Our data further support the importance of EGFR mutation with regard to gefitinib sensitivity. In addition to its predictive role, EGFR mutation confers significant survival benefits on NSCLC patients treated with gefitinib.
Background:Colorectal cancer (CRC) is a leading cause of death in the United States. Increased level of interleukin-8 (IL-8) and CXCR2 on tumours and in the tumour microenvironment has been associated with CRC growth, progression and recurrence in patients. Here, we aimed to evaluate the effects of tissue microenvironment-encoded IL-8 and CXCR2 on colon cancer progression and metastasis.Methods:A novel immunodeficient, skin-specific IL-8-expressing transgenic model was generated to evaluate colon cancer growth and metastasis. Syngeneic mouse colon cancer cells were grafted in CXCR2 knockout (KO) mice to study the contribution of CXCR2 in the microenvironment to cancer growth.Results:Elevated levels of IL-8 in the serum and tumour microenvironment profoundly enhanced the growth of human and mouse colon cancer cells with increased peri-tumoural angiogenesis, and also promoted the extravasation of the cancer cells into the lung and liver. The tumour growth was inhibited in CXCR2 KO mice with significantly reduced tumour angiogenesis and increased tumour necrosis.Conclusion:Increased expression of IL-8 in the tumour microenvironment enhanced colon cancer growth and metastasis. Moreover, the absence of its receptor CXCR2 in the tumour microenvironment prevented colon cancer cell growth. Together, our study demonstrates the critical roles of the tumour microenvironment-encoded IL-8/CXCR2 in colon cancer pathogenesis, validating the pathway as an important therapeutic target.
This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m À2 at week 1 and 250 mg m À2 weekly thereafter until disease progression. Oxaliplatin (100 mg m À2 ) and leucovorin (100 mg m À2) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m À2 ) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1 -65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5 -6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-a levels showed a 100% RR compared to 37.0% in the remaining 27 patients (Po0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.
Non-invasive genomic profiling of tumors may be possible with next-generation sequencing (NGS) of blood-derived circulating tumor DNA (ctDNA), but proof of concept in a large cohort of patients with diverse cancers has yet to be reported. Here we report the results of an analysis of plasma-derived ctDNA from 670 patients with diverse cancers. The tumors represented in the patient cohort were mainly gastrointestinal (31.8%), brain (22.7%) or lung (20.7%). ctDNA obtained from most patients (N = 423 (63%)) displayed at least 1 alteration. The most frequent alterations seen, as characterized mutations or variations of unknown significance, occurred in TP53 (32.5% of patients), EGFR (13%), KRAS (12.5%) and PIK3CA (9.1%); for characterized alterations, 30.7% (TP53), 7.6% (EGFR), 12.2% (KRAS), and 7.7% (PIK3CA). We found that 32% of brain tumors had at least 1 ctDNA alteration. Head and neck tumors were independently associated with a higher number of alterations in a multivariable analysis (P=0.019). Notably, 320/670 (48%) of patients displayed potentially actionable alterations with 241 patients possible candidates for on-label or off-label treatment with an FDA-approved drug. Several illustrations of the clinical utility of the information obtained for improving treatment of specific patients is provided. Our findings demonstrate the feasibility and impact of genomic profiling of tumors by ctDNA next-generation sequencing, greatly encouraging broader investigations of the application of this technology for precision medicine in cancer management.
