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Pu-Yuan Xing,1,* Shou-Zheng Wang,1,* Ju-Fang Shi,2 Le Wang,2 Zhou-Guang Hui,3 Jian-Song Ren,2 Shang-Mei Liu,4 You-Lin Qiao,5 Min Dai,2 Jun-Ling Li1 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 4Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun-Ling Li; Ju-Fang Shi Email lijunling@cicams.ac.cn; shijf@cicams.ac.cnBackground: Chemotherapy has improved the survival of non-small cell lung cancer (NSCLC) patients over the past few decades. However, there have not been any epidemiological studies on chemotherapy for Chinese NSCLC patients.Patients and Methods: The patients diagnosed as primary lung cancer between January 1, 2005, and December 31, 2014, in eight hospitals from eight provinces in China were retrospectively reviewed. Demographic and clinical data were extracted from medical history systems. Chi-square test and logistic regression were used to analyze the changes of chemotherapy usage and influential factors.Results: A total of 7184 lung cancer cases were eligible, among which 6481 NSCLC cases were included in this analysis. Among stage I/II patients, the percentages of receiving adjuvant chemotherapy did not change significantly between the earlier (28.5%) and the latter five years (25.7%) (p = 0.1288). Among stage IIIA patients, the percentages of chemotherapy usage did not change significantly between the earlier and the latter five years in neo-adjuvant (7.5% vs 5.6%, p = 0.1478) and adjuvant (23.1% vs 26.8%, p = 0.1129) treatment. The proportions of first-line platinum-based doublets for stage IIIB/IV patients changed significantly over the 10 years (p < 0.0001). Patients from provinces with inferior gross domestic product, with lower medical reimbursement rates and without smoking history were more likely to use the docetaxel/paclitaxel doublets, comparing with the gemcitabine doublets.Conclusion: From 2005 to 2014, there was no significant change in the chemotherapy pattern of early NSCLC. Economic factors mainly contributed to the significant changes in the first-line chemotherapy regimen selection for advanced patients.Keywords: non-small cell lung cancer, chemotherapy, neo-adjuvant chemotherapy, adjuvant chemotherapy, epidemiology

Background: Esophageal cancer (EC) metastasized to the kidney is extremely rare clinically. Here, we present a case of metachronous renal metastasis of esophageal squamous cell carcinoma (ESCC) through epithelial-mesenchymal transition (EMT)., Case Presentation: A 60-year-old patient, male, complained of left waist pain for 5 days, 11 months after radical esophagectomy. Laboratory tests revealed haematuria. Both CT and PET-CT scan showed retroperitoneal lymph nodes and left renal masses. Subsequently the patient received a left nephrectomy and lymph nodes resection, and squamous cell carcinoma of kidney and renal hilar lymph nodes was diagnosed, combined with morphology, medical history and immunophenotype, it was presumed to be metastasis of ESCC through the EMT pathway., Conclusions: The renal metastasis of squamous cell carcinoma should be considered in patients with history of EC, although this is very rare. Histopathological examination combined with immunochemical detection is helpful in differential diagnosis., Competing Interests: None., (AJTR Copyright © 2024.)

Gut microbes supporting body growth are known but the mechanisms are less well documented. Using the microbial tryptophan metabolite indole, known to regulate prokaryotic cell division and metabolic stress conditions, we mono-colonized germ-free (GF) mice with indole-producing wild-type Escherichia coli ( E. coli ) or tryptophanase-encoding tnaA knockout mutant indole-non-producing E. coli . Indole mutant E. coli mice showed multiorgan growth retardation and lower levels of glycogen, cholesterol, triglycerides, and glucose, resulting in an energy deficiency despite increased food intake. Detailed analysis revealed a malfunctioning intestine, enlarged cecum, and reduced numbers of enterochromaffin cells, correlating with a metabolic phenotype consisting of impaired gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice displayed reduction in serum levels of tricarboxylic acid (TCA) cycle intermediates and lipids. In stark contrast, a massive increase in serum melatonin was observed-frequently associated with accelerated oxidative stress and mitochondrial dysfunction. This observational report discloses functional roles of microbe-derived indoles regulating multiple organ functions and extends our previous report of indole-linked regulation of adult neurogenesis. Since indoles decline by age, these results imply a correlation with age-linked organ decline and levels of indoles. Interestingly, increased levels of indole-3-acetic acid, a known indole metabolite, have been shown to correlate with younger biological age, further supporting a link between biological age and levels of microbe-derived indole metabolites. The results presented in this resource paper will be useful for the future design of food intervention studies to reduce accelerated age-linked organ decline.

Background: Evidence on the influence of programmed death-ligand 1 (PD-L1) expression on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients is at variance., Methods: A single-center retrospective study was conducted to evaluate the influence of PD-L1 expression on the efficacy of EGFR-TKIs for NSCLC patients with EGFR mutation. Clinical information was retrieved from electronic medical records. The patients were divided into three subgroups according to PD-L1 expression level: PD-L1 < 1% (negative), PD-L1 1%-49% and PD-L1 ≥ 50%. The clinicopathological features, overall response rate (ORR), progression-free survival (PFS) and comutation information were collected and compared between the three subgroups., Results: A total of 117 patients were included. For PD-L1 < 1%, PD-L1 1%-49% and PD-L1 ≥ 50% group, there were 39 (33.3%), 51 (43.5%) and 27 (23.0%) patients respectively, and the ORR was 43.2%, 64.0%, and 51.9%, respectively (p = 0.162), and the median progression-free survival (mPFS) was 22.0 months (95% CI: 14.0-29.9 months), 15.4 months (95% CI: 8.9-21.8 months) and 13.0 months (95% CI: 10.6-15.3 months), respectively (log-rank, p = 0.01). The mPFS was negatively correlated with PD-L1 expression level (r = -0.264, p = 0.041) and PD-L1 expression was an independent risk factor for worse PFS of EGFR-TKIs in multivariate Cox regression. Patients with concurrent TP53 mutation had shorter PFS (p = 0.039) and the patients harboring both mutant TP53 and positive PD-L1 had the shortest PFS (p = 0.006)., Conclusions: The efficacy of EGFR-TKIs was influenced by the baseline PD-L1 expression. Higher PD-L1 expression was associated with shorter PFS. The combined indicators of TP53 and PD-L1 identified subgroups showing divergent benefits from EGFR-TKIs., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene ( EGFR ) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 ( p = 0.006), but fewer G3 ( p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

Background: Synergistic anti-tumor effects were observed in vivo and in vitro when immune checkpoint inhibitors (ICIs) were combined with denosumab. However, the clinical benefit and safety of this synergy have not been adequately evaluated in non-small cell lung cancer (NSCLC)., Methods: Consecutive charts of NSCLC patients with bone metastases between December 2020 and December 2021 in the Chinese National Cancer Center were reviewed. The entire cohort was divided into one experimental group (denosumab + ICIs [DI]) and three control groups (denosumab + non-ICIs [DnI], phosphates + ICIs [PI], phosphates + non-ICIs [PnI]). Real-world objective response rates (ORRs), median progression-free survival (mPFS), skeletal-related events (SREs), and adverse events (AEs) were compared between groups., Results: A total of 171/410 (41.7%) patients with advanced or recurrent NSCLC carrying bone metastases who received bone-targeted therapy were eligible for analysis. Although the DI group showed a better benefit trend, differences were not statistically significant concerning the therapeutic efficacy among the DI group (n = 40), PI group (n = 74), DnI group (n = 15), and PnI group (n = 42) (ORRs: 47.5%, 43.2%, 33.3%, and 40.5%, respectively, p = 0.799; and mPFS: 378, 190, 170, and 172 days, respectively, p = 0.115; SREs: 5%, 10.8%, 13.3%, and 11.9%, respectively, p = 0.733). Nevertheless, further analysis in the NON-DRIVER cohort revealed a greater benefit for the DI group ( p = 0.045). Additionally, the AEs of the DI group were not significantly different from those of the PI, DnI, and PnI groups (AEs: 27.5%, 39.2%, 26.7%, and 28.6%, respectively, p = 0.742). Furthermore, the multivariate analysis revealed the independent prognostic role of DI treatment for PFS in the overall cohort. Within the DI group, we did not observe differences in benefit among different mutational subgroups ( p = 0.814), but patients with single-site bone metastasis ( p = 0.319) and high PD-L1 expression ( p = 0.100) appeared to benefit more, though no significant differences were observed., Conclusions: Denosumab exhibited synergistic antitumor efficacy without increasing toxicity when used concomitantly with ICIs in patients with advanced non-small cell lung cancer carrying bone metastases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Lei, Li, Xing, Hao, Xu, Xu and Wang.)

Objective: To describe the actual efficacy of programmed death-1 (PD-1)/ programmed-death ligand 1 (PD-L1) inhibitors in patients with metastatic non-small cell lung cancer (NSCLC) and explore potential prognostic predictive biomarkers. Methods: Patients with metastatic NSCLC who were treated with PD-1/PD-L1 inhibitors at Cancer Hospital, Chinese Academy of Medical Sciences from January 2016 to December 2019, either as monotherapy or in combination with other agents, were consecutively enrolled into this study. We retrospectively collected the data of demographics, clinical information and pathologic assessment to evaluate the therapeutic efficacy and conduct the survival analysis. Major endpoint of our study is progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: The ORR of 174 patients who underwent PD-1/PD-L1 inhibitor was 28.7%, and the DCR was 79.3%. Immune-related adverse events (irAEs) occurred in 23 patients (13.2%). Brain metastasis, line of treatment, and treatment patterns were associated with the ORR of metastatic NSCLC patients who underwent immunotherapy ( P <0.05). After a median follow-up duration of 18.8 months, the median PFS was 10.5 months (ranged from 1.5 to 40.8 months) while the median OS was not reached. The 2-year survival rate was estimated to be 63.0%. The pathologic type was related with the PFS of metastatic NSCLC patients who underwent immunotherapy ( P =0.028). Sex, age, brain metastasis and autoimmune diseases were associated with OS ( P <0.05). Analysis of the receptor characteristic curve (ROC) of neutrophil/lymphocyte ratio (NLR) predicting ORR of immunotherapy in metastatic NSCLC showed that the areas under the curve of NLR before immunotherapy (NLR(C0)), NLR after one cycle of immunotherapy (NLR(C1)) and ΔNLR were 0.600, 0.706 and 0.628, respectively. Multivariate logistic regression analysis showed that NLR(C1) was an independent factor of the ORR of metastatic NSCLC patients who underwent immunotherapy ( OR =0.161, 95% CI: 0.062-0.422), and the efficacy of combination therapy was better than that of single agent ( OR =0.395, 95% CI: 0.174-0.896). The immunotherapy efficacy in patients without brain metastasis was better than those with metastasis ( OR =0.291, 95% CI: 0.095-0.887). Multivariate Cox regression analysis showed that NLR(C1) was an independent influencing factor of PFS of metastatic NSCLC patients after immunotherapy ( HR =0.480, 95% CI: 0.303-0.759). Sex ( HR =0.399, 95% CI: 0.161-0.991, P =0.048), age ( HR =0.356, 95% CI: 0.170-0.745, P =0.006) were independent influencing factors of OS of metastatic NSCLC patients after immunotherapy. Conclusions: PD-1/PD-L1 inhibitors are proved to be efficacious and have tolerable toxicities for patients with metastatic NSCLC. Patients at advanced age could still benefit from immunotherapy. Brain metastasis is related to compromised response. Earlier application of immunotherapy in combination with other modalities enhances the efficacy without elevating risk of irAEs. NLR(C1) is an early predictor of clinical outcome. The OS of patients younger than 75 years may be improved when treated with immunotherapy.

