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BACKGROUND: Small-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies. METHODS: Eligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate. RESULTS: Forty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand-foot syndrome, increased L-gamma-glutamyltransferase. CONCLUSIONS: Apatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted. TRIAL REGISTRATION: NCT02945852.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Piridinas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Adulto , Anciano , Neoplasias Encefálicas/secundario , Femenino , Síndrome Mano-Pie/etiología , Humanos , Hipertensión/inducido químicamente , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Compuestos de Platino/uso terapéutico , Supervivencia sin Progresión , Carcinoma Pulmonar de Células Pequeñas/secundario , Tasa de Supervivencia , Insuficiencia del Tratamiento , Resultado del Tratamiento , gamma-Glutamiltransferasa/sangreRESUMEN
BACKGROUND: Esophageal sarcomatoid carcinoma (ESC) is a rare disease with a mixture of both carcinomatous and sarcomatous components in the tumor. Its genetic background and mechanisms of oncogenesis remain largely unknown. METHODS: Here we performed targeted next generation sequencing (NGS) on a pan-cancer gene panel in 15 ESC tumors to explore their genetic alterations, and aimed to identify clinically actionable mutations for future treatment instructions. RESULTS: TP53 alterations were identified in all patients. Alterations in receptor tyrosine kinases (RTK) were identified in 10 out of 15 patients. Members of downstream RAS and PI3-kinase pathways are also mutated in 10 patients, and PIK3CA is the top mutated gene in these pathways. In addition, we identified mutations on histone modification genes in 5 patients, including histone acetyltransferase gene EP300 and its homologue CREBBP, lysine methyltransferase genes KMT2A and KMT2B, and lysine demethylase gene KDM5A. Finally, mismatch repair (MMR) genes and proofreading gene POLE all together were mutated in one third of the ESC patients. CONCLUSIONS: This is the first study to unravel the mutational profile of ESC tumors. Our findings could match 9 patients to the targeted therapies currently available in clinical practice or in active clinical trials, suggesting the potential utility of targeted therapies for this rare disease in the future.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Anciano , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Background: Bone metastasis (BM) seriously affects the quality of life and reduces the survival time of patients with non-small-cell lung cancer (NSCLC). The genomic characteristics and potential targets of BMs are yet to be fully explored. Objective: To explore the genetic characteristics and potential targets of BM in NSCLC. Design: In all, 83 patients with NSCLC were retrospectively selected in this study. Genomic characterization of BMs was explored with the analysis of NGS results from primary tumors and BMs in 6 patients, then combined with NGS results of lung tumors in 16 patients with initial recurrence in bone to analyze mutations potentially associated with BMs, and finally, the correlation was further validated in 61 postoperative patients. Methods: The next generation sequencing (NGS) was performed to identify genomic differences between pulmonary primary tumors and BM. Fluorescence in situ hybridization and immunohistochemistry were performed in postoperative tumor tissues from patients who had undergone radical surgery to validate the predictive role of molecular targets for BM. The correlation between cyclin-dependent kinase 4 (CDK4) and BM was evaluated by Pearson's chi-square test. The university of alabama at birminghan cancer data analysis portal (UALCAN) was carried out for the detection of CDK4 expression in lung cancer and the relationship between CDK4 and clinicopathological parameters. The relationship between prognosis and CDK4 expression was analyzed by the Kaplan-Meier plotter. Results: The rate of gene amplification was increased (24% versus 36%) while gene substitution/indel was decreased (64% versus 52%) in BMs. The BM-specific mutations were analyzed in 16 recurrent patients which revealed the highest incidence of CDK4 amplification (18.8%). According to the Kaplan-Meier plotter database, the NSCLC patients with high CDK4 gene expression showed poor overall survival (OS) and recurrence-free survival (RFS) (p < 0.05). The incidence of CDK4 amplification tended to be higher in recurrent patients compared to the patients without BM (18.8% versus 4.7%, p = 0.118). Conclusion: Compared to the primary tumors of NSCLC, the genome of BMs showed an increased proportion of amplification and a decreased proportion of gene substitution/indel. Furthermore, the CDK4 amplification ratio seemed to be elevated in NSCLC patients with BM which may be associated with poor OS and RFS.