Convection is the primary transport process in the Earth's atmosphere. About two-thirds of the Earth's rainfall and severe floods derive from convection. In addition, two-thirds of the global rain falls in the tropics, while the associated latent heat release accounts for three-fourths of the total heat energy for the Earth's atmosphere. Cloud-resolving models (CRMs) have been used to improve our understanding of cloud and precipitation processes and phenomena from micro-scale to cloud-scale and mesoscale as well as their interactions with radiation and surface processes. CRMs use sophisticated and realistic representations of cloud microphysical processes and can reasonably well resolve the time evolution, structure, and life cycles of clouds and cloud systems. CRMs also allow for explicit interaction between clouds, outgoing longwave (cooling) and incoming solar (heating) radiation, and ocean and land surface processes. Observations are required to initialize CRMs and to validate their results. The Goddard Cumulus Ensemble model (GCE) has been developed and improved at NASA/Goddard Space Flight Center over the past three decades. It is a multi-dimensional non-hydrostatic CRM that can simulate clouds and cloud systems in different environments. Early improvements and testing were presented in and Tao et al. (2003a). A review on the application of the GCE to the understanding of precipitation processes can be found in Tao (2003). In this paper, recent model improvements (microphysics, radiation and land surface processes) are described along with their impact and performance on cloud and precipitation events in different geographic locations via comparisons with observations. In addition, recent advanced applications of the GCE are presented that include understanding the physical processes responsible for diurnal variation, examining the impact of aerosols (cloud condensation nuclei or CCN and ice nuclei or IN) on precipitation processes, utilizing a satellite simulator to improve the
Background: Optimal chemotherapy for advanced biliary tract cancer (BTC) is yet to be defined. We carried out this study to evaluate the efficacy and toxicity of combination chemotherapy with S-1 and cisplatin in metastatic or relapsed BTC. , and progressive disease in 9 (18%). With a median follow-up of 12.4 months, the median time to progression was 4.8 months (95% CI, 3.3-6.3) and median overall survival was 8.7 months (95% CI, 6.0-11.4). Major toxic effects were grade 3/4 neutropenia (8.9% of all cycles) and febrile neutropenia was observed in six cycles (2.7% of all cycles). Conclusion:Combination chemotherapy with S-1 and cisplatin was a moderately effective outpatient-based regimen in BTC patients. Toxic effects were moderate but manageable.
Background The prognostic potential of PD-L1 is currently unclear in gastric carcinomas, although the immune checkpoint PD-1/PD-L1 inhibitors have produced promising results in clinical trials. Methods We explored the prognostic implications of programmed death ligand 1 (PD-L1) in 514 consecutive surgically-resected gastric carcinomas. Overall survival and recurrence-free survival were evaluated. Immunohistochemistry for PD-L1, CD8, FOXP3, and PD-1, and molecular grouping by in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs and multiplex PCR for microsatellite instability (MSI) markers were performed. Additionally, to explore the function inherent to PD-L1, PD-L1-specific siRNA transfection, cell proliferation, invasion, migration and apoptosis assays were conducted in five gastric carcinoma cell lines. Results PD-L1(+) tumor and immune cells were observed in 101 (20%) and 244 patients (47%), respectively. “Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8+/low tumor-infiltrating lymphocytes (TILs),” and more advanced-stage tumors were associated with unfavorable clinical outcomes in the entire cohort through multivariate analysis. Furthermore, tumoral PD-L1(+)/FOXP3+/low TILs were associated with worse clinical outcomes in EBV-positive and MSI-high carcinomas. Tumoral PD-L1(+) alone was an adverse prognostic factor in EBV-positive carcinomas, but not in MSI-high carcinomas, whereas PD-L1(+) immune cells or FOXP3+/high TILs alone were correlated with a favorable prognosis. PD-L1 knockdown in gastric carcinoma cells suppressed cell proliferation, invasion and migration, and increased apoptosis, which were all statistically significant in two EBV(+) cell lines, but not all in three EBV(−) cell lines. Conclusions The prognostic impact of PD-L1 may depend on the tumor microenvironment, and statuses of EBV and MSI, although PD-L1 innately promotes cancer cell survival in cell-based assays. The combination of “tumoral PD-L1/immune cell PD-L1/CD8+ TILs” may serve as an independent prognostic factor. Tumoral PD-L1(+)/immune cell PD-L1(−)/CD8+/low TILs showing a worse prognosis may be beneficial for combinatorial therapies of anti-PD-L1/PD-1 and anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA4) that would promote effector T cells, thus attack the tumor.
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