RESUMEN
BACKGROUND: Clinical impact of the Geriatric Nutritional Risk Index (GNRI) in patients with extensive-stage disease small cell lung cancer (ED-SCLC) have not previously been reported. METHODS: This study analyzed 352 patients enrolled in a previous randomized phase III trial comparing the efficacy of irinotecan plus cisplatin with that of etoposide plus cisplatin as the first-line therapy for ED-SCLC. GNRI values were calculated using serum albumin levels and actual and ideal bodyweights. Patients with a GNRI > 98, 92-98, and <92 were grouped into no, low, and moderate/major risk groups, respectively. RESULTS: The objective response rates were 63.2%, 52.6%, and 49.2% in the no, low, and moderate/major risk groups, respectively (P = 0.024). The median progression-free survival (PFS) was shorter in patients with a lower GNRI than in those with a higher GNRI (no vs. low vs. moderate/major risk group; 6.5 vs. 5.8 vs. 5.9 months, respectively; P = 0.028). There were significant differences in median overall survival (OS) according to GNRI (no vs. low vs. moderate/major risk group; 13.2 vs. 10.3 vs. 8.4 months, respectively; P < 0.001). Multivariate analysis revealed that being in the moderate/major risk group was an independent poor prognostic factor for PFS (hazard ratio [HR]: 1.300, 95% confidence interval [CI]: 1.012-1.670; P = 0.040) and OS (HR: 1.539; 95% CI: 1.069-2.216; P = 0.020). CONCLUSIONS: This prospective study shows that a low GNRI value was associated with a poor prognosis, and it supports the relationship between systemic inflammation, nutritional status, and clinical outcomes in patients with ED-SCLC.Key points SIGNIFICANT FINDINGS OF THE STUDY: The lower GNRI group had a low response rate to chemotherapy for ED-SCLC. The HRs for PFS and OS were 1.300 and 1.539 in the patients with GNRI < 92. WHAT THIS STUDY ADDS: Low GNRI is associated with poor prognosis in ED-SCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Evaluación Geriátrica/métodos , Neoplasias Pulmonares/patología , Estado Nutricional , Carcinoma Pulmonar de Células Pequeñas/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Tasa de SupervivenciaRESUMEN
We evaluated the preliminary efficacy and feasibility of a next-generation sequencing (NGS)-based targeted anticancer therapy in refractory solid tumors at a Korean institution. Thirty-six patients with advanced cancer underwent molecular profiling with NGS with the intent of clinical application of available matched targeted agents. Formalin-fixed paraffin-embedded (FFPE) tumors were sequenced using the Comprehensive Cancer Panel (CCP) or FoundationOne in the Clinical Laboratory Improvement Amendments-certified laboratory in the USA. Response evaluations were performed according to RECIST v1.1. Four specimens did not pass the DNA quality test and 32 specimens were successfully sequenced with CCP (n = 31) and FoundationOne (n = 1). Of the 32 sequenced patients, 10 (31.3%) were ≤40 years. Twelve patients (37.5%) had received ≥3 types of prior systemic therapies. Of 24 patients with actionable mutations, five were given genotype-matched drugs corresponding to actionable mutations: everolimus to PIK3CA mutation in parotid carcinosarcoma (partial response) and tracheal squamous cell carcinoma (stable disease; 21% reduction), sorafenib to PDGFRA mutation in auditory canal adenocarcinoma (partial response), sorafenib to BRAF mutation in microcytic adnexal carcinoma (progressive disease), and afatinib to ERBB2 mutation in esophageal adenocarcinoma (progressive disease). Nineteen of 24 patients with actionable mutations could not undergo targeted therapy based on genomic testing because of declining performance status (10/24, 41.7%), stable disease with previous treatment (5/24, 20.8%), and lack of access to targeted medication (4/24, 16.7%). NGS-based targeted therapy may be a good option in selected patients with refractory solid tumors. To pursue this strategy in Korea, lack of access to clinical-grade NGS assays and a limited number of genotype-matched targeted medications needs to be addressed and resolved.
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Antineoplásicos/uso terapéutico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Adulto , Afatinib , Anciano , Pueblo Asiatico/genética , Fosfatidilinositol 3-Quinasa Clase I , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Everolimus/uso terapéutico , Estudios de Factibilidad , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias/etnología , Neoplasias/genética , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Fosfatidilinositol 3-Quinasas/genética , Proyectos Piloto , Medicina de Precisión/métodos , Proteínas Proto-Oncogénicas B-raf/genética , Quinazolinas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , República de Corea , Sorafenib , Adulto JovenRESUMEN
BACKGROUND: Given the modest responses to everolimus, a mTOR inhibitor, in multiple tumor types, there is a pressing need to identify predictive biomarkers for this drug. Using targeted ultra-deep sequencing, we aimed to explore genomic alterations that confer extreme sensitivity to everolimus. RESULTS: We collected formalin-fixed paraffin-embedded tumor/normal pairs from 39 patients (22 with exceptional clinical benefit, 17 with no clinical benefit) who were treated with everolimus across various tumor types (13 gastric cancers, 15 renal cell carcinomas, 2 thyroid cancers, 2 head and neck cancer, and 7 sarcomas). Ion AmpliSeqTM Comprehensive Cancer Panel was used to identify alterations across all exons of 409 target genes. Tumors were sequenced to a median coverage of 552x. Cancer genomes are characterized by 219 somatic single-nucleotide variants (181 missense, 9 nonsense, 7 splice-site) and 22 frameshift insertions/deletions, with a median of 2.1 mutations per Mb (0 to 12.4 mutations per Mb). Overall, genomic alterations with activating effect on mTOR signaling were identified in 10 of 22 (45%) patients with clinical benefit and these include MTOR, TSC1, TSC2, NF1, PIK3CA and PIK3CG mutations. Recurrently mutated genes in chromatin remodeling genes (BAP1; n = 2, 12%) and receptor tyrosine kinase signaling (FGFR4; n = 2, 12%) were noted only in patients without clinical benefit. CONCLUSIONS: Regardless of different cancer types, mTOR-pathway-activating mutations confer sensitivity to everolimus. Targeted sequencing of mTOR pathway genes facilitates identification of potential candidates for mTOR inhibitors.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Everolimus/uso terapéutico , Aparato Lagrimal/patología , Neurofibromina 1/genética , Serina-Treonina Quinasas TOR/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mutación/genética , Fosfatidilinositol 3-Quinasas/genética , Polimorfismo de Nucleótido Simple/genética , Sarcoma/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Neoplasias de la Tiroides/tratamiento farmacológico , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
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).
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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 TratamientoRESUMEN
Transglutaminase 2 (TG2), a cross-linking enzyme, is involved in drug resistance and in the constitutive activation of nuclear factor kappa B (NF-κB). We investigated the association of non-small cell lung cancer (NSCLC) treatment efficacy with TG2 and NF-κB expression in 120 patients: 102 with adenocarcinoma and 18 with other histologic types. All patients underwent surgery; 88 received adjuvant chemotherapy, with 28 receiving platinum-based doublet chemotherapy as first-line treatment and 29 receiving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Patients' TG2 and NF-κB expression values were calculated semiquantitatively. The median TG2 value was 50 (range, 0-300) and the median NF-κB value was 20 (range, 0-240). Disease-free survival did not differ between the low- and high-TG2 groups. Among patients who received palliative platinum-based doublet chemotherapy, progression free survival (PFS) was longer in the low-TG2 group than in the high-TG2 group (11.0 vs. 7.0 months; P=0.330). Among those who received EGFR-TKI therapy, PFS was also longer in the low-TG2 group than in the high-TG 2 group (11.0 vs. 2.0 months; P=0.013). Similarly, in EGFR wild-type patients treated with EGFR-TKI, PFS was longer in patients with low TG2 expression (9.0 vs. 2.0 months; P=0.013). TG2 expression levels can predict PFS in patients with NSCLC treated with EGFR-TKI.
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Adenocarcinoma/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Proteínas de Unión al GTP/biosíntesis , Neoplasias Pulmonares/tratamiento farmacológico , Transglutaminasas/biosíntesis , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Supervivencia sin Enfermedad , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , FN-kappa B/biosíntesis , Proteína Glutamina Gamma Glutamiltransferasa 2 , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
Curcumin as an anticancer agent was investigated in regards to its ability to regulate the switching of cancer cells from survival to necrotic cell death. At higher concentrations, curcumin induced ROS production leading to JNK and p38 phosphorylation in DU-145 prostate cancer cells. Of the MAP kinases, ERK or p38/JNK were phosphorylated earlier during curcumin treatment, and were responsible for curcumin-induced cell survival at early time of treatment with the help of phosphorylated Akt, while significant amounts of ROS production in later periods stimulated cell death with caspase degradation. In addition to autophagic signaling, necrosis was dominant with little apoptotic cell death. Caspase activation was completely prohibited by procaspase degradation, which contributed to curcumin-induced early necrosis. At the later incubation period (24h), cytotoxicity caused by curcumin peaked, at which time survival or proliferation signals, such as phosphorylated Akt and phosphorylated ERK, was almost completely diminished. Curcumin-induced ROS were shown to function, biphasically depending on the incubation period; facilitating survival, in the earlier incubation period, and necrotic death in the later. Based on all of these results, we concluded that curcumin contributes to a complex signaling network, affecting cell survival and necrotic cell death, which in turn could inhibit apoptotic cell death.
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Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Curcumina/toxicidad , Caspasas/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Necrosis/metabolismo , Fosforilación , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: In locally advanced head and neck cancer, concurrent chemoradiotherapy (CRT) with combined 5-fluorouracil (5-FU) and cisplatin has increased acute toxicities as well as survival. Once-weekly chemotherapeutic administration schedule may reduce severe toxicities. Thus, we investigated CRT using weekly administration of 5-FU-cisplatin in locally advanced head and neck cancer. METHODS: In a single-arm, phase II study, CRT included radiation (70.0 Gy/35 fr) and weekly 5-FU (750 mg/m2) and cisplatin (20 mg/m2). RESULTS: Thirty-two patients completed planned radiation. Thirteen (41%) achieved complete response, and 16 (50%) partial response. Twelve patients (38%) experienced acute grade 3 toxicities. Grade 3 mucositis, which was the most common toxicity, developed in 5 (16%) patients. The survival rates at 1 and 2 years were 81% and 76%, respectively. The progression-free survival rates at 1 and 2 years were 69% and 66%, respectively. CONCLUSIONS: We demonstrated weekly 5-FU-cisplatin with conventional radiotherapy was efficacious and feasible with high compliance rate in locally advanced head and neck cancer.