessoa de Meia-Idade , Periodontite/epidemiologiaRESUMO
BACKGROUND: The favourable safety profile and the increasing confidence with immune checkpoint inhibitors (ICIs) might have boosted their prescription in frail patients with short life expectancies, who usually are not treated with standard chemotherapy. METHODS: The present analysis aims to describe clinicians' attitudes towards ICIs administration during late stages of life within a multicenter cohort of advanced cancer patients treated with single agent PD-1/PD-L1 checkpoint inhibitors in Italy. RESULTS: Overall, 1149 patients with advanced cancer who received single agent PD-1/PD-L1 checkpoint inhibitors were screened. The final study population consisted of 567 deceased patients. 166 patients (29.3%) had received ICIs within 30 days of death; among them there was a significantly higher proportion of patients with ECOG-PS ≥ 2 (28.3% vs 11.5%, p < 0.0001) and with a higher burden of disease (69.3% vs 59.4%, p = 0.0266). In total, 35 patients (6.2%) started ICIs within 30 days of death; among them there was a higher proportion of patients with ECOG-PS ≥ 2 (45.7% vs 14.5%, p < 0.0001) and with a higher burden of disease (82.9% vs 60.9%, p = 0.0266). Primary tumors were significantly different across subgroups (p = 0.0172), with a higher prevalence of NSCLC patients (80% vs 60.9%) among those who started ICIs within 30 days of death. Lastly, 123 patients (21.7%) started ICIs within 3 months of death. Similarly, within this subgroup there was a higher proportion of patients with ECOG-PS ≥ 2 (29.3% vs 12.8%, p < 0.0001), with a higher burden of disease (74.0% vs 59.0%, p = 0.0025) and with NSCLC (74.0% vs 58.8%, p = 0.0236). CONCLUSION: Our results confirmed a trend toward an increasing ICIs prescription in frail patients, during the late stages of life. Caution should be exercised when evaluating an ICI treatment for patients with a poor PS and a high burden of disease.
Assuntos
Antígeno B7-H1 , Neoplasias Pulmonares , Humanos , Inibidores de Checkpoint Imunológico , Itália , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1RESUMO
The outbreak of COVID-19 pandemia is a major health worldwide concern. Patients with cancer might have a worse outcome, because of the immunosuppression determined by the tumor itself and anti-cancer treatments, including chemotherapy and radiotherapy. The impact and course of viral infection in patients receiving immunotherapy remains unknown. We report the case of a patient with metastatic melanoma, long responder to anti PD-1 blockade who got infected with Sars CoV-2, recovering without sequelae. A critical review of literature was performed. Limited data available in literature support the possibility to continue the immunotherapy in patients with cancer under control.
Assuntos
COVID-19/prevenção & controle , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/tratamento farmacológico , SARS-CoV-2/isolamento & purificação , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , COVID-19/epidemiologia , COVID-19/virologia , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Pandemias , SARS-CoV-2/fisiologiaRESUMO
NR+ is a highly effective vitamin B3 type supplement due to its unique ability to replenish NAD+ levels. While NR+ chloride is already on the market as a nutritional supplement, its synthesis is challenging, expensive, and low yielding, making it cumbersome for large-scale industrial production. Here we report the novel crystalline NR+ salts, d/l/dl-hydrogen tartrate and d/l/dl-hydrogen malate. Their high-yielding, one-pot manufacture does not require specific equipment and is suitable for multi-ton scale production. These new NR+ salts seem ideal for nutritional applications due to their bio-equivalence compared to the approved NR+ chloride. In addition, the crystal structures of all stereoisomers of NR+ hydrogen tartrate and NR+ hydrogen malate and a comparison to the known NR+ halogenides are presented.
Assuntos
Aditivos Alimentares/química , Tecnologia de Alimentos/métodos , Niacinamida/análogos & derivados , Niacinamida/química , Compostos de Piridínio/química , Ânions , Técnicas de Química Sintética , Cloretos , Cristalização , Suplementos Nutricionais , Hidrogênio/química , Espectroscopia de Ressonância Magnética , Malatos/química , Oxirredução , Sais , Estereoisomerismo , Tartaratos/química , Difração de Raios XRESUMO
Many mitochondrial metabolites and bioactive molecules contain two carboxylic acid moieties that make them unable to cross biological membranes. Hence, there is considerable interest in facilitating the uptake of these molecules into cells and mitochondria to modify or report on their function. Conjugation to the triphenylphosphonium (TPP) lipophilic cation is widely used to deliver molecules selectively to mitochondria in response to the membrane potential. However, permanent attachment to the cation can disrupt the biological function of small dicarboxylates. Here, we have developed a strategy using TPP to release dicarboxylates selectively within mitochondria. For this, the dicarboxylate is attached to a TPP compound via a single ester bond, which is then cleaved by intramitochondrial esterase activity, releasing the dicarboxylate within the organelle. Leaving the second carboxylic acid free also means mitochondrial uptake is dependent on the pH gradient across the inner membrane. To assess this strategy, we synthesized a range of TPP monoesters of the model dicarboxylate, malonate. We then tested their mitochondrial accumulation and ability to deliver malonate to isolated mitochondria and to cells, in vitro and in vivo. A TPP-malonate monoester compound, TPP11-malonate, in which the dicarboxylate group was attached to the TPP compound via a hydrophobic undecyl link, was most effective at releasing malonate within mitochondria in cells and in vivo. Therefore, we have developed a TPP-monoester platform that enables the selective release of bioactive dicarboxylates within mitochondria.
Assuntos
Ácidos Carboxílicos/química , Cátions/química , Mitocôndrias/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Ésteres/química , Feminino , Células HeLa , Compostos Heterocíclicos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Malonatos/química , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organofosforados/química , Ratos , Ratos WistarRESUMO
Mucosal melanoma is rare and accounts for 1.3-1.4% of all melanomas. Kit mutations are found in approximately 15-20% of mucosal melanomas. Immunotherapy with anti cytotoxic T-lymphocyte associated protein 4 and antiprogrammed cell death protein 1 have reported low clinical efficacy in this melanoma subtype. Studies with Kit inhibitor Imatinib showed response rates ranging from 20 to 30%. We present the case of a patient with a c-kit mutated metastatic melanoma who developed autoimmune vitiligo during treatment with oral tyrosine kinase inhibitor Masitinib.
Assuntos
Antineoplásicos/efeitos adversos , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Tiazóis/efeitos adversos , Vitiligo/patologia , Neoplasias Vulvares/tratamento farmacológico , Benzamidas , Feminino , Humanos , Metástase Linfática , Melanoma/patologia , Pessoa de Meia-Idade , Piperidinas , Prognóstico , Piridinas , Vitiligo/induzido quimicamente , Neoplasias Vulvares/secundárioRESUMO
AIM: To investigate the efficacy of a combination of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) versus an optimized degludec-based multiple daily injections (MDI) regimen + self-monitoring of blood glucose (SMBG) in people with type 1 diabetes with regard to optimizing glucose control. MATERIAL AND METHODS: The trial included 28 individuals who underwent a 4-week run-in phase, and were then randomized 1:1 to: (a) CSII + CGM followed by MDI + SMBG or (b) an MDI basal-bolus regimen followed by CSII + CGM. RESULTS: In patients randomized to the CSII + CGM â MDI + SMBG arm, a significant reduction in glycated haemoglobin (HbA1c) versus baseline was found at the end of the first phase (CSII + CGM) without significant variation in the following MDI + SMBG phase. In the arm randomized to the MDI + SMBG â CSII + CGM sequence, a significant improvement in HbA1c was observed in the first phase (MDI + SMBG), together with a further decrease in the following CSII + CGM phase. In the comparison of the two treatments using a mixed linear model, CSII + CGM was superior to MDI + SMBG with respect to change in HbA1c (P = 0.001). CONCLUSIONS: This study suggests that CSII + CGM improves glycaemic control without relevant safety issues in type 1 diabetes, in comparison with MDI + SMBG.
Assuntos
Automonitorização da Glicemia , Diabetes Mellitus Tipo 1 , Glicemia , Estudos Cross-Over , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Injeções Subcutâneas , Insulina/uso terapêutico , Sistemas de Infusão de InsulinaRESUMO
The ability to detect, identify and quantify bacteria is crucial in clinical diagnostics, environmental testing, food security settings and in microbiology research. Recently, the threat of multidrug-resistant bacterial pathogens pushed the global scientific community to develop fast, reliable, specific and affordable methods to detect bacterial species. The use of synthetically modified enzyme substrates is a convenient approach to detect bacteria in a specific, economic and rapid manner. The method is based on the use of specific enzyme substrates for a given bacterial marker enzyme, conjugated to a signalogenic moiety. Following enzymatic reaction, the signalophor is released from the synthetic substrate, generating a specific and measurable signal. Several types of signalophors have been described and are defined by the type of signal they generate, such as chromogenic, fluorogenic, luminogenic, electrogenic and redox. Signalophors are further subdivided into groups based on their solubility in water, which is key in defining their application on solid or liquid media for bacterial culturing. This comprehensive review describes synthetic enzyme substrates and their applications for bacterial detection, showing their mechanism of action and their synthetic routes.
Assuntos
Bactérias/isolamento & purificação , Técnicas Biossensoriais/métodos , Enzimas/metabolismo , Bactérias/metabolismo , Biomarcadores/metabolismoRESUMO
BACKGROUND: Invasive lobular carcinomas (ILCs) account for 10-15% of all breast cancers. They are characterized by an elevated endocrine responsiveness and by a long lasting risk of relapse over time. Here we report for the first time an analysis of clinical and pathological features associated with the risk of late distant recurrence in ILCs. PATIENTS AND METHODS: We retrospectively analyzed all consecutive patients with hormone receptor-positive ILC operated at the European Institute of Oncology (EIO) between June 1994 and December 2010 and scheduled to receive at least 5 years of endocrine treatment. The aim was to identify clinical and pathological variables that provide prognostic information in the period beginning 5 years after definitive surgery. The cumulative incidence of distant metastases (CI-DM) from 5 years after surgery was the prospectively defined primary endpoint. RESULTS: One thousand eight hundred seventy-two patients fulfilled the inclusion criteria. The median follow-up was 8.7 years. Increased tumor size and positive nodal status were significantly associated with higher risk of late distant recurrence, but nodal status had a significant lower prognostic value in late follow-up period (DM-HR, 3.21; 95% CI, 2.06-5.01) as compared with the first 5 years of follow-up (DM-HR, 9.55; 95% CI, 5.64-16.2; heterogeneity p value 0.002). Elevated Ki-67 labeling index (LI) retained a significant and independent prognostic value even after the first 5 years from surgery (DM-HR, 1.81; 95% CI 1.19-2.75), and it also stratified the prognosis of ILC patients subgrouped according to lymph node status. A combined score, obtained integrating the previously validated Clinical Treatment Score post 5 years (CTS5) and Ki-67 LI, had a strong association with the risk of late distant recurrence of ILCs. CONCLUSION: We identified factors associated with the risk of late distant recurrence in ER-positive ILCs and developed a simple prognostic score, based on data that are readily available, which warrants further validation.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Lobular/mortalidade , Carcinoma Lobular/patologia , Gerenciamento Clínico , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Recidiva , Estudos RetrospectivosRESUMO
AIM: To conduct a meta-analysis to assess the effect of continuous subcutaneous insulin infusion (CSII), continuous glucose monitoring (CGM), and the combination of the two, on glycaemic control in type 2 diabetes. MATERIALS AND METHODS: The analysis included randomized clinical trials comparing CSII with multiple daily injections (MDI) in people with type 2 diabetes, as well as studies comparing CGM or flash glucose monitoring (FGM) with self-monitoring of blood glucose (SMBG), with a duration of at least 12 weeks, identified in Medline or clinicaltrials.gov. The principal endpoint was glycated haemoglobin (HbA1c) at the end of the trial. Mean and 95% confidence intervals (CIs) for HbA1c and Mantel-Haenzel odds ratios for severe hypoglycaemia were calculated, using random-effect models. RESULTS: The retrieved trials showed a significant heterogeneity (I2 = 90%). The difference in HbA1c between CSII and MDI was not statistically significant (-0.26% [95% CI -0.74;0.22]; P = .29). The difference in endpoint HbA1c between CGM and SMBG was marginally significant (-0.24 [95% CI -0.49;0.00]; P = .05), and CGM was possibly associated with a lower hypoglycaemic risk. Only one trial explored the effect of FGM, as compared with SMBG, on HbA1c in type 2 diabetes, finding no difference across groups (at study end: 8.4% ± 0.8% vs 8.3% ± 1.1% with FGM and SMBG, respectively). Conversely, FGM was associated with an improvement in quality of life and with a lower incidence of hypoglycaemic events. The small number of retrieved trials indicates that the results should be interpreted with caution. CONCLUSIONS: The analysis showed that CSII, CGM and FGM provide only small benefits compared with MDI (on either HbA1c, hypoglycaemic risk or quality of life) in insulin-treated people with type 2 diabetes.
Assuntos
Automonitorização da Glicemia , Glicemia , Diabetes Mellitus Tipo 2 , Sistemas de Infusão de Insulina , Glicemia/análise , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Despite the acknowledged sex-related dimorphism in immune system response, little is known about the effect of patients' sex on the efficacy of immune checkpoint inhibitors as cancer treatments. We did a systematic review and meta-analysis to assess the heterogeneity of immune checkpoint inhibitor efficacy between men and women. METHODS: We systematically searched PubMed, MEDLINE, Embase, and Scopus, from database inception to Nov 30, 2017, for randomised controlled trials of immune checkpoint inhibitors (inhibitors of PD-1, CTLA-4, or both) that had available hazard ratios (HRs) for death according to patients' sex. We also reviewed abstracts and presentations from all major conference proceedings. We excluded non-randomised trials and considered only papers published in English. The primary endpoint was to assess the difference in efficacy of immune checkpoint inhibitors between men and women, measured in terms of the difference in overall survival log(HR) reported in male and female study participants. We calculated the pooled overall survival HR and 95% CI in men and women using a random-effects model, and assessed the heterogeneity between the two estimates using an interaction test. FINDINGS: Of 7133 studies identified in our search, there were 20 eligible randomised controlled trials of immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab, or pembrolizumab) that reported overall survival according to patients' sex. Overall, 11â351 patients with advanced or metastatic cancers (7646 [67%] men and 3705 [33%] women) were included in the analysis; the most common types of cancer were melanoma (3632 [32%]) and non-small-cell lung cancer (3482 [31%]). The pooled overall survival HR was 0·72 (95% CI 0·65-0·79) in male patients treated with immune checkpoint inhibitors, compared with men treated in control groups. In women treated with immune checkpoint inhibitors, the pooled overall survival HR compared with control groups was 0·86 (95% CI 0·79-0·93). The difference in efficacy between men and women treated with immune checkpoint inhibitors was significant (p=0·0019). INTERPRETATION: Immune checkpoint inhibitors can improve overall survival for patients with advanced cancers such as melanoma and non-small-cell lung cancer, but the magnitude of benefit is sex-dependent. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of immunotherapies in women, perhaps exploring different immunotherapeutic approaches in men and women. FUNDING: None.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Feminino , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde , Humanos , Imunoterapia/efeitos adversos , Masculino , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/patologia , Fatores de Risco , Caracteres Sexuais , Fatores Sexuais , Resultado do TratamentoRESUMO
The discovery of ALK rearrangement in non-small-cell lung cancer (NSCLC) triggered rapid clinical development of a family of specific drugs targeting this alteration, called ALK inhibitors. Despite high rate of responses, the vast majority of patients treated with first-generation ALK inhibitor crizotinib will ultimately develop disease progression. The second-generation ALK inhibitor, ceritinib, is an oral, small-molecule that inhibits the ALK kinase activity with a potency 20-fold greater than crizotinib, being able to tackle some of the principal mechanisms of resistance to crizotinib. Evidences from five large prospective clinical trials have so far showed impressive activity of ceritinib in ALK inhibitor pretreated and naive NSCLC patients. This review will focus on the preclinical and clinical data available regarding ceritinib pharmacology, clinical efficacy and safety profile.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sulfonas/uso terapêutico , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Sulfonas/farmacologiaRESUMO
Cancer-related inflammation may play an important role in disease progression and patient outcome, and could be easily monitored through indirect parameters routinely evaluated at diagnosis. Here, we investigated if peripheral blood cells and the ratios of neutrophils to lymphocytes (NLR) and of lymphocytes to monocytes (LMR) as surrogate markers of cancer related inflammation are associated with disease progression and survival of melanoma patients at any stage of the disease. Records of 1,182 melanoma patients included in an Institutional tumor registry in the period 2000-2010, were reviewed. Among them, 584 patients with a cutaneous or unknown primary melanoma and available pre-operative blood tests were analyzed. Survival was estimated with the Kaplan-Meier method, and analyzed using Log-rank test, Cox regression and multivariate Cox proportional hazard models. We found that patients presenting with distant metastases had higher leukocytes, neutrophils and monocytes, and lower lymphocytes compared to Stage I-III patients. Furthermore, at a single-patient level, hematological profiles changed on disease progression from regional to distant metastatic, with significantly increased circulating leukocytes, neutrophils and monocytes, and decreased lymphocytes. Peripheral blood cell counts were not associated with survival of patients with a localized or regionally metastasized melanoma. Instead, in Stage IV patients, leukocytes (p = 0.001), neutrophils (p = 0.0002), monocytes (p = 0.002), NLR (p < 0.0001) and LMR (p = 0.005) were all significantly associated with survival, independently of other known prognostic factors. These results suggest that cellular components of peripheral blood do count for survival of patients with advanced melanoma.