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Background Positron emission tomography/computed tomography (PET/CT) has been recognized for diagnosing and staging lung cancer, but the prognostic value of standardized uptake value (SUV) on 18 F-FDG PET/CT imaging in patients with advanced non-small cell lung cancer (NSCLC) remains controversial. Methods We performed a retrospective analysis of patients with advanced NSCLC who had undergone 18 F-FDG PET/CT before systemic treatment between June 2012 and June 2016. The relationship between the maximum SUV (SUVmax) of the pulmonary lesion and lesion size was evaluated via Spearman's correlation analysis. We collected patients' clinical and pathological data. Univariate and multivariate analyses were performed to analyze the factors influencing survival. Results We included 157 patients with advanced NSCLC. Among these, 135 died, 13 survived, and nine were lost to follow-up (median follow-up period, 69 months). SUVmax was correlated with lesion size and was significantly greater for tumors ≥3 cm than for tumors 6 (HR = 0.651, 95% confidence interval, 0.436-0.972; Wald value, 4.400; p = 0.036). Conclusions The SUVmax of the primary lung lesion on PET/CT is significantly correlated with survival in treatment-naive patients with advanced NSCLC.

Background and objectives Systemic sclerosis (SSc) is a connective tissue disorder (CTD) associated with an increased risk of malignancy including lung cancer (LC). Our objective was to provide a description of demographics and clinicopathological characteristics of LC patients with SSc. Methods Lung cancer patients with SSc admitted to Peking Union Medical College Hospital from January 2000 to August 2017 were reviewed. Demographic and clinicopathologic data were collected. Results Of the 12 cases included in our study, all were female. No patients had a history of smoking. The most common histological type was adenocarcinoma, followed by squamous cell carcinoma and small‐cell carcinoma. No driver mutation was identified in the five patients undergoing genetic testing. Eight patients had interstitial lung disease (ILD). Six were manifested as nonspecific interstitial pneumonia (NSIP) and two as usual interstitial pneumonia (UIP). Four (33.3%) patients underwent surgical resection. Among them, two had ILD with a normal preoperative pulmonary function tests (PFT). Eight (66.7%) patients received chemotherapy. Radiotherapy was administered in only one (8.3%) patient. No grade 3/4 adverse events were documented. Conclusion The predominance of female patients in our study is different from that reported in general lung cancer patients. A high proportion of patients has SSc‐ILD, including NSIP and UIP. Surgery or radiotherapy could still be considered in carefully selected patients with ILD.