Genomic characterization and potential targets of bone metastasis in non-small cell lung cancer NGS was performed on the matched primary tumors and bone metastases to explore the differences in the genomes of bone metastases, and it was found that gene amplification increased in bone metastases. Combined with the results of NGS in NSCLC patients with the first postoperative recurrence site in the bone, it was found that CDK4 amplification expression increased in bone metastases. Finally, the correlation between bone metastasis and CDK4 amplification was verified by expanding the sample.
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BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR alterations typically have worse treatment outcomes than patients with classically EGFR-mutated NSCLC. This study aimed to investigate the efficacy and safety of PD-1 blockade with sintilimab plus anti-angiogenic treatment with anlotinib in patients with NSCLC harboring uncommon EGFR mutations. METHODS: Patients with metastatic NSCLC harboring uncommon EGFR mutations after two previous treatments, including a platinum-based chemotherapy regimen and a targeted treatment (or chemotherapy only for patients harboring EGFR ex20ins), received sintilimab combined with anlotinib. The primary endpoint was objective response rate (ORR). RESULTS: At data cutoff (September 27, 2022), median follow-up was 22.3 months (range, 1.2-37.6). Among 21 enrolled patients, 12 had EGFR ex20ins and nine had other uncommon EGFR mutations such as L861Q, G719A, and G709X. Overall, eight patients (38.1%) achieved an objective response, and 18 (85.7%) achieved disease control. Median (95% CI) progression-free survival (PFS) was 7.0 (5.4-8.6) months, and median overall survival (OS) was 20.0 (15.6-24.4) months. The 12-month PFS rate (95% CI) was 22.2% (7.4-42.0), and the 12-month OS rate was 66.7% (42.5-82.5). Patients harboring EGFR ex20ins had similar ORR and PFS to those with other mutations. Six patients (28.6%) experienced grade 3 treatment-related adverse events (TRAEs); hand-foot syndrome was the most common grade 3 TRAE (2 patients; 9.5%). No grade ≥4 TRAEs were observed. CONCLUSIONS: The combination of sintilimab and anlotinib demonstrated durable efficacy and was generally well tolerated in patients with NSCLC and uncommon EGFR mutations who had received prior standard-of-care treatments. (ClinicalTrials.gov identifier: NCT04790409).
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Estudios Prospectivos , Mutación , Receptores ErbB/genéticaRESUMEN
Background: QL1604 is a humanized immunoglobulin G4 monoclonal antibody against programmed cell death protein 1. This first-in-human, open-label phase I study aimed to investigate the safety and tolerability and to identify the recommended doses of QL1604 for future studies. Pharmacokinetics/pharmacodynamics (PK/PD) and preliminary antitumor activity were also assessed. Methods: Patients with advanced or metastatic solid tumors who failed or had no standard therapies available were recruited. In the dose-escalation phase, patients were treated with QL1604 at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg intravenously once every 2 weeks (Q2W) in an accelerated titration with a traditional 3 + 3 design, followed by a dose-expansion phase at 3 mg/kg Q2W, 3 mg/kg once every 3 weeks (Q3W), 10 mg/kg Q2W and a fixed dose of 200 mg Q3W. Dose-limiting toxicities (DLTs) were assessed during the first 28 days after the first dose of study drug. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, and antitumor activity of QL1604 was evaluated by investigators on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. Results: A total of 35 patients with advanced or metastatic solid tumors were enrolled. DLTs were reported in one patient at the dose level of 3 mg/kg Q2W (grade 3 immune-mediated myositis and myasthenia gravis), and maximum tolerated dose was not reached. The most frequent treatment-related AEs (≥10%) were fatigue (37.1%), anemia (22.9%), increased blood thyroid-stimulating hormone (17.1%), increased aspartate aminotransferase (AST) (17.1%), increased alanine aminotransferase (ALT) (14.3%), decreased white blood cell (WBC) count (11.4%), rash (14.3%), and pruritus (14.3%). AEs leading to discontinuation of QL1604 occurred in three of the 35 patients (8.6%). Partial responses (PRs) occurred in seven patients, resulting in an objective response rate of 20.0% (7/35). Single dose of QL1604 exhibited a dose-dependent increase in the exposure ranging from 0.3 mg/kg to 10 mg/kg. Mean receptor occupancy (RO) for QL1604 at the dose of 3 mg/kg (Q2W and Q3W) and 200 mg (Q3W) was greater than 80% during cycle 1 after one infusion. Conclusion: QL1604 monotherapy exhibited favorable safety, PK, and signal of antitumor activity in patients with advanced or metastatic solid tumors, and the results supported further clinical studies of QL1604. On the basis of the safety, PK, and RO data, the recommended dosage for further clinical trials is 3 mg/kg or a fixed dose of 200 mg given every 3 weeks. Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT05649761?term=QL1604&draw=2&rank=1, identifier NCT05649761.
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Miositis , Neoplasias Primarias Secundarias , Neoplasias , Humanos , Neoplasias/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Criterios de Evaluación de Respuesta en Tumores Sólidos , Miositis/inducido químicamenteRESUMEN
Osimertinib, a mutant-specific third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is emerging as the preferred first-line of treatment for EGFR-mutant lung cancer. However, osimertinib resistance inevitably develops among patients treated with the drug. The modal resistance mechanisms of osimertinib include the occurrence of epithelial transition factor (c-MET) amplification and C797S mutation, whereas rare mutations are presented as case reports. Recently, the L718Q/V mutation in exon 18 of EGFR has been reported to contribute to one of the possible mechanisms of resistance. The clinical features and subsequent treatment strategies for this mutation require further research. This study retrospectively enrolled NSCLC patients with the L718Q/V mutation from 2017 to 2021 at the Cancer Hospital of the University of the Chinese Academy of Sciences (Zhejiang Cancer Hospital), as well as additional patients with the same mutation from PubMed literature, to summarize the clinical features of the mutation. The association between the detection of L718Q/V and resistance to osimertinib, as well as impacts on the therapeutic process and outcome, was analyzed. We included a total of two patients diagnosed at Zhejiang Cancer Hospital and twelve patients from the literature. Of the fourteen total patients, 64.3% were male and 35.7% were female. The average age of the group was 60.2 years (range 45-72). A history of tobacco use was common among the group. In all of the cases we considered, the L718Q/V mutation was secondary to the L858R mutation. The second-generation TKI afatinib was found to provide a high disease control rate (DCR) (85.7%, 6/7) and relatively low objective response rate (ORR) (42/9%, 3/7). The median progression free survival (mPFS) for this treatment reached 2 months (1-6 months). The patients failed to benefit from chemotherapy combined with immunotherapy or other TKI medications. Due to the limited number of cases considered in this study, future studies should explore drugs that more precisely target the L718Q/V mutation of EGFR exon 18.
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BACKGROUND: By using cDNA microarray analysis, we identified a G protein-coupled receptor, GPR39, that is significantly up-regulated in ESCC. The aim of this study is to investigate the role of GPR39 in human esophageal cancer development, and to examine the prevalence and clinical significance of GPR39 overexpression in ESCC. METHODS: The mRNA expression level of GPR39 was analyzed in 9 ESCC cell lines and 50 primary ESCC tumors using semi-quantitative RT-PCR. Immunohistochemistry was used to assess GPR39 protein expression in tissue arrays containing 300 primary ESCC cases. In vitro and in vivo studies were done to elucidate the tumorigenic role of GPR39 in ESCC cells. RESULTS: We found that GPR39 was frequently overexpressed in primary ESCCs in both mRNA level (27/50, 54%) and protein level (121/207, 58.5%), which was significantly associated with the lymph node metastasis and advanced TNM stage (P < 0.01). Functional studies showed that GPR39 has a strong tumorigenic ability. Introduction of GPR39 gene into ESCC cell line KYSE30 could promote cell proliferation, increase foci formation, colony formation in soft agar, and tumor formation in nude mice. The mechanism by which amplified GPR39 induces tumorigenesis was associated with its role in promoting G1/S transition via up-regulation of cyclin D1 and CDK6. Further study found GPR39 could enhance cell motility and invasiveness by inducing EMT and remodeling cytoskeleton. Moreover, depletion of endogenous GPR39 by siRNA could effectively decrease the oncogenicity of ESCC cells. CONCLUSIONS: The present study suggests that GPR39 plays an important tumorigenic role in the development and progression of ESCC.
