RESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs. PATIENTS AND METHODS: We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor. RESULTS: This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070). CONCLUSIONS: To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment.
Assuntos
Antineoplásicos Imunológicos , Miocardite , Miosite , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Estudos Retrospectivos , Miocardite/induzido quimicamente , Miocardite/tratamento farmacológico , Qualidade de Vida , Neoplasias/tratamento farmacológico , Miosite/induzido quimicamente , Miosite/tratamento farmacológicoRESUMO
BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Quinazolinonas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundário , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Taxa de SobrevidaAssuntos
Anemia Ferropriva , Gastroscopia/métodos , Ipilimumab/administração & dosagem , Melanoma Amelanótico , Neoplasias Cutâneas , Neoplasias Gástricas , Estômago/diagnóstico por imagem , Idoso , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/etiologia , Antineoplásicos Imunológicos/administração & dosagem , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Masculino , Melanoma Amelanótico/complicações , Melanoma Amelanótico/tratamento farmacológico , Melanoma Amelanótico/patologia , Melanoma Amelanótico/secundário , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Estômago/patologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/secundárioAssuntos
Pé/patologia , Perna (Membro)/patologia , Linfedema/tratamento farmacológico , Linfedema/etiologia , Papiloma/patologia , Neoplasias Cutâneas/patologia , Idoso , Diuréticos/uso terapêutico , Feminino , Humanos , Linfedema/diagnóstico , Linfedema/patologia , Masculino , Pessoa de Meia-Idade , Papiloma/complicações , Papiloma/diagnóstico , Papiloma/tratamento farmacológico , Fitoterapia/métodos , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Resultado do TratamentoRESUMO
Multi-drug-resistant tuberculosis (MDR-TB) has emerged as an obstacle to the control of tuberculosis. Recent data however, suggest that interferon-(IFN)-gamma and IFN-alpha may improve disease evolution in subjects affected with pulmonary tuberculosis caused by multi-resistant (IFN-gamma) and sensitive (IFN-alpha) strains. The mechanisms involved are not known, even though it has been reported that IFN-gamma-secreting CD4+ Th cells may possess antitubercular effects. In addition, IFN-alpha can induce IFN-gamma secretion by CD4+ Th cells, and both types of IFN may stimulate macrophage activities. The aim of this study was to explore the possibility that aerosolized IFN-alpha, administered concomitantly with conventional antitubercular chemotherapy, may improve the course of pulmonary tuberculosis. After six months of directly observed therapy (DOT), seven patients who were non-responders to a second line antitubercular therapy were given an IFN-alpha aerosol (3 MU, three times a week) for two months as adjunctive therapy. All strains were resistant to at least two first-line drugs. After IFN-alpha administration, the patients were followed up for a further six months with the same DOT. Sputum samples were collected monthly during the study period, with the exception of the IFN-alpha administration period, when the observations were performed weekly. High resolution computed tomography (HRCT) chest scans were performed before and after IFN-alpha inhalations. The analysis of the results showed that the mean number of Mycobacterium tuberculosis (Mt) had remained statistically unchanged (p = 0.80) during the first 6 months of DOT. During the following 2 months of IFN-alpha administration, 5 patients became negative (p = 0.02). After the end of treatment a progressive increase in Mt number was observed (p = 0. 02). Sputum cultures remained positive for all patients throughout the study period, although a significant decrease (p = 0.02) in the colony number per culture was observed after adjunctive treatment with IFN-alpha. After stopping administration of IFN-alpha, a significant increase (p = 0.03) in the colony number per culture was noted as well as in Mt numbers. HRCT scans were slightly improved in all patients. These preliminary data suggest that aerosolized IFN-alpha may be a promising adjunctive therapy for patients with MDR-TB. Optimal doses and schedules however, require further studies.
Assuntos
Resistência a Múltiplos Medicamentos , Interferon-alfa/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Aerossóis , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Humanos , Interferon-alfa/administração & dosagem , Interleucinas/análise , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Escarro/microbiologia , Fator de Necrose Tumoral alfa/análiseRESUMO
BACKGROUND: The phenotypic characteristics that allow some tumor cells to metastasize have not been fully identified. The production and/or response of tumor cells to various growth factors have been shown to distinguish cells of differing metastatic potentials. OBJECTIVES: To determine (1) whether rat hepatocellular carcinoma cell lines produce interleukin-6 (IL-6) and (2) whether production of IL-6 correlates with either metastatic potential or tumorigenicity. METHODS: The clonal cell lines 1682.C.2.9.L0 (poorly metastatic) and 1682.C.2.9.L10 (highly metastatic) were selected from a parental hepatocellular carcinoma induced in ACI rats by feeding an ethionine-containing diet and adapted to growth in vitro. RESULTS: Both cell lines resulted in primary tumors with equal frequency and developed a 40-mm nodule in a similar period time, when an inoculum of 5 X 10(6) cells was injected subcutaneously; however, only L10 cells metastasized to the lung. These cell lines did not demonstrate differential expression of several antigens noted to correlate with metastatic potential, including CD44 variant glycoprotein, p53, transferrin receptor, and E-cadherin. In contrast, L0 cells produced less than 10 U of IL-6 per milliliter in culture (as determined by bioassay using 7TD1 cells), whereas L10 cells released more than 95 U of this cytokine per milliliter under identical culture conditions (P<.01, Student's t test). In addition, serum concentrations of IL-6 were elevated in animals bearing L10-induced primary tumors but not in those with L0-induced tumors of comparable mass. Exogenous addition of IL-6 to both tumor cell lines had no effect on the rate of growth in vitro, supporting the similar the tumorigenic potentials observed in vivo. CONCLUSION: Excess IL-6 production appears to identify cells with metastatic potential and does not appear to be essential to the establishment of a primary tumor.
Assuntos
Interleucina-6/biossíntese , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Animais , Linhagem Celular/efeitos dos fármacos , Células Clonais/efeitos dos fármacos , Interleucina-6/farmacologia , Masculino , Metástase Neoplásica , Ratos , Ratos EndogâmicosRESUMO
Using an automated cytochemical analyzer used for routine differential counts, we have been able to demonstrate acquired myeloperoxidase deficiency in 102 patients at our institution. Clinical and laboratory data on these patients showed a high incidence of diabetes mellitus (25.5%) and thrombotic diseases (24.5%), as well as a strikingly constant hyperfibrinogenemia (mean = 635 mg/100 ml; range = 360-1015 mg/100 ml). In 4 additional acute leukemia patients in complete remission, a close time correlation was noted between acquired MPO deficiency, diffuse intravascular coagulation and relapse. These findings indicate the importance of the relationships between neutrophil granulocytes and blood coagulation, and suggest that similar changes in neutrophil MPO activity may represent an early morphological indicator of subclinical activation of blood coagulation.
Assuntos
Coagulação Sanguínea , Neutrófilos/enzimologia , Peroxidase/deficiência , Peroxidases/deficiência , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Diabetes Mellitus/enzimologia , Coagulação Intravascular Disseminada/enzimologia , Feminino , Fibrinogênio/metabolismo , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/enzimologia , Masculino , Pessoa de Meia-Idade , Peroxidase/sangue , Trombose/enzimologiaRESUMO
A sensitive, reproducible and easily performed enzyme immunoassay (EIA) based on a sandwich technique is described for serological detection of HBeAg and anti-HBe. EIA appears to be 600 times more sensitive than immunodiffusion and counterimmunoelectrophoresis and its performance compares well with available radioimmunoassays.