Background Immunotherapy plays an important role in advanced non-small cell lung cancer (NSCLC). However, radiological evaluation is challenging due to the potential inflammatory effects of immunotherapy, which can lead to atypical response patterns. Identifying these atypical responses is critical to making treatment decisions and prognostication. Methods We performed a retrospective analysis of consecutive advanced NSCLC patients treated with immunotherapy (alone or in combination). We collected patients' clinical and pathological data, analyzed the proportion of patients who continued immunotherapy beyond progressive disease (PD) per RECIST 1.1, and compared the differences in response patterns between the RECIST 1.1 and iRECIST criteria. Results A total of 43 patients treated at the Peking Union Medical College, China from January 2018 to April 2019 were included. Continued immunotherapy beyond PD per RECIST 1.1 was observed in 10 (33.3%, 10/30) patients, of which there were discordant assessments (30%, 3/10) between the RECIST 1.1 and iRECIST, which were evaluated as PD by RECIST 1.1 and immune unconfirmed PD by iRECIST. Among seven patients with immune confirmed PD, one (1/30, 3.3%) had pseudoprogression. Patients who continued immunotherapy beyond PD (n = 10) experienced significantly prolonged overall survival (not reached vs. 8.1 months: hazard ratio, 2.8; 95% confidence interval: 2.7-13.6, P = 0.03) compared with patients who did not continue immunotherapy beyond PD (n = 20). Conclusions RECIST 1.1 evaluation underestimated the benefit of immunotherapy. Further research is required to optimize iRECIST and establish some criteria for selecting patients who will benefit from continued immunotherapy beyond PD per RECIST 1.1.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and has a poor prognosis. Current treatments for advanced NSCLC included traditional chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The efficacy of targeted therapy relies on oncogene addiction. Mesenchymal-epithelial transition factor (MET) gene can encode unconventional receptor tyrosine kinases with pleiotropic functions, when signals are abnormally activated, it can initiate and maintain tumor transformation, promote cell proliferation, survival, tumor invasion and angiogenesis. Thus, it is a promising therapeutic target. Previous studies have shown that elevated levels of HGF and/or overexpression of c-Met are associated with poor prognosis in lung cancer. In preclinical and clinical trials, c-MET inhibitors have shown some antitumor activity in NSCLC. Although the efficacy results of MET inhibitors in Phase III clinical trials are disappointing, given the molecular heterogeneity of NSCLC, only subgroups of patients with MET gene alterations may benefit from c-MET inhibitors. The challenge for the future is to screen out the potential beneficiaries. To solve this problem, there is need for large data analysis for the detection methods and treatment effects, to establish standards that meet the MET activation status, and determine reliable thresholds to achieve effective patient stratification and clinical decision making. This article summarized the structure of the hepatocyte growth factor (HGF)/c-Met axis, the different mechanisms of MET addiction, as well as MET amplification as acquired resistance mechanism to epidermal growth factor receptor-tyrosine kinase inhibitors, the latest advances of MET inhibitors, and immuotherapy in the treatment of NSCLC with MET alterations.

Hongge Liang1, Di Ma2, Yan Xu1, Jing Zhao1, Minjiang Chen1, Xiaoyan Liu1, Wei Zhong1, Junling Li2, Mengzhao Wang1 1Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Oncology, Chinese Academy of Medical Sciences Cancer Institute and Hospital, Beijing, People’s Republic of ChinaCorrespondence: Wei ZhongDepartment of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, No. 1 Shuanfuyuan Wangfujing Dongcheng District, Beijing 100730, People’s Republic of ChinaTel +86 0 106 915 5039Email zw_pumch@126.comMengzhao WangDepartment of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, No. 1 Shuanfuyuan Wangfujing Dongcheng District, Beijing 100730, People’s Republic of ChinaTel +86 0 106 915 5154Email mengzhaowang@sina.comBackground: Targeted therapy is an important treatment for advanced non-small cell lung cancer (NSCLC) patients with specific genetic mutations, crizotinib can prolong survival in advanced NSCLC patients with echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) rearrangement. We performed a retrospective analysis to investigate the association between the lactate dehydrogenase (LDH) levels and progression-free survival (PFS) in patients with EML4-ALK rearrangement NSCLC receiving treatment with crizotinib.Methods: Advanced (stage IIIb–IV) NSCLC patients with EML4-ALK rearrangement receiving treatment with crizotinib were enrolled between January 2007 and January 2016 at Peking Union Medical College and Cancer Hospital Chinese Academy of Medical Sciences.Results: Overall, 212 patients were enrolled. Kaplan–Meier univariate analysis showed that elevated pre-treatment LDH level (7.9 vs 14.1 months, HR =1.251, CI: 1.008–1.553, P=0.004) was significantly associated with shorter PFS, while the post-treatment mean-LDH level (13.3 vs 14.3 months, HR=1.439, 95% CI: 0.994–2.082, P=0.970) was not significantly associated with PFS. Cox proportional hazards model also identified that pre-treatment LDH level (HR=2.085, 95% CI: 1.150–3.781, P=0.016) was associated with the PFS. Logistic regression analysis showed that post-treatment LDH level was associated with creatine kinase (OR=6.712, 95% CI 3.395–13.273, P250 U/L) was significantly associated with shorter PFS in patients with EML4-ALK rearrangement NSCLC. Post-treatment elevated serum LDH level was not significantly associated with PFS, which related to adverse events including muscle damage and anemia.Keywords: non-small cell lung cancer, lactate dehydrogenase, crizotinib, echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase, progression-free survival