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Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Receptores Acoplados a Proteínas G/genética , Animales , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , Análisis por Micromatrices , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiología , Análisis de Matrices Tisulares , Trasplante Heterólogo , Regulación hacia Arriba/genética , Regulación hacia Arriba/fisiologíaRESUMEN
Purpose: The Myc family, especially C-MYC and MYCL1, has been found involved in small-cell lung carcinoma (SCLC). Identification of the frequency of C-MYC and MYCL1 expression among SCLC patients may help to identify potential targets for therapeutic intervention. Our aim was to detect MYCL1 amplification, L-Myc and c-Myc expression, and investigate clinicopathological characteristics and survival status in patients with surgically resected SCLC. Methods: MYCL1 amplification was detected using fluorescence in situ hybridization (FISH), while L-Myc and c-Myc protein expressions were determined using immunohistochemistry (IHC) in the primary tumors of 46 resected SCLC patients. Results: Among the 46 evaluated specimens, MYCL1 amplification was identified in 3/46 cases (6.5%). One of the positive cases was MYCL1 gene amplification combined with fusion. 3/46 (6.5%) was positive for L-myc protein expression, and 4/46 (8.7%) was positive for c-Myc protein expression. Conclusion: Our study firstly multidimensional explored the expression of MYCL1 amplification, L-Myc and c-Myc protein and investigated clinicopathological characteristics and survival status in patients with surgically resected SCLC, which makes a contribution to subsequent research and therapeutic strategies.
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Biomarcadores de Tumor/metabolismo , Amplificación de Genes , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Biomarcadores de Tumor/genética , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/cirugía , Tasa de SupervivenciaRESUMEN
E10A, a replication-defective adenovirus carrying human endostatin gene, has finished Phase I clinical trials for solid cancers. We assessed whether the combination of E10A with docetaxel would enhance antiangiogenic activities and inhibit prostate cancer growth and metastases. Combination use of conditioned medium from prostate cancer cells infected by E10A and docetaxel exerted synergistic inhibition of HUVECs proliferation, migration and tube formation, compared with either agent alone. In prostate cancer s.c. xenograft models, combined therapy resulted in significant tumor growth inhibition and survival improvement. The antitumoral effect was tightly correlated with a remarkable decrease in tumor cell proliferation, microvessel, especially immature vasculature and significant increase in apoptosis induction. Systemic administration of E10A and docetaxel also effectively inhibited orthotopic growth and metastases of prostate cancer and achieved better in vivo antiangiogenic effects than either agent alone. Our data indicate that E10A in combination with docetaxel exert enhanced antiangiogenic activities and inhibit prostate cancer growth and metastases. Therefore, this approach may be an effective treatment for advanced prostate cancer and deserves more extensive investigation.
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Inhibidores de la Angiogénesis/uso terapéutico , Endostatinas/genética , Terapia Genética , Neoplasias de la Próstata/terapia , Taxoides/uso terapéutico , Adenoviridae/genética , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Terapia Combinada , Docetaxel , Endostatinas/farmacología , Vectores Genéticos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Desnudos , Metástasis de la Neoplasia/terapia , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/fisiopatología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Purpose: Fibroblast growth factor receptor 1 (FGFR1) alterations have been described in many cancers, including lung cancer, but the role has not been elucidated specifically in small cell lung cancer (SCLC). The present study aimed to identify the frequency of FGFR1 alterations among Chinese patients with surgically resected SCLC and the association with the clinicopathological characteristics and the survival were also investigated. Methods: FGFR1 protein expression, FGFR1 amplification, FGFR1 mutations, and messenger RNA (mRNA) levels, were determined by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) and reverse transcription-polymerase chain reaction (RT-PCR), respectively in primary tumors from 33 patients with resected SCLC. Results: 7/33(21.2%) of the specimens were positive for FGFR1 protein expression. FGFR1 amplification was identified in 4/28 cases (14.3%). If the cut-off value was determined to be 3.5, FGFR1 mRNA positivity was considered in 7/33 cases (21.2%). However, no mutation was detected in the 33 SCLC postoperative tissue specimens. No significant association was observed between FGFR1 protein expression or amplification and clinicalcharacteristics or prognosis. There was a distinct trend for mRNA level and poor prognosis, including recurrence-free survival (RFS) (p = 0.07) and overall survival (OS) (p= 0.08), but they did not reach statistical significance. Conclusions: As novel FGFR1-targeted therapies are developed, FISH, IHC, especially mRNA were detected, which should be considered as biomarkers of FGFR1 pathway dysregulation in SCLC.
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Two patients with rare GCC2-ALK fusion G13:A20 which were found in Chinese population by next generation sequencing (NGS) developed resistant to crizotinib with a prolonged progression-free survival (PFS). Both patients showed unfavorable response to subsequent second or third generation tyrosine kinase inhibitors (TKIs) treatment with shorten PFS. In conclusion, non-small cell lung cancer (NSCLC) patients with rare GCC2-ALK fusion G13:A20 may be optimal candidates for crizotinib as front-line therapy and may have a high possibility to exhibit unsatisfactory response to subsequent second or third generation TKIs target therapy after acquiring resistance to crizotinib.
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BACKGROUND: Irinotecan (CPT-11) can be used as a first-line therapeutic drug against extensive-stage small cell lung cancer (SCLC); it can also be used in second-line treatment for SCLC. CPT-11-induced delayed diarrhea restricts its clinical application. This study aimed to confirm whether Banxia Xiexin decoction was effective in preventing and controlling CPT-11-induced delayed diarrhea. METHODS: A total of 27 patients with recurrent SCLC undergoing chemotherapy regimens including CPT-11 were enrolled for the study. UGT1A1*28, UGTlAl*6, ABCB1*2, and SLCO1B1*15 gene polymorphisms were detected. If delayed diarrhea occurred in the first cycle of chemotherapy, Banxia Xiexin decoction was orally administered for 5 consecutive days starting 1 day before the second cycle of chemotherapy to prevent and control the delayed diarrhea. The objective response, overall survival, and toxicity were recorded. RESULTS: Complete response, partial response, and stable disease were observed in none, 6, and 10 patients, respectively. Delayed diarrhea occurred in 6 patients, and 4 of 5 patients were relieved or controlled using Banxia Xiexin decoction. The median overall survival was 6 months. CONCLUSION: Banxia Xiexin decoction appeared to prevent and control delayed diarrhea induced by CPT-11 in this small observational study, and further study with a larger sample size, including potentially randomized trials, is suggested.
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Diarrea/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Irinotecán/efectos adversos , Irinotecán/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/efectos de los fármacosRESUMEN
BACKGROUND: The prognosis for small-cell lung cancer (SCLC) is very poor, so a new therapeutic strategy and new drugs are imperative. OBJECTIVES: The aim of this study was to examine the effect of metformin on the prognosis of patients with SCLC combined with diabetes mellitus (DM). MATERIAL AND METHODS: From 2005 to 2013, 32 patients (4 female and 28 male) with SCLC combined with DM were included in this retrospective study at the Zhejiang Cancer Hospital, China. All patients were diagnosed with SCLC by pathological analysis and had received more than 4 cycles of chemotherapy. Metformin was used in 12 patients. Seventeen patients had limited-stage disease (LD) and 15 patients had extensive-stage disease (ED). Patients with LD SCLC were administered thoracic radiotherapy. The follow-up deadline was January 27, 2016. At that point, 4 patients were alive, 21 patients had died, and 7 patients did not participate in follow-up examinations. RESULTS: In patients with SCLC combined with DM using metformin, a complete response (CR) was observed in 4 patients, a partial response (PR) in 6 patients, a stable disease (SD) in 1 patient, and a progressive disease (PD) in 1 patient, whereas in patients who did not use metformin, CR was observed in 2 patients, PR in 15 patients, SD in 2 patients, and PD in 1 patient (p = 0.384). There was no difference in the median survival time (MST) between patients using metformin and those who did not (12 vs 13 months; p = 0.784). There was a trend toward prolonged MST in patients with LD SCLC using metformin compared with those who did not use metformin (58 vs 29 months; p = 0.084). There was no difference due to the use of metformin observed in MST of patients with ED SCLC (12 vs 13 months; p = 0.396). CONCLUSIONS: Metformin use may have a prognostic benefit in patients with SCLC combined with DM. This combination is promising and further clinical trials are required.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Metformina/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , China/epidemiología , Diabetes Mellitus/patología , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Pronóstico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/complicaciones , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Small cell lung cancer (SCLC) is an aggressive and deadly neuroendocrine tumor derived from bronchial epithelial cells. Although it results in a 95% mortality rate, the development of targeted therapies for SCLCs has lagged behind. The aim of this study is to better research mutation characteristics of SCLC and identify potential biomarkers for target therapy. METHODS: We utilized high-resolution melting analysis to identify the mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatase and tensin homolog (PTEN), and phosphatidylinositol-3-kinase catalytic (PIK3CA) from the blood. A cohort of 99 SCLC patients including 44 limited-stage disease patients and 55 extensive-stage disease patients were prospectively collected. RESULTS: EGFR 18 (G719X) mutation was found in 5 patients, EGFR 19 (del) mutation in 2, EGFR 20 (T790M) in 3, EGFR 21 (L858R) in 2, KRAS 2 (G13D) in 5, BRAF 15 (V600E) in 1, PIK3CA 9 (E542K) in 1, and no mutations in PTEN 5 (R130G), PTEN 6 (R173C), PTEN 8 (T319fs*1), and PIK3CA 20 (H1047R) were identified. Among these patients, two harbored EGFR double mutation, one patient with EGFR double mutation and KRAS 2 (G13D) mutation. CONCLUSION: The mutation form of EGFR may differ from lung adenocarcinoma, and mutations of KRAS, BRAF, and PIK3CA were rare in SCLC. These results aided us in comprehensively analyzing genetic features and laid the foundation for exploring the possibility of target therapy.
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The present study describes the case of a 48-year-old man who was diagnosed with lung adenocarcinoma with an epidermal growth factor receptor (EGFR) 21 L858R mutation. The patient received surgery and adjuvant chemotherapy. When multiple lung metastases appeared, icotinib was administered. Following resistance to icotinib, biopsy by endobroncheal ultrasonography for a right lung hilar lymph node revealed transformation to a neuroendocrine morphology. Neuron-specific enolase (NSE) levels were elevated, accompanied with disease progression following transformation to the neuroendocrine morphology. The post-operative and biopsy specimens were analyzed for 416 genes using next-generation sequencing, and phosphatidylinositol-3-kinase catalytic α mutation and retinoblastoma loss were evident. Five cycles of etoposide combined with cisplatin were administered and a partial response was achieved. The disease progressed again accompanied with an elevated NSE level, and bronchoscopy examination revealed small cell lung cancer (SCLC) after 3 months. The patient received chemotherapy consisting of irinotecan combined with carboplatin for two cycles and achieved stable disease. Overall, a secondary biopsy is important for the evaluation of genetic and histological changes and the selection of an appropriate treatment following tyrosine kinase inhibitor (TKI) resistance, and NSE may be useful for the early detection of SCLC transformation in cases that are resistant to EGFR-TKI therapy.
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Fasudil has been proven to be a promising chemotherapeutic drug for various malignancies. However, the potential anticancer effects of fasudil in oesophageal squamous cell carcinoma (ESCC) remain to be established. We confirmed the RhoA activity is inhibited by fasudil in ESCC cells. Then measured the effects of fasudil on apoptosis and autophagy in ESCC. Our study showed fasudil could both induce ESCCs apoptosis and autophagy, and when fasudil-induced autophagy was inhibited by knockdown of the essential autophagy genes (Beclin 1 or ATG7), and pharmacologic agent (chloroquine) treatment, both treatments also significantly sensitized ESCC to fasudil-induced apoptosis, reducing cell viability in vitro. Our study showed autophagy inhibitors combined with fasudil could significantly induce ESCC apoptosis, which may provide a novel therapeutic strategy for ESCC.
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Interferon gamma (IFNgamma) is regarded as a potent antitumor agent, but therapy with IFNgamma is hampered by its short half-life and significant side effects. We developed a replication defective adenovirus carrying the human IFNgamma gene and evaluated the effects of adenovirus-mediated IFNgamma (Ad-IFNgamma) gene transfer on human prostate cancer cell lines in vitro and on xenografts in vivo. Our results showed infection of prostate cancer cells with Ad-IFNgamma led to production of an active cytokine and resulted in an antiproliferative effect on the prostate cancer cells. Intratumoral injection of Ad-IFNgamma significantly inhibited the growth of DU-145 cell xenografts in vivo, while no significant toxicity effect was observed. RT-PCR analysis indicated transgene expression mainly enriched in tumors in vivo, and slightly distributed in livers. These findings suggest adenovirus-mediated IFNgamma gene transfer is a promising approach in the treatment of advanced prostate cancer.
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Adenoviridae/genética , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Vectores Genéticos , Interferón gamma/genética , Neoplasias de la Próstata/terapia , Animales , Línea Celular Tumoral , Proliferación Celular , Humanos , Interferón gamma/biosíntesis , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias de la Próstata/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Small cell lung cancer (SCLC) is sensitive to first-line chemotherapy and radiotherapy, but frequently recurs. Temozolomide is a chemotherapeutic drug suitable for the treatment of relapsed SCLC, particularly when brain metastases are present. The response of SCLC to temozolomide may be associated with the methylation status of O6-methyl-guanine-DNA methyltransferase (MGMT). Isocitrate dehydrogenase (IDH) mutation is an independent prognostic factor of good outcome in gliomas and appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. In order to identify the status of MGMT promoter methylation and IDH1/2 mutation of SCLC in China, 33 SCLC specimens from patients that underwent surgery were retrospectively collected in Zhejiang Cancer Hospital (Hangzhou, China) between 2008 and 2014. High-resolution melting analysis and methylation-specific polymerase chain reaction were used to detect MGMT promoter methylation, and polymerase chain reaction amplification and Sanger sequencing were utilized to detect IDH1/2 mutation. Of the 33 examined SCLC specimens, MGMT promoter methylation was detected in 17 patients (51.5%), and no IDH1/2 mutations were detected in the analyzed samples. These findings indicate that the IDH1/2 mutation may not be an ideal marker in SCLC patients treated with temozolomide. Future studies on the predictive and prognostic value of MGMT promoter methylation are urgently required for patients with relapsed SCLC treated with temozolomide in China.
RESUMEN
EGFR-TKIs and radiation therapy (RT) are the principal treatment for patients with brain metastases (BM) and EGFR mutant NSCLC. However, the optimal use of brain RT for patients with asymptomatic BM remains undefined. A total of 152 patients were identified. 58 patients were excluded. Of the remaining 97 patients, 56 patients received upfront RT followed by icotinib, including WBRT or SRS. 41 patients received icotinib therapy alone. The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9-30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P = 0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P = 0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P = 0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P = 0.043). Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Éteres Corona/uso terapéutico , Receptores ErbB/genética , Neoplasias Pulmonares/terapia , Quinazolinas/uso terapéutico , Radiocirugia/métodos , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Éteres Corona/administración & dosificación , Éteres Corona/efectos adversos , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Radiocirugia/efectos adversosRESUMEN
Blood-tumor barrier (BTB) reduce the permeability for drugs into tumor tissues. We found that histamine might serve as an essential regulator of BTB function. Further, we aim to determine the role of H2 receptor expression in BTB permeability, and elucidate the underlying mechanisms thereof. Transmission electron microscopy showed that histamine disrupted the integrity of tight junctions (TJ) and increased the number of pinosomes in the cytoplasm. Horseradish peroxidase (HRP) and trans-endothelial resistance detection (TEER) assays revealed that histamine could open BTB and this action was inhibited by cimetidine. Western blot and immunofluorescence assays showed that histamine decreased the expression of tight junction proteins zonula occluden-1(ZO-1), occludin, and claudin-5. Further, quantitative RT-PCR assay showed that the expression of H2 receptor could represent and predicted histamine-induced BTB permeability. In conclusion, histamine opened BTB by down-regulating the TJ-associated proteins. The levels of H2 receptor expression was correlated with the histamine-induced BTB permeability.