Objective: Dacomitinib has been approved for the first-line treatment of non-small cell lung cancer (NSCLC) carrying classical epidermal growth factor receptor (EGFR) mutations; however, real-world data on its later-line application are lacking., Materials and Methods: Patients' data were retrospectively collected from the Chinese National Cancer Center and the PLA hospital between August 2019 and August 2021. Kaplan-Meier method and Log-rank test were utilized to assess progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox regression analysis was conducted to determine prognostic indicators., Results: In total, 56 NSCLC patients harboring EGFR mutations treated with later-line single dacomitinib or combinatory dacomitinib were enrolled. A total of 53 patients (94.6%) had treatment-related adverse events; eight patients (14.3%) had grade 3 or 4 events. Among 49 evaluable patients, 26.5% (13 patients) had a confirmed partial response and 73.5% (36 patients) had disease control; the median duration of follow-up was 9.6 months (95% confidence interval [CI], 8.4-10.8 months), the median progression-free survival was 5.4 months (95% CI, 3.5-7.3 months), and the half-year, 1-year, and 2-year OS rate were 79.2%, 70.6%, and 64.1%, respectively. Univariate analysis suggested that smoking, line of dacomitinib, and interval between last EGFR-tyrosine kinase inhibitor (TKI) and dacomitinib were associated with PFS and OS; chemotherapy between last EGFR-TKI and dacomitinib, and EGFR-TKI generation followed by dacomitinib were respectively associated with PFS and OS; multivariate analysis indicated chemotherapy between last EGFR-TKI and dacomitinib negatively affect PFS, and smoking and third-generation EGFR-TKI followed by dacomitinib negatively affect OS., Conclusions: This real-world study has shown that dacomitinib is active and well-tolerated in NSCLC patients harboring different EGFR mutations in later-line settings, even for those with brain metastases. Patients who benefited more from the first TKI were more likely to benefit from dacomitinib, and earlier application of dacomitinib after front-line TKI resistance may be considered., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The aim of the study was to define the clinical significance of circulating tumor cells (CTCs)/circulating tumor endothelial cells (CTECs) and their subtypes in small cell lung cancer (SCLC) patients., Methods: CTCs/CTECs and their subtypes were determined using SE-iFISH technology in 33 SCLC patients before initial treatment (B1), after two cycles of chemotherapy (B2), at the completion of chemotherapy (B3), and disease progression (B4). The correlations with clinical characteristics, progression-free survival (PFS), and overall survival (OS) were analyzed., Results: CTCs and CTECs were detected in 96.6% and 65.5% of patients, respectively. Patients had higher levels of CTCs compared with CTECs in circulation (p < 0.05). Extensive-stage SCLC patients tended to have higher CTEC counts (p = 0.035), and the detection of CTC-white blood cell (CTC-WBC) clusters was associated with a worse response to treatment (p = 0.030). Patients with CTC-WBC clusters at B1 (17.3 vs. 22.6 months, p = 0.041) and B2 (19.9 vs. 25.2 months, p = 0.018) had significantly shorter OS than those with no detection. Additionally, their presence was revealed as independent predictors for a worse OS in multivariable analyses (B1: HR 9.3, 95% CI: 1.4-48, p = 0.0079; B2: HR 4.4, 95% CI: 1.1-18, p = 0.041). A high CTC level at B4 was an adverse prognostic factor for SCLC patients (PFS: 8.7 vs. 22.5 months, p = 0.0026; OS: 19 months vs. not reached, p = 0.0086). CTC clusters and CTECs also showed prognostic values., Conclusions: The presence of CTC-WBC clusters at baseline and after two-cycle chemotherapy and the total CTC counts at the completion of chemotherapy are strong predictors for the prognostic survival of SCLC patients receiving first-line treatment., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR -/- ) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of β-catenin , Neurog2 , and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities., Competing Interests: Author contributions: G.Z.W., K.A.M., and S.P. designed research; G.Z.W., K.A.M., P.Y.X., R.A., L.W., S.H., Y.Z.N., and J.Z.Y.L. performed research; T.K.W., J.R., R.N., E.H., J.K.N., E.K.T., P.M.M., and S.P. contributed new reagents/analytic tools; G.Z.W., K.A.M., P.Y.X., R.A., L.W., and S.P. analyzed data; and K.A.M. and S.P. wrote the paper. Competing interest statement: P.M.M. has been reimbursed for service on a Scientific Advisory Board to Ipsen Pharmaceuticals. He has received consultancy fees from Roche, Adelphi Communications, Celgene, Neurodiem, and Medscape. He has received honoraria or speaker's fees from Novartis and Biogen and has received research or educational funds from Biogen, Novartis, and GlaxoSmithKline., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: This study aims to investigate the value of radiomics parameters derived from contrast enhanced (CE) MRI in differentiation of hypovascular non-functional pancreatic neuroendocrine tumors (hypo-NF-pNETs) and solid pseudopapillary neoplasms of the pancreas (SPNs)., Methods: Fifty-seven SPN patients and twenty-two hypo-NF-pNET patients were enrolled. Radiomics features were extracted from T1WI, arterial, portal and delayed phase of MR images. The enrolled patients were divided into training cohort and validation cohort with the 7:3 ratio. We built four radiomics signatures for the four phases respectively and ROC analysis were used to select the best phase to discriminate SPNs from hypo-NF-pNETs. The chosen radiomics signature and clinical independent risk factors were integrated to construct a clinic-radiomics nomogram., Results: SPNs occurred in younger age groups than hypo-NF-pNETs (P < 0.0001) and showed a clear preponderance in females (P = 0.0185). Age was a significant independent factor for the differentiation of SPNs and hypo-NF-pNETs revealed by logistic regression analysis. With AUC values above 0.900 in both training and validation cohort (0.978 [95% CI, 0.942-1.000] in the training set, 0.907 [95% CI, 0.765-1.000] in the validation set), the radiomics signature of the arterial phase was picked to build a clinic-radiomics nomogram. The nomogram, composed by age and radiomics signature of the arterial phase, showed sufficient performance for discriminating SPNs and hypo-NF-pNETs with AUC values of 0.965 (95% CI, 0.923-1.000) and 0.920 (95% CI, 0.796-1.000) in the training and validation cohorts, respectively. Delong Test did not demonstrate statistical significance between the AUC of the clinic-radiomics nomogram and radiomics signature of arterial phase., Conclusion: CE-MRI-based radiomics approach demonstrated great potential in the differentiation of hypo-NF-pNETs and SPNs.