In the latest years, some drugs have been approved by European Medicines Agency (EMA) and/or the US Food and Drug Administration (FDA) for the treatment of patients with advanced non-small cell lung cancer (NSCLC), particularly for the treatment of those who have no targeted gene mutations or who have progressed on previously targeted therapy or platinum-containing dual-agent chemotherapy. In general, these drugs fall into two categories: anti-angiogenic agents and immune checkpoint inhibitors (ICIs). Anti-angiogenic agents currently approved by the FDA and/or EMA for advanced NSCLC treatment include bevacizumab, nintedanib, and ramucirumab. Anlotinib has been approved in advanced NSCLC by Chinese Food and Drug Administration (CFDA). These anti-angiogenic agents can induce anti-angiogenesis by targeting vascular endothelial growth factor (VEGF)/VEGF2 or inhibiting multiple small molecules involved in angiogenic and proliferative pathways such as platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs). Although these drugs show significant therapeutic efficacy, most patients inevitably experience disease progression resulting in death. ICIs approved by the FDA and/or EMA for advanced NSCLC treatment include nivolumab, pembrolizumab, and atezolizumab. These ICIs can significantly improve efficacy compared with standard chemotherapy by targeting programmed cell death protein 1 (PD-1) receptor or PD-2 receptor with longer response duration and acceptable toxicity. However, the response rate of ICIs is suboptimal, and only a few patients ultimately benefit from immunotherapy. So current efforts have focused on exploring new potential combinatorial strategies with synergistic antitumor activity. Here, we summarized the theoretical basis, current clinical data, and potential future perspective of immunotherapy combined with anti-angiogenic agents for advanced NSCLC.

Background Tyrosine kinase inhibitors (TKIs) can significantly prolong overall survival for patients with advanced non‐small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)‐mutation or anaplastic lymphoma kinase (ALK)‐rearrangement. However, the real‐world evaluation status of ALK/EGFR in China remains unclear. Methods We conducted a prospective study including 1134 patients with cytologically or histologically confirmed advanced NSCLC (stage IIIb–IV) at 12 Chinese hospitals. Results The most common evaluation methods were amplification‐refractory mutation system for EGFR status and immunohistochemistry targeting D5F3 for ALK status. Among patients with non‐squamous, the EGFR mutation rate was 44.1% and the ALK rearrangement rate was 10.0%. Among patients with squamous cell carcinoma, the EGFR mutation rate was 8.3% and the ALK rearrangement rate was 3.7%. Among all patients, gender (HR = 1.7, 95%CI = 1.2–2.4, P = 0.006), smoking history (HR = 1.8, 95%CI = 1.3–2.7, P = 0.001), histology (HR = 5.0, 95%CI = 2.4–10.1, P < 0.001), and brain metastases (HR = 1.5, 95%CI = 1.1–2.2, P = 0.017) were independent predictors of EGFR mutation, while age (HR = 2.6, 95%CI = 1.7–4.1, P < 0.001) was an independent predictor of ALK rearrangement. The median time from tumor diagnosis to EGFR or ALK status confirmation was 7 and 5 days, respectively. Targeted therapy rate was 73.8% in EGFR‐positive patients and 51.4% in ALK‐positive patients. There was a negative correlation between the first‐line targeted therapy rate and the EGFR mutation detection period (r = −0.152, P = 0.02), while no significant correlation among patients with ALK rearrangement (r = −0.179, P = 0.076). Conclusion Squamous NSCLC patients should also be routinely tested to determine their EGFR/ALK statuses. The first‐line targeted therapy rate remains low in Chinese patients with NSCLC.

