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1.
Nat Cancer ; 4(6): 844-859, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37308678

RESUMEN

Immune-related adverse events (irAEs) induced by checkpoint inhibitors involve a multitude of different risk factors. Here, to interrogate the multifaceted underlying mechanisms, we compiled germline exomes and blood transcriptomes with clinical data, before and after checkpoint inhibitor treatment, from 672 patients with cancer. Overall, irAE samples showed a substantially lower contribution of neutrophils in terms of baseline and on-therapy cell counts and gene expression markers related to neutrophil function. Allelic variation of HLA-B correlated with overall irAE risk. Analysis of germline coding variants identified a nonsense mutation in an immunoglobulin superfamily protein, TMEM162. In our cohort and the Cancer Genome Atlas (TCGA) data, TMEM162 alteration was associated with higher peripheral and tumor-infiltrating B cell counts and suppression of regulatory T cells in response to therapy. We developed machine learning models for irAE prediction, validated using additional data from 169 patients. Our results provide valuable insights into risk factors of irAE and their clinical utility.


Asunto(s)
Enfermedades del Sistema Inmune , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neutrófilos , Factores de Riesgo
2.
Lung Cancer ; 93: 1-8, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26898607

RESUMEN

OBJECTIVES: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their synergistic activity in combination, we conducted a phase II study to determine the clinical activity of sorafenib in combination with erlotinib in patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with advanced NSCLC who have received one or two prior chemotherapy regimens for metastatic disease, ECOG 0-2, and adequate organ function were eligible. Patients received 400mg twice daily sorafenib and 150 mg daily erlotinib in 28-day cycles. Epidermal growth factor receptor mutation and its downstream pathways were analyzed from available tumor samples. Changes in plasma cytokine and angiogenic factors were correlated with clinical outcomes. RESULTS: A total of 46 patients were enrolled. Twenty patients (43%) were never smokers and 35 patients (75%) had adenocarcinoma histology. The overall response rate was 30.4%. Response to sorafenib/erlotinib was observed more commonly in patients with EGFR mutation than in those with EGFR wild type (WT) or EGFR unknown tumors (62.5% vs. 6.7% vs. 34.8%; P=0.013). Likewise, DCR was higher among patients with EGFR mutation than in those with EGFR WT or EGFR unknown tumors (87.5% vs. 46.7% vs. 60.9%; P=0.161). The most frequent adverse events (AEs) of all grades were hand-foot skin reaction (67.4%) followed by acneiform rash (58.7%). CONCLUSION: Sorafenib combined with erlotinib is well-tolerated with manageable toxicity and appears to be effective against advanced NSCLC with one or two prior line of systemic treatment (NCT00801385).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Progresión de la Enfermedad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/administración & dosificación , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Riesgo , Sorafenib , Resultado del Tratamiento
3.
J Clin Apher ; 22(5): 277-82, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17880017

RESUMEN

We previously showed that at least 5/mm(3) hematopoietic progenitor cells (HPCs) could be used as a marker for initiating autologous blood stem cell collection (ABSCC). However, the timing of efficient ABSCC following mobilization is still to be determined. We conducted a prospective, randomized comparison of 5/mm(3) versus 50/mm(3) peripheral blood (PB) HPCs as a surrogate marker to initiate efficient ABSCC. Forty-five consecutive patients, 26 with multiple myeloma (MM) and 19 with non-Hodgkin's lymphoma (NHL), were enrolled between October 2004 and October 2006. Chemotherapy was cyclophosphamide 4 g/m(2) for MM and ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), with or without Rituximab, for NHL. Circulating HPCs were monitored daily with the Sysmex SE9000 automated hematology analyzer, and harvested CD34+ cells were counted by flow cytometry. ABSCC was initiated when HPC levels reached at least 5/mm(3) (HPC5 group) or 50/mm(3) (HPC50 group). The median number of harvested CD34+ cells was 15.0 x 10(6)/kg and 21.0 x 10(6)/kg in the HPC5 and HPC50 groups, respectively (P = 0.23). Optimal collection (>5 x 10(6) CD34+ cells/kg) in a single session (day 1) was attained in 15 HPC5 patients (63%) and in 14 HPC50 patients (67%), and targeted collection of 5 x 10(6) CD34+ cells/kg was achieved in 100 and 95% of HPC5 and HPC50 patients, respectively (P = 0.47), with a median number of 1 apheresis in both groups (P = 0.58). There were no between group differences in optimal collection rate on day 1, median number of aphereses to achieve optimal collection, and overall optimal collection rate. HPC > or = 5/mm(3) and > or =50/mm(3) are both reliable indices for the timing of ABSCC.


Asunto(s)
Recuento de Células Sanguíneas/métodos , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Adulto , Transfusión de Sangre Autóloga , Femenino , Humanos , Linfoma no Hodgkin/cirugía , Masculino , Persona de Mediana Edad , Mieloma Múltiple/cirugía , Estudios Prospectivos , Factores de Tiempo
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