EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer.

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.

Intracranial response pattern, tolerability and biomarkers associated with brain metastases in non-small cell lung cancer treated by tislelizumab plus chemotherapy.

Background: Programmed cell death protein-1/programmed cell death protein-ligand 1 (PD-1/PD-L1) inhibitor and chemotherapy are the standard treatment for advanced non-small cell lung cancer (NSCLC) without sensitizing mutations. However, patients with untreated, symptomatic or recently-irradiated brain metastases (BMs) are mostly excluded from immunochemotherapy trials. This study aims to evaluate the intracranial response pattern, tolerability and biomarkers of tislelizumab plus chemotherapy in NSCLC with untreated, symptomatic or recently-irradiated BM. Methods: This multicenter, single-arm, phase 2 trial enrolled patients with treatment-naïve, brain-metastasized NSCLC. BM could be untreated or irradiated. Symptomatic or recently-irradiated BMs that were deemed clinically stable were allowed. Patients received tislelizumab (200 mg) plus pemetrexed (500 mg/m2) and carboplatin (AUC =5) on day 1 every 3 weeks for 4 cycles, followed by maintenance with tislelizumab plus pemetrexed. Primary endpoint was 1-year progression-free survival (PFS) rate. Secondary endpoints included intracranial efficacy and tolerability. PD-L1 expression, tumor mutational burden (TMB) and genomic alterations were evaluated as potential biomarkers. Results: A total of 36 patients were enrolled, 19.2% had prior brain radiotherapy, 8.3% had symptomatic BMs that required corticosteroids ≤10 mg/d or antiepileptics. Confirmed systemic and intracranial ORR (iORR) was 43.8% and 46.7%, respectively. One-year systematic PFS rate and One-year iPFS rate was 36.8% and 55.8%, respectively. About 41.7% patients had neurological adverse events, 90% patients had concordant intracranial-extracranial responses. No intracranial pseudoprogression or hyperprogression occurred. Patients with prior brain radiation trended towards higher systemic (83.3% vs. 34.6%) and iORR (75.0% vs. 42.3%). Similar intracranial efficacy was observed in tumors with different PD-L1 and TMB levels, while alterations in cytokine receptors pathway predicted higher iORR (P=0.081), prolonged systematic PFS [hazard ratio (HR) =0.16, P=0.021] and overall survival (OS) (HR =0.71, P=0.029). Conclusions: Untreated or irradiated BMs in NSCLC follows a conventional response and progression pattern under immunochemotherapy with altered cytokine receptors pathway being a potential biomarker for systemic and intracranial outcomes.

Sintilimab plus anlotinib as second or further-line therapy for extensive disease small cell lung cancer: a phase 2 investigator-initiated non-randomized controlled trial.

Background: Treatment options remain rather limited for extensive disease small cell lung cancer (ED-SCLC) patients in second or further-line setting. Methods: The phase 2 investigator-initiated non-randomized study enrolled patients who had disease progression on at least one line of platinum-based chemotherapy. Participants received intravenous sintilimab 200 mg on day one and oral daily anlotinib 12 mg on days 1-14 once every three weeks per cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov (NCT04055792). Findings: Forty-two patients were enrolled between August 29, 2019 and December 26, 2021 at Henan Cancer Hospital in China. 37 patients were evaluable for efficacy. The median follow-up was 24.8 months (IQR: 16.9-28.2). The median PFS was 6.1 months (95% CI: 5.0-7.3). The OS was 12.7 months (95% CI: 7.1-18.2). The ORR was 56.8% (21/37, 95% CI: 40.0-73.5) and the DCR was 89.2% (33/37, 95% CI: 78.7-99.7). Forty patients (40/42, 95%) had at least one treatment-related adverse event (TRAE). Immune-related adverse events (irAEs) were reported in 39 patients (39/42, 93%), while grade 3 or higher irAEs occurred in 11 patients (11/42, 26%). The most frequent irAEs were hypothyroidism (16/42, 38%), elevated gamma-glutamyl transpeptidase (15/42, 36%) and elevated creatine kinase MB (15/42, 36%). The most frequent grade 3 or higher irAEs were elevated gamma-glutamyl transpeptidase (5/42, 12%) and increased aspartate aminotransferase (3/42, 7%). Interpretation: Sintilimab plus anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further randomized controlled trials of this combination regimen for ED-SCLC. Funding: Henan Province Health and Youth Subject Leader Training Project, Henan Health Science and Technology Innovation Talents, ZHONGYUAN QIANREN JIHUA, Henan International Joint Laboratory of drug resistance and reversal of targeted therapy for lung cancer, Tumor Research Fund of Anti-Angiogenesis Targeted Therapy of China Anti-Cancer Association.

A Retrospective Real-World Study of Prognostic Factors Associated With EGFR Mutated Lung Cancer With Leptomeningeal Metastasis.

OBJECTIVE: To analyze the factors associated with EGFR-mutated lung cancer with leptomeningeal metastasis (LM) in the real world that affects the prognosis of patients. MATERIALS AND METHODS: The clinical data of 123 patients with advanced EGFR mutated lung cancer combined with LM treated at Henan Cancer Hospital and confirmed by histology between January 2016 and December 2020 were retrospectively collected, and all patients were followed up until September 2021. Analyze the median overall survival (mOS) time of patients with clinical characteristics and treatment factors to explore the factors influencing the prognosis of lung cancer patients with LM. RESULTS: A total of 123 patients with EGFR-mutated lung cancer and LM were included in this study. Overall, patients with exon 19 deletion (19del) in the classical mutation of the EGFR gene had a prolonged mOS compared to patients with exon 21 L858R mutation (21L858R) (30.1 months vs. 26.0 months); patients with primary LM (mOS 21.2 months) had a significantly shorter mOS than those with secondary LM (mOS 28.3 months); mOS was also significantly shorter in patients with combined brain metastases (mOS of 25.4 months) than in patients without combined brain metastases (mOS of 33.4 months); Patients treated with tyrosine kinase inhibitors (TKI) combined with antiangiogenic therapy (bevacizumab) experienced delayed onset of LM (mOS1: 19.4 months vs. 13.9 months), and prolonged survival after LM compared with those treated with EGFR-TKI alone (mOS2: 14.5 months vs. 10.0 months); There is no survival benefit to the patients treated with EGFR-TKI combined with chemotherapy compared to the patients treated with EGFR-TKI alone. CONCLUSION: Among NSCLC-LM patients with EGFR mutation, receiving EGFR-TKI combined with antiangiogenic therapy may result in a better survival benefit. The factors of primary LM, combined brain metastasis may be prognostic factors for poor OS.

EGFR mutation types and abundance were associated with the overall survival of advanced lung adenocarcinoma patients receiving first-line tyrosine kinase inhibitors.

Background: Epidermal growth factor receptor tyrosine kinases inhibitors (EGFR-TKIs) are currently recognized as the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. Clinically found patients with different EGFR mutational status have different prognosis. Methods: A retrospective cohort study was performed to explore the relationship between EGFR mutations and abundance with patient survival by using patient data from the Affiliated Cancer Hospital of Zhengzhou University between January 2013 and November 2016. All patients involved in the present study had sensitive EGFR mutations [either exon 19 deletion (DEL) or exon 21 L858R] and treated by EGFR-TKIs. They were followed up every three months until lost or dead. Mutation abundance was calculated as the copies of EGFR mutation divided by copies of EGFR locus, and the cut-off values for 19DEL and L858R were 4.9% and 9.5%, respectively. Results: Total of 236 patients were included, comprising 116 (49.2%) patients with 19DEL mutation and 120 (50.8%) patients with L858R mutation. The median follow-up duration was 23.2 months (95% CI: 14.9-26.7 months). Overall survival (OS) was significantly longer in patients with 19DEL mutation (20.9 months, 95% CI: 17.7-24.1 months versus 17.0 months, 95% CI: 14.4-19.6 months in patients with L858R; P=0.008) and in patients with high mutation abundance (20.9 months, 95% CI: 18.3-23.5 months versus 13.0 months, 95% CI: 10.3-15.7 months in patients with low mutation abundance; P<0.001). Multivariate Cox regression including age, performance status and tumor stage revealed that longer OS was independently associated with 19DEL mutation (HR: 0.48, 95% CI: 0.39-0.67, P=0.033) and high mutation abundance (HR: 0.62, 95% CI: 0.50-0.79, P=0.027). Conclusions: EGFR mutation types and abundance was associated with the patients' survival which might be used to predict the efficacy of targeted therapy by EGFR-TKIs.

Reporting quality of clinical practice guidelines on head and neck cancer: a systematic review.

Background: Head and neck cancer (HNC) comprises a heterogeneous group of cancers. In view of the distinct biological characteristics and treatment strategies, clinical physicians require high-quality clinical practice guidelines (CPGs) which could provide reliable recommendations on medical practices. We aimed to evaluate the reporting quality of CPGs in the field of HNC. Methods: We developed rigorous search strategies before searching the domestic and international literature databases (n=568) including Medline (via PubMed), Chinese National Knowledge Infrastructure (CNKI) and Wanfang as well as websites of guideline organizations (n=8) published between January 1, 2018 to July 1, 2021 for appropriate guidelines on HNC. We included all evidence-based guidelines about HNC in English or Chinese. We excluded translations, summaries and interpretations of guidelines, as well as older versions of guidelines if an updated edition was available. Data were extracted and the reporting quality was evaluated by two investigators independently guided by the Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist. Results: A total of 21 guidelines complied with the inclusion criteria. Items show distinctions with reporting proportions among seven RIGHT domains. The proportions of reported items in each RIGHT domain were 75.4% for basic information, 63.1% for background, 42.9% for evidence, 55.1% for recommendations, 42.9% for review and quality assurance, 26.2% for funding and declaration and management of interests, and 50.8% for other information. Discussion: The average reporting quality of the recently published guidelines for HNC was moderate. Our research would help optimize the development processes of guidelines, resulting in high-quality guidelines for healthcare professionals.

EGFR exon 20 insertion mutations in advanced non-small-cell lung cancer: current status and perspectives.

Platinum-based chemotherapy was previously the first-choice treatment for lung cancer. The discovery of epidermal growth factor receptor (EGFR) gene mutations and the development of EGFR tyrosine kinase inhibitors (TKIs) marked the beginning of the targeted therapy era for non-small-cell lung cancer (NSCLC). Thirty percent of NSCLC patients carry EