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Purpose To identify the somatic mutated genes for optimal targets of non-small-cell lung cancer after resistance to osimertinib treatment. Patients and Methods Study patients all had advanced lung adenocarcinoma and acquired resistance to osimertinib as a second- or third-line treatment. These patients had harboring EGFR T790M mutation before osimertinib treatment, which was confirmed by Amplification Refractory Mutation System (ARMS) PCR or Next-Generation Sequencing (NGS). After resistance to osimertinib treatment, tumor tissue was collected by core needle biopsy. DNA was extracted from 15 × 5 um sliced section of formalin-fixed paraffin-embedded (FFPE) material and NGS was done. The genetic changes were analyzed. Results A total of 9 Chinese patients were studied, 5 females and 4 males, age 51–89 years. After progression with osimertinib treatment, core needle biopsy was performed and next-generation sequencing was performed. Nine patients had harboring 62 point mutations, 2 altered gene copies, 2 amplifications, and 1 EML4-ALK gene fusion. No MET or HER2 amplification was found in this cohort study. Nine patients still maintained initial EGFR 19 del or L858R activating mutations, while 7 of them kept EGFR T790M mutations. Among the 7 patients, 5 had secondary EGFR C797S and/or C797G mutations, which all happened in the same allele with T790M mutation. All patients were treated with targets therapies, chemotherapy, or best supportive care (BSC) in accordance with NGS genetic results and patients' performance status; 7 of them are still alive and 2 of them died of disease progression at last follow-up. Conclusions EGFR C797S/G mutation and the same one presented on the same allele with EGFR T790M mutation were the most common mutation feature and played a key role in resistance to osimertinib in Chinese patients with NSCLC. Tumor cells losing T790M mutation and maintaining EGFR activating mutation might benefit from first-generation EGFR-TKI treatment.

BackgroundTo compare the efficiency and toxicity of bevacizumab by intrapleural or intravenous infusion in the management of malignant pleural effusion in patients with non‐small‐cell lung cancer (NSCLC).MethodsSensitizing mutation negative NSCLC patients with malignant pleural effusion were randomized into two groups in 1:1 ratio. The pleural effusion was completely drained in 24 hours; one group received intrapleural infusion and the second group received intravenous infusion of bevacizumab at a dose of 7.5 mg per kg bodyweight. The serum vascular endothelial growth factor (VEGF) was tested before and 72 hours after injection of bevacizumab. Computerized tomography (CT) scan to evaluate pleural effusions was carried out at four weeks for each patient and their survival followed‐up.ResultsA total of 67 patients were screened and 43 enrolled into the study. The response rate was 80% (16 of 20) in the intrapleural group and 66.7% (14 of 21) in the intravenous group. The median duration of response (DoR) of pleural effusion was 4.50 months and 3.70 months, respectively. The median serum VEGF level at 72 hours decreased 67.25% in the intrapleural group and 57.19% in the intravenous group compared to baseline level (P = 0.276). The median serum VEGF level at 72 hours decreased 52.02% compared to baseline level in patients’ DoR less than three months and 68.33% in patients' DoR longer than three months, respectively (P = 0.014). The main side effects noted were mild to moderate hypertension, proteinuria and epistaxis.ConclusionsBevacizumab intrapleural infusion had higher efficiency and higher safety than intravenous infusion in the management of malignant pleural effusion caused by NSCLC. The decreased level of serum VEGF at 72 hours after bevacizumab treatment was closely related to the response rate and duration of the response of pleural effusion.

Sorafenib is safe in patients with liver function impaired advanced HCC. It is effective in terms of progression-free survival and overall survival compared with best supportive care. Liver functions are the important predictive factors.

