RESUMO
Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy. T-cells from mesothelioma patients were uniformly amenable to T4 genetic modification and expansion/enrichment thereafter using IL-4. Patient-derived T4+ T-cells were activated upon contact with a panel of four mesothelioma cell lines, leading to cytotoxicity and cytokine release in all cases. Adoptive transfer of T4 immunotherapy to SCID Beige mice with an established bioluminescent LO68 mesothelioma xenograft was followed by regression or eradication of disease in all animals. Despite the established ability of T4 immunotherapy to elicit cytokine release syndrome in SCID Beige mice, therapy was very well tolerated. These findings provide a strong rationale for the clinical evaluation of intracavitary T4 immunotherapy to treat mesothelioma.
Assuntos
Receptores ErbB/metabolismo , Terapia Genética/métodos , Imunoterapia Adotiva/métodos , Interleucina-4/metabolismo , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/transplante , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/transplante , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Receptores ErbB/imunologia , Humanos , Interleucina-4/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Mesotelioma/genética , Mesotelioma/imunologia , Mesotelioma/metabolismo , Mesotelioma Maligno , Camundongos SCID , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-4/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Transdução Genética , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: In patients presenting with acute cardiac symptoms, abnormal ECG and raised troponin, myocarditis may be suspected after normal angiography. AIMS: To analyse cardiac magnetic resonance (CMR) findings in patients with a provisional diagnosis of acute coronary syndrome (ACS) in whom acute myocarditis was subsequently considered more likely. METHODS AND RESULTS: 79 patients referred for CMR following an admission with presumed ACS and raised serum troponin in whom no culprit lesion was detected were studied. 13% had unrecognised myocardial infarction and 6% takotsubo cardiomyopathy. The remainder (81%) were diagnosed with myocarditis. Mean age was 45±15 years and 70% were male. Left ventricular ejection fraction (EF) was 58±10%; myocardial oedema was detected in 58%. A myocarditic pattern of late gadolinium enhancement (LGE) was detected in 92%. Abnormalities were detected more frequently in scans performed within 2 weeks of symptom onset: oedema in 81% vs 11% (p<0.0005), and LGE in 100% vs 76% (p<0.005). In 20 patients with both an acute (<2 weeks) and convalescent scan (>3 weeks), oedema decreased from 84% to 39% (p<0.01) and LGE from 5.6 to 3.0 segments (p=0.005). Three patients presented with sustained ventricular tachycardia, another died suddenly 4 days after admission and one resuscitated 7 weeks following presentation. All 5 patients had preserved EF. CONCLUSIONS: Our study emphasises the importance of access to CMR for heart attack centres. If myocarditis is suspected, CMR scanning should be performed within 14 days. Myocarditis should not be regarded as benign, even when EF is preserved.
Assuntos
Síndrome Coronariana Aguda/diagnóstico , Miocardite/diagnóstico , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Meios de Contraste , Diagnóstico Diferencial , Edema Cardíaco/diagnóstico , Feminino , Gadolínio , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Fatores de Tempo , Troponina/sangue , Adulto JovemRESUMO
Collapsing focal segmental glomerulosclerosis can be idiopathic but has been associated with human immunodeficiency virus infection as well as lymphoproliferative, myeloproliferative, and autoimmune disorders. It has a more rapid progression to end-stage renal failure. Treatment of this condition is poorly defined with no clear evidence of response to any treatment regimens. We report a case of collapsing focal segmental glomerulosclerosis in association with multiple myeloma that underwent partial remission following treatment for the underlying disease.