Microorganisms that colonize the gastrointestinal tract, collectively known as the gut microbiota, are known to produce small molecules and metabolites that significantly contribute to host intestinal development, functions, and homeostasis. Emerging insights from microbiome research reveal that gut microbiota-derived signals and molecules influence another key player maintaining intestinal homeostasis-the intestinal stem cell niche, which regulates epithelial self-renewal. In this review, the literature on gut microbiota-host crosstalk is surveyed, highlighting the effects of gut microbial metabolites on intestinal stem cells. The production of various classes of metabolites, their actions on intestinal stem cells are discussed and, finally, how the production and function of metabolites are modulated by aging and dietary intake is commented upon., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background : Response Evaluation Criteria in Solid Tumors (RECIST) has been widely utilized to evaluate new therapeutic strategies in cancer. However, RECIST fails to assess the heterogeneity of response in highly active therapies. Depth of response (DepOR), defined as the maximum percentage change in tumor size compared with baseline, may provide a new strategy to evaluate disease response. In the present study, we studied the association between DepOR and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Methods : Advanced NSCLC patients harboring EGFR driver mutation (L858R or exon 19 deletion) treated with EGFR-TKI from August 2014 to July 2017 from two sites were retrospetively collected for analysis. Patients were divided into four groups by DepOR (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, Q4 = 76-100%). Kaplan-Meier curves were plotted for PFS against DepOR and the hazard ratio (HR) was determined through univariable and multivariable cox regression models. Results : In total, 265 patients were included for analysis. The number of patients in Group Q1-Q4 were 91 (34.3%), 73 (27.5%), 65 (24.5%) and 36 (13.6%), respectively. A greater DepOR was significantly associated with a longer PFS (Log-rank P <0.0001). The HRs (95% CI) for PFS comparing patients with different DepOR status were 0.58 (0.42-0.80) for Q2, 0.49 (0.35-0.69) for Q3, and 0.33 (0.22-0.50) for Q4, all compared with patients in Q1. DepOR as a continuous variable was also associated with prolonged PFS (HR, 0.20; 95% CI, 0.13-0.33; P<0.001). Additionally, in the multivariable cox regression model, abnormal LDH, brain metastasis and male were found to be associated with worse PFS outcomes (P<0.05). Conclusion : A greater DepOR is significantly associated with PFS benefit in advanced NSCLC treated with EGFR-TKI, suggesting that it may be a useful clinical outcome to evaluate the response of targeted therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Most lung cancer patients are diagnosed after the onset of symptoms. However, whether the symptoms of lung cancer were independently associated with the diagnosis of lung cancer is unknown, especially in the Chinese population., Methods: We conducted a 10 years (2005-2014) nationwide multicenter retrospective clinical epidemiology study of lung cancer patients diagnosed in China. As such, this study focused on nonsmall cell lung cancer (NSCLC). We calculated the odds ratios (ORs) for variables associated with the symptoms and physical signs using multivariate unconditional logistic regressions., Results: A total of 7184 lung cancer patients were surveyed; finally, 6398 NSCLC patients with available information about their symptoms and physical signs were included in this analysis. The most common initial symptom and physical sign was chronic cough (4156, 65.0%), followed by sputum with blood (2110, 33.0%), chest pain (1146, 17.9%), shortness of breath (1090, 17.0%), neck and supraclavicular lymphadenectasis (629, 9.8%), weight loss (529, 8.3%), metastases pain (378, 5.9%), fatigue (307, 4.8%), fever (272, 4.3%), and dyspnea (270, 4.2%). Patients with squamous carcinoma and stage III disease were more likely to present with chronic cough (P < 0.0001) and sputum with blood (P < 0.0001) than patients with other pathological types and clinical stages, respectively. Metastases pain (P < 0.0001) and neck and supraclavicular lymphadenectasis (P = 0.0006) were more likely to occur in patients with nonsquamous carcinoma than in patients with other carcinomas. Additionally, patients with stage IV disease had a higher percentage of chest pain, shortness of breath, dyspnea, weight loss, and fatigue than patients with other stages of disease. In multivariable logistic analyses, compared with patients with adenocarcinoma, patients with squamous carcinoma were more likely to experience symptoms (OR = 2.885, 95% confidence interval [CI] 2.477-3.359) but were less likely to present physical signs (OR = 0.844, 95% CI 0.721-0.989). The odds of having both symptoms and physical signs were higher in patients with late-stage disease than in those with early-stage disease (P < 0.0001)., Conclusions: The symptoms and physical signs of lung cancer were associated with the stage and pathological diagnosis of NSCLC. Patients with squamous carcinoma were more likely to develop symptoms, but not signs, than patients with adenocarcinoma. The more advanced the stage at diagnosis, the more likely that symptoms or physical signs are to develop. Further prospective cohort studies are needed to explore these results., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become important treatment options for non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutation. However, the detection of EGFR driver mutation is impeded by the lack of adequate tumor tissues, histopathological type, long detection period, and the heterogeneity of a tumor. Therefore, it is necessary to develop a more convenient method to guide the clinical use of EGFR-TKI. Circular RNAs (circRNAs) are characterized as a closed structure with covalently joined ends resistant to exonucleases may be a potential biomarker. In the present study, we aimed to screen circRNAs that may be associated with the efficacy of EGFR-TKI., Methods: The expression of circRNAs sequenced by circular microarray in plasma samples between gefitinib effective and ineffective groups were compared. RT-qPCR further validated the results in an independent cohort. Kaplan-Meier curves were used to analyze the association between circRNA and progression-free survival (PFS) of NSCLC patients treated with gefitinib., Results: In total, 52 NSCLC patients treated with gefitinib were included for analysis. 1,377 circRNAs were differentially expressed in gefitinib effective and ineffective groups, among which 989 circRNAs were up-regulated, and 388 circRNAs were down-regulated in the effective group. Furthermore, two differentially expressed circRNAs, hsa&#95;circ&#95;0109320 and hsa&#95;circ&#95;0134501, were validated by RT-qPCR in an independent cohort of 38 gefitinib-treated NSCLC patients. Elevated hsa&#95;circ&#95;0109320 was associated with longer PFS in gefitinib-treated NSCLC patients., Conclusions: Taken together, hsa&#95;circ&#95;0109320 may be a potential biomarker for the efficacy of EGFR-TKI in NSCLC patients. This provides a new molecular typing method for individualized precision treatment., Competing Interests: Conflicts of Interest: ZH Yang is employee of Beijing CapitalBio Technology Company. The other authors have no conflicts of interest to declare.

Objectives: This study aimed to explore the clinical profile and its trajectory of lung cancer on clinicopathological characteristics and medical service utilization in China., Methods: Patients diagnosed with primary lung cancer in tertiary hospitals during 2005-14 were selected from seven geographic regions of China. Data on clinical characteristics and medical service utilization was extracted from medical record, and the ten-year trends were explored., Results: A total of 7184 patients were included, the mean age was 58.3 years and the male-to-female-ratio was 2.7. From 2005 to 2014, the proportion of ≥60 year-old patients increased from 41.2% to 56.2% (p < 0.001). The smoking rate decreased from 62.9% to 51.1% (p < 0.001) and the proportion of females increased from 23.5% to 31.9% (p < 0.001). The proportion of advanced stage increased from 41.9% to 47.4% (p < 0.001). Adenocarcinoma's proportion increased from 36.4% to 53.5% (p < 0.001) while that of squamous carcinoma decreased from 45.4% to 34.4% (p < 0.001). The application of chest X-ray dropped from 50.2% to 31.0% (p < 0.001) but that of chest CT increased from 65.8% to 81.4% (p < 0.001). As two main treatment options, chemotherapy (p = 0.290) and surgery (p = 0.497) remained stable. The medical expenditure per patient increased from 40,508 to 66,020 Chinese Yuan (p < 0.001)., Conclusions: The sustaining high smoking exposure, increasing proportion of female patients, advancing clinical stage, shifting of predominant pathology and increasing medical expenditure demonstrate potential challenges and directions on lung cancer prevention and control in China. Despite substantial changes of clinical characteristics, main treatment options remained unchanged, which needs further investigation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To investigate the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) on patients with lung adenosquamous carcinoma, and to analyze relative factors. Methods: From August 2007 to July 2017, 40 patients who were pathologically diagnosed as lung adenosquamous carcinoma in our hospital and received EGFR TKIs treatment were retrospectively analyzed. All patients underwent EGFR mutation detection, resulted in 11 wild type, 13 19Del, 13 21L858R mutations, and 3 uncommon EGFR mutations in 20 exon and 19/21 complex mutation. A higher frequency of EGFR mutation was found in non-smokers and patients with adenocarcinoma components over 50.0%. Results: Twenty-six (65.0%) patients had disease progression after EGFR TKIs treatment, with a median progression-free survival (PFS) of 5.5 months (95% CI 0.52-10.49 months). A total of 20 (50.0%) patients died with an median overall survival (OS) of 15 months (95% CI 11.03-18.97 months). Multivariate analysis showed that gender, age, smoking, histopathological subtypes, EGFR mutations, and brain metastasis had no influence on PFS (all P >0.05). Gender, age, smoking, histopathological subtypes, and the presence of brain metastasis during TKI treatment had no influence on OS ( P >0.05), while EGFR mutation is the only influencing factor of OS ( P <0.05) in the current study. Conclusions: EGFR TKIs had modest efficacy in lung adenosquamous carcinoma, especially in patients with EGFR mutation. Based on the pathological features, EGFR mutation and EGFR TKIs treatment should be introduced into the routine clinical practice to improve the survival of patients with lung adenosquamous carcinoma.

Betulinic acid is a pentacyclic plant compound obtained from the bark of white birch trees and has been demonstrated to exhibit notable pharmacological properties. In the present study, the anticancer potential of betulinic acid on paclitaxel-resistant lung cancer cell line (H460) was evaluated. Cell viability was evaluated by an MTT assay, and a clonogenic assay was performed to assess the effects on cancer cell colony formation. DAPI staining using fluorescence microscopy and flow cytometry were employed to evaluate the effects of betulinic acid on apoptosis. The effects of betulinic acid on the cell cycle and mitochondrial membrane potential were also evaluated by flow cytometry. The effects of betulinic acid on the protein expression of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X (Bax) were evaluated by western blot analysis. The results of the present study indicated that the half-maximal inhibitory concentration value of betulinic acid on paclitaxel-resistant H460 lung cancer cells was 50 µM. The treatment with betulinic acid was able to inhibit the colony formation potential in a dose-dependent manner. A lower cytoxicity by betulinic acid against normal human epithelial FR2 cells was observed compared with H460 cells. The betulinic acid exerted anticancer activity via the induction of apoptosis by regulating the Bcl-2/Bax signaling pathway. Additionally, treatment with betulinic acid resulted in cell cycle arrest of paclitaxel-resistant lung cancer H460 cells at the G2/M phase. Betulinic acid was also reported to cause reductions in the mitochondrial membrane potential in a dose-dependent manner. In conclusion, the results of the present study indicated that betulinic acid may be a useful drug candidate for the management of drug-resistant lung cancer.

Objective: To observe the safety and short-term efficacy of sigle drug albumin-bound paclitaxel (ABP) in the treatment of elderly patients with advanced non-small cell lung cancer (NSCLC)., Methods: A total of 23 elderly patients with advanced NSCLC who received weekly ABP regimen (130 mg/m(2)/week) in our hospital from October 2011 to March 2014 were retrospectively evaluated. The short-term efficacy, progression-free survival (PFS), and overall survival (OS) were analyzed., Results: The median treatment period was 4 cycles (2-10 cycles). Partial response, stable disease, progressive disease, overall response rate, and disease control rate were 26.1%, 43.5%, 30.4%, 26.1% and 69.6%, respectively. The median PFS was 5.33 months (95% CI: 2.95-7.70 months), while the median OS was 40.33 months (95% CI: 29.82-50.83 months). Major adverse events included leucopenia (82.6%), neutropenia (78.3%), nausea or vomiting (56.5%), fatigue (52.2%), peripheral neuropathy (26.1%), myalgia/arthralgia (30.4%), thrombocytopenia (13.0%) and arrhythmia (4.3%). The patients accompanied with chronic diseases had significantly higher incidence rate of peripheral neuropathy and myalgia/arthralgia compared with the patients without accompanied chronic diseases (50.0% vs. 9.1% and 66.7% vs. 9.1%, P<0.05 for both)., Conclusion: The weekly single drug ABP regimen is effective and well-tolerated in elderly patients with advanced NSCLC.

Toona sinensis Roem has an important value as a type of traditional vegetable and Chinese medicinal herb, and is also a valuable source of wood in China. In this study, we used the inter-simple sequence repeat (ISSR) and sequence-related amplified polymorphism (SRAP) markers to assess the level and pattern of genetic diversity in five domesticated T. sinensis populations in China. Our results indicated a relatively low level of genetic diversity both at species (Hs = 0.1662, 0.2098, respectively) and population levels (Hs = 0.0978, 0.1145, respectively). Molecular variance analyses revealed a relatively high degree of differentiation among populations (GST = 0.3901, 0.4498), and low levels of gene flow (Nm = 0.7816 and 0.6116). We divided the five populations into two groups by cluster analysis: group one consists of populations collected from the south part of China (e.g., Yuxi, Yunan Province and Zuanjiang, Chongqing Municipality), and group two contains those cultivated in north part of China (e.g., Hengshui, Hebei Province, Jinan and Rizhao, Shandong Province). The correlation of genetic relationships among populations fits well with their geographical distribution (Mantel test; r = 0.7236 and 0.6789, respectively). Asexual propagation, limited gene flow and geographic isolation are most likely the key factors associated with the observed genetic structure of T. sinensis grown in China. The present study indicated that both ISSR and SRAP markers were effective and reliable for assessing the degree of T. sinensis genetic variations., Competing Interests: The authors declare no conflict of interest.

Objective: To explore the association between different epidermal growth factor receptor (EGFR) mutation status and survival in pemetrexed-based chemotherapy for advanced non-small-cell lung cancer (NSCLC)., Methods: A retrospective cohort study was performed to assess 146 patients with advanced NSCLC at Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The first-line regimens included pemetrexed based chemotherapy (pemetrexed first-line therapy group, n = 79), pemetrexed based chemotherapy plus pemetrexed maintenance chemotherapy (pemetrexed maintenance therapy group, n = 38) and pemetrexed based chemotherapy plus tyrosine kinase inhibitors (TKI) maintenance therapy (TKI maintenance therapy group, n = 29). Median progression-free survival (PFS) was determined.For comparison, median PFS was evaluated for EGFR-positive,EGFR-negative versus EGFR mutation unknown NSCLC patients in first-line pemetrexed therapy and pemetrexed maintenance therapy groups., Results: The median PFS was 4.6 (95%CI: 2.8-6.4), 9.8 (95%CI: 6.1-13.5) and 14.5 (95%CI: 11.8-17.2) months in pemetrexed first-line therapy, pemetrexed maintenance therapy and TKI maintenance therapy groups respectively (P = 0.000). No difference existed in PFS for pemetrexed first-line therapy group with a median PFS of 5.2 (95%CI: 2.8-7.7), 4.0 (95%CI: 0-10.8) and 4.6 (95%CI: 3.4-5.8) months respectively (P = 0.661). Among EGFR-positive,EGFR-negative and EGFR mutation status unknown patients in pemetrexed maintenance therapy group, the median PFS was 8.5 (95%CI: 4.0-13.1), 12.6 (95%CI: 11.6-13.7) and 8.0 (95%CI: 5.8-10.3) months with no significant statistical difference (P = 0.468)., Conclusions: No significant difference exists in survival between different EGFR mutation status for pemetrexed based first-line chemotherapy. And TKI maintenance therapy is associated with better survival than pemetrexed maintenance therapy regardless of EGFR status.

Objective: To observe the efficacy and safety of albumin-bound paclitaxel (ABP) monotherapy in treating recurrent advanced non-small-cell lung cancer (NSCLC)., Methods: We retrospectively analyzed the short-term efficacy and toxicities of ABP monotherapy in treating 21 patients who had previously undergone multiple cycles of therapy for their advanced NSCLC in our hospital since 2010. The treatment-related survival was also analyzed., Results: Of these 21 patients, the best overall response was partial response (PR) in 6 patients (28.6%), stable disease (SD) in 10 patients (47.6%), and progressive disease (PD) in 5 patients (23.8%). The overall response rate (ORR) was 28.6% and the disease control rate (DCR) (PR + SD) was 76.2%. The median progression-free survival (PFS) was 4.0 months (95% CI, 5.0-7.0 months). The main grade 3/4 toxicities included neutropenia (11.1%), peripheral nerve toxicity (5.6%), muscle and joint aches (5.6%), and fatigue (5.6%)., Conclusions: The ABP monotherapy can achieve good objective response in advanced NSCLC patients who have previously received multiple cycles of treatment and be well tolerated.

Objective: The aim of this study was to investigate the clinicopathological characteristics, effective treatment and prognosis in childhood and adolescent Hodgkin's lymphoma., Methods: A total of 88 patients with childhood and adolescent Hodgkin's lymphoma were treated in the Cancer Hospital of CAMS from 1998 to 2005. The clinicopathological and follow-up data of the patients were retrospectively reviewed. The survival rate was calculated by Kaplan-Meier method and compared by log-rank test. COX multivariate prognosis analysis was performed., Results: The 2-year event-free survival rate of the 88 patients was 86.4%, the 5-year event-free survival rate was 61.4%, and the 5-year overall survival rate was 95.5%. Univariate analysis showed that the stage of disease (P = 0.033), "B" symptoms (P = 0.028), bulky disease (P = 0.007), splenomegaly (P = 0.050), LDH elevation (P = 0.020), chemotherapy regimen (P = 0.003) were prognostic factors in the 5-year event-free survival rate. Splenomegaly (P = 0.039), LDH elevation (P = 0.033), chemotherapy regimen (P = 0.008) were prognostic factors of 5-year overall survival rate. Multivariate analysis showed that chemotherapy regimen (P = 0.033), stage of disease (P = 0.023), LDH elevation (P = 0.008), "B" symptoms (P = 0.044), bulky disease (P = 0.009) were independent prognostic factors of 5-year event-free survival rate. The chemotherapy regimen (P = 0.012) and LDH elevation (P = 0.046) were independent prognostic factors of 5-year overall survival rate., Conclusions: The non-ABVD chemotherapy regimen, stage IV disease, LDH elevation, associated with "B" symptoms and bulky disease are independent prognostic factors of 5-year event-free survival rate. LDH elevation and non-ABVD chemotherapy regimen are independent prognostic factors of 5-year overall survival rate.

Purpose: Chidamide (CS055/HBI-8000) is a new benzamide class of histone deacetylase inhibitor with marked anti-tumor activity. This study reports the phase I results., Methods: Patients with advanced solid tumors or lymphomas received oral doses of 5, 10, 17.5, 25, 32.5, or 50 mg chidamide either twice (BIW) or three times (TIW) per week for 4 consecutive weeks every 6 weeks. Safety, characteristics of pharmacokinetics (PK) and pharmacodynamics (PD), and preliminary efficacy were evaluated., Results: A total of 31 patients were enrolled. No DLTs were identified in the BIW cohorts up to 50 mg. DLTs were grade 3 diarrhea and vomiting in two patients in the TIW cohort at 50 mg, respectively. PK analysis revealed t(1/2) of 16.8-18.3 h, T(max) of 1-2 h in most cases, and a dose-related increase in C(max) and AUC. Significant induction of histone H3 acetylation in peripheral white blood cells was observed after a single dose of chidamide. Four patients with T-cell lymphomas and 1 patient with submandibular adenoid cystic carcinoma achieved a partial response., Conclusions: Chidamide was generally well tolerated in patients with advanced solid tumors or lymphomas in the tested regimens. Favorable PK and PD profiles, as well as encouraging preliminary anti-tumor activity, were demonstrated.

Objective: To assess the efficacy of calcium-magnesium (Ca/Mg) infusion and glutathione (GSH) for preventing the neurotoxicity induced by oxaliplatin., Methods: This is a randomized, double blind, placebo controlled clinical trail. The patients receiving FOLFOX4 chemotherapy for their solid tumor were randomized to receive Ca/Mg, GSH or normal saline with chemotherapy simultaneously. The incidence and severity of oxaliplatin-induced neurotoxicity were observed. The ECOG performance status was recorded and compared among the 3 groups., Results: Ninety-three patients admitted in our department from Mar 2006 to Dec 2007 were entered into this study, including 29 patients in the Ca/Mg group, 33 in the GSH group and 31 in the chemotherapy alone group. The incidences of acute neurotoxicity were 82.8%, 90.9% and 93.5%, respectively. At the third cycle, the incidences of grade 1-2 chronic neurotoxicity were 37.9%, 48.5% and 42.0%, respectively. No grade 3 neuropathy was observed. After 6 cycles, the incidence of grade 1-2 neuropathy was increased to 68.2%, 88.9% and 85.2%, respectively. A lower percentage was observed in Ca/Mg arm without a statistically significant difference, and grade 3 neuropathy occurred in 5 patients. After 9 cycles, the incidence of grade 1-2 neuropathy was increased to 81.3%, 90.0% and 92.9%, respectively. Grade 3 neuropathy occurred in another 2 patients. No statistically significant difference was observed among the 3 arms. Changes of patient's ECOG score after chemotherapy were similar., Conclusion: This study didn't provide evidence that Ca/Mg infusion and GSH can prevent the oxaliplatin-induced neurotoxicity.

Objective: To investigate the clinical characteristics and treatment of desmoplastic small round cell tumor., Methods: Five patients with DSRCT were diagnosed and treated in our Hospital from January 1999 to May 2009. Forty-eight cases with complete clinical data were collected and reviewed from 23 published reports. Therefore totally 53 patients with DSRCT were analysed. The survival rate was calculated by Kaplan-Meier method and compared by log-rank test., Results: The median age of all cases was 23 (1.5 - 66) years old at the time of diagnosis. 75.5% of patients were male. The most common presenting complaint was intra-abdominal mass or pain (77.4%). In 46 patients (86.8%), the primary tumor was located in the abdomen or pelvis. Fifteen (28.3%) had positive lymph nodes or distant parenchymal metastases. The median follow-up was 1.8 years (range, 0.1 - 10.0 years). The overall 1-, 3- and 5-year survivals were 45.8%, 20.8% and 5.7%, respectively. Forty-seven patients underwent surgery. Complete tumor resection was significantly correlated with long survival. The 1- and 3-year survival rates were 70.5% and 53.7% in patients treated with complete tumor resection compared to 37.2% and 4.8% in the incomplete tumor resection cohort (P = 0.0020). Thirty-four patients received chemotherapy and the 1- and 3-year survival rates were 60.1% and 35.2%, respectively, however, only 29.7% and 12.7% in patients without chemotherapy (P = 0.0396). Twelve patients had radiotherapy and the 1- and 3-year survival rates were 75.0% and 38.9%, respectively, compared with 36.9% and 14.8% in those without radiotherapy (P = 0.0314)., Conclusion: Complete tumor resection results in improved survival in patients with DSRCT. Chemotherapy and radiotherapy correlate with improved patient outcome. Multimodal therapy may improve the survival in patients with DSRCT.

Background & Objective: The incidence of brain metastases from breast cancer seems to be increasing with the improvement of systemic control and survival prolongation. This study was to analyze the clinical characteristics, treatment modalities, and prognostic factors of brain metastases from breast cancer., Methods: The time from primary diagnosis of breast cancer to brain metastases of 67 breast cancer patients were 0-15 years, and the median time was 2.5 years. Of the 67 patients, 3 received surgery plus radiotherapy, 30 received radiotherapy alone, 3 received chemotherapy alone, 26 received radiochemotherapy, and 5 received no treatment. Kaplan-Meier analysis and log-rank test were used to analyze survival status., Results: Headache was the most common symptom of brain metastases from breast cancer. The median survival time was 4 years. After brain metastases, the median survival time was 11 months. Menstrual status, number of brain metastases, systemic metastases, and different treatment modalities had no correlations to survival time of the patients., Conclusions: The prognosis of brain metastases from breast cancer is still poor. Radiotherapy remains the standard treatment of brain metastases. The function of chemotherapy needs further study.