9017 Background: Osimertinib, an oral irreversible EGFR tyrosine kinase inhibitor, had promising results in patients with EGFR T790M resistance mutation of non-small-cell lung cancer (NSCLC). This study compared efficacy and toxicities of osimertinib versus docetaxel -bevacizumab as third-line treatment in EGFR T790M mutated NSCLC. Methods: In this phase 3, open-label, three-center study, we randomly assigned previously treated with TKI-chemotherapy or chemotherapy-TKI recurrent or metastatic advanced non-squamous lung cancer patients who had acquired EGFR T790M resistance mutation confirmed by tumor tissues or serum genetic test. Patients were randomly assigned in a ratio of 1:1 to receive oral osimertinib (80mg/day) or receive intravenous infusion docetaxel (75mg/m2) and bevacizumab (7.5mg/kg) until disease progression or unacceptable toxic effects. Docetaxel -bevacizumab group patients might crossover to osimertinib group after disease progression. The primary end-point of this study was progression-free survival and the secondary end-point were response rates, toxicities and OS. Results: A total of 147 patients were treated. Among them, 74 enrolled in the osimertinib group and 73 in the docetaxel-bevacizumab group. The median progression-free survival was 10.20 months and 2.95 months in the osimertinib group and docetaxel -bevacizumab group respectively (Hazard ratio 0.23; 95% confidence interval, 0.12 to 0.38; P < 0.0001). The overall response rate and disease control rate was 61.6% or 87.6% in osimertinib group 8.3% or 43.0% in docetaxel-bevacizumab group respectively. The median overall survival time was not reached. The main grade 3 or 4 toxic effects were diarrhea (2.7%) and interstitial lung disease (1.2%) in the osimertinib group and alopecia (15.1%), anorexia (12.3%), neutropenia (9.6%) and nausea (8.6%) in docetaxel -bevacizumab group. Conclusions: Response rate and progression-free survival of osimertinib group were superior to docetaxel-bevacizumab group in third-line treatment of EGFR T790M positive NSCLC. There was no survival difference between patients with EGFR 19 Del-T790M mutation and EGFR L858R-T790M mutation. Clinical trial information: NCT02959749.

<b><i>Objective:</i></b> Esophageal fistula is a critical and fatal complication of esophageal cancer. The aim of this meta-analysis was to explore the risk factors for esophageal perforation in esophageal cancer patients treated with radiotherapy. <b><i>Methods:</i></b> Data from the PubMed and Embase databases were retrieved for clinical research published between 1990 and 2018. The Newcastle-Ottawa Scale was used to evaluate the quality of the articles. A meta-analysis was performed using the RevMan 5.3 software provided by the Cochrane Collaboration Network. <b><i>Results:</i></b> Seventeen articles were eligible for the meta-analysis. In these articles, over 35 risk factors for esophageal fistula formation were described and 17 risk factors were analyzed. Significant differences in the odds of developing an esophageal perforation were found with regard to age (OR 2.34, 95% CI 1.08–5.03, <i>p</i> = 0.001), ulcerative type (OR 2.72, 95% CI 1.43–5.16, <i>p</i> = 0.002), histology (OR 4.16, 95% CI 1.14–15.12, <i>p</i> = 0.03), T stage (OR 2.66, 95% CI 1.44–4.91, <i>p</i> = 0.002), short-term response (OR 2.21, 95% CI 1.06–4.62, <i>p</i> = 0.03), chemotherapy regimen (OR 2.80, 95% CI 1.38–5.68, <i>p</i> = 0.005), and stenosis (OR 2.00, 95% CI 1.03–3.89, <i>p</i> = 0.04). <b><i>Conclusions:</i></b> An age of &#x3c;60–65 years, ulcerative type, squamous cell cancer, T4 stage, incomplete response, fluorouracil-based regimen, and stenosis were associated with an increased risk of esophageal fistula during or after radiotherapy. However, further, large-scale prospective studies are needed to establish the validity of this associ­ation.

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Objective: To study the efficacy and toxicity of irinotecan combined with oxaliplatin and S-1 in patients with metastatic pancreatic adenocarcinoma. Patients and methods: Previously untreated patients with cytologically or histologically confirmed metastatic pancreatic adenocarcinoma underwent a treatment regimen consisting of an intravenous infusion of irinotecan 165 mg/m2 and oxaliplatin 85 mg/m2 on day 1, and oral S-1 40 mg/m2 twice daily on days 1–14, repeating the regimen every 21 days until one of the following occurred: disease progression, intolerable toxicity, or patient death. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), response rate, toxicity, and quality of life. This ongoing study had been registered on ClinicalTrials.gov, NCT03726021. Results: A total of 41 patients were enrolled in this study, 18 men and 23 women. The median PFS was 4.33 months [95% confidence interval (CI): 2.83–5.88] and the median OS was 11.00 months (95% CI: 9.16–12.84). There were no instances of a complete response; the partial response, stable disease, and disease progression rates were 39.02% (16/41), 29.27% (12/41), and 31.71% (13/41), respectively. The most common adverse side effects were mild to moderate nausea, vomiting, neutropenia, and thrombocytopenia. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 29.27% (12/41) and 12.20% (5/41) of the patients, respectively. No treatment-related death was observed. Conclusion: Irinotecan combined with oxaliplatin and S-1 is a safe and effective treatment for metastatic pancreatic adenocarcinoma, and any toxicities are mild to moderate and tolerable. A larger study population is needed for further evaluation.