The efficacy of crizotinib for anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) patients with brain metastasis is controversial. Real-world research data are needed as further evidence. We conducted a multicenter, retrospective study to explore how crizotinib affects the control of brain metastasis and the survival outcomes among Chinese patients. We reviewed the medical records of unselected ALK-rearranged NSCLC patients treated with crizotinib at five hospitals in China from January 1, 2013 to November 30, 2017. Patients developing brain metastasis either before or during crizotinib treatment were included. Survival outcomes were analyzed by the Kaplan–Meier method, and prognostic factors were analyzed by multivariate Cox regression. A total of 174 patients were included in the analysis; 95 of these patients had baseline brain metastasis, while 79 patients developed brain metastasis during crizotinib treatment. Among patients with baseline brain metastasis, the median intracranial time to progression was 19.3 months (95% confidence interval [CI] 12.5–26.2) and the median overall survival (OS) was 53.4 months (95% CI not reached). A total of 135 patients experienced intracranial progression, and 94 of these patients continued crizotinib beyond progressive disease (CBPD). There was no significant difference in the median OS between patients with CBPD and without CBPD (48.3 months vs 53.4 months; p = 0.296). ALK-rearranged advanced NSCLC patients with baseline brain metastasis can still achieve OS benefits from crizotinib treatment. However, patients with intracranial progression may not obtain a long-term survival benefit from continuation of CBPD.

Background Crizotinib is associated with a favorable survival benefit in patients with ALK‐positive non‐small cell lung cancer (NSCLC); however, a subset of patients harboring ALK rearrangement shows a poor response. Methods We collected the clinical features and survival outcomes of 28 primary‐resistant responders (PRR) with progression‐free survival (PFS) of < 3 months on crizotinib and compared these with 78 long‐term responders (LTR) that achieved > 24 months PFS (control). Results Primary resistance was observed in 6.5% of the patients. The median PFS of the PRR and LTR groups was 1.2 months (95% confidence interval [CI] 0.70–1.73) and 47.0 months (95% CI 34.39–59.64), respectively. A better Eastern Cooperative Oncology Group performance status score was significantly associated with longer PFS (odds ratio 0.06, 95% CI 0.01–0.33; P = 0.001). The median overall survival (OS) of the PRR group was 8.4 months (95% CI 3.47–13.42) and crizotinib as first‐line treatment was an independent predictive factor for survival outcome (P = 0.005). Patients administered ALK‐tyrosine kinase inhibitors after crizotinib progression had significantly longer survival than the PRR group treated with best supportive care (P = 0.007), but no significant difference was found between ALK‐tyrosine kinase inhibitor treatment and single chemotherapy (P = 0.944). Conclusion Patients with primary resistance to crizotinib displayed unfavorable survival outcomes and the underlying mechanism cannot be identified in clinical features. Nevertheless, next‐generation ALK inhibitors and chemotherapy after crizotinib progression could confer a therapeutic and survival benefit in this population.

Objective Crizotinib has demonstrated promising efficacy in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in clinical trials. We conducted this retrospective multicenter study to assess the outcomes of crizotinib therapy in, to our knowledge, a large sample cohort of patients with ALK-positive advanced NSCLC. Methods We reviewed the medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at 5 cancer centers in China from January 2013 to November 2017. Clinical data were collected from the initiation of crizotinib therapy to Response Evaluation Criteria in Solid Tumors (RECIST)-defined progressive disease (PD). Results A total of 428 eligible ALK-positive NSCLC patients were enrolled, 273 (63.8%) of whom received crizotinib as first-line treatment. The median progression-free survival (PFS) and overall survival (OS) from the initiation of crizotinib treatment were 14.4 [95% confidence interval (95% CI), 12.4−16.4] months and 53.4 (95% CI, 33.7−73.1) months, respectively. In subgroup analyses, patients who received crizotinib as first-line treatment showed a higher disease control rate (DCR) and a longer median OS compared with second-/later-line crizotinib treatment (94.8% and OS not reachedvs. 89.0% and 40.5 months, respectively). For 261 patients with RECIST-defined PD, multivariate Cox analysis revealed that in patients who received first-line crizotinib therapy, continued crizotinib beyond progressive disease (CBPD) and next-generation ALK inhibitors after crizotinib failure were associated with improved survival. Conclusions This study has demonstrated the clinically meaningful benefit of crizotinib treatment in a large cohort of Chinese ALK-positive NSCLC patients. CBPD and next-generation ALK inhibitor treatment may provide improved survival after RECIST-defined progression on crizotinib.

The role of PI3K in cancer has been well established, and mutations of PIK3CA, the gene coding for catalytic subunit p110α of PI3K, are found in approximately 30% human cancers. The hyperactivated PI3K pathway plays a central role in the tumor cell activities such as proliferation, differentiation, chemotaxis, survival, trafficking and metabolism. Besides, PI3K pathway is involved in the regulation of angiogenesis and the host immune response against cancer. Therefore, the inhibition of PI3K pathway can yield multifaceted tumor cell-extrinsic effects that may synergize with chemotherapy, and more importantly, with the newly revived immunotherapy. Here, we review the structures and activation modes of PI3Ks and its implications in angiogenesis, extracellular matrix remodeling and tumor immunity.

In recent years, targeted therapy and immunotherapy have played important roles in the treatment of patients with non-small-cell lung cancer (NSCLC). Drugs that target epidermal growth factor receptor (EGFR) mutations (eg, gefitinib, erlotinib, icotinib, and osimertinib) are among the most commonly used targeted therapies. Afatinib is an irreversible second-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI), and the LUX-Lung 3 trial demonstrated the superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of treatment-naive patients with advanced EGFR mutation adenocarcinoma of the lung. Although these drugs show significant therapeutic efficacy, most patients invariably experience disease progression resulting in death. Immunotherapy targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) has now been approved for the first-line treatment of patients with advanced NSCLC. These can produce sustained clinical responses by reversing negative regulators of T-cell function; however, immunotherapy response rates remain low, and only a few patients ultimately benefit from this approach. Here, we discuss the potential of EGFR-TKIs for inducing antitumor immunity and the feasibility of their combination with immunotherapy (including PD-1/PD-L1 inhibitors) in NSCLC patients and the associated challenges for clinical application.

Background: Rheumatoid arthritis (RA) is a connective tissue disorder (CTD) associated with an increased risk of malignancy including lung cancer (LC). Methods: Clinicopathologic characteristics of LC patients with RA and without systemic CTD were compared to identify the potential differences. A further intra-group comparison was conducted in LC patients with RA according to smoking status to explore the effect of smoking on the clinicopathologic characteristics of LC patients with RA. Results: A total of 44 LC patients with RA and 176 LC patients without systemic CTD were included in this study. There were no statistically significant differences in the distribution of age, gender, smoking status, histology type, and tumor location between the two groups. However, a significantly larger proportion of patients with stage IV LC was noted in LC with RA group (59.1% vs . 39.2%, P=0.017). Besides, more LC patients with RA had an Eastern Cooperative Oncology Group (ECOG) performance score (PS) ≥2 (8.0% vs . 20.5%, P=0.015). On multivariate analysis, tumor stage (OR: 1.41, 95% CI: 1.23–13.70, P=0.021) and presence of RA (OR: 1.35, 95% CI: 1.34–11.16, P=0.012) demonstrated independent associations with poorer ECOG PS. RA-interstitial lung disease (RA-ILD) was observed in 18 LC patients (40.9%) with RA. Among them, usual interstitial pneumonia (UIP) was observed only in past or current smokers, whereas non-specific interstitial pneumonia (NSIP) was observed only in non-smokers. Conclusions: There were no statistically significant differences in the distribution of age, gender, smoking status, histology type, and tumor location between LC patients with RA and those without systemic CTD. Compared with LC patients without CTD, LC patients with RA were more likely to be diagnosed at an advanced stage and have a poorer ECOG PS score, and were less likely to receive surgery, radiotherapy, chemotherapy and targeted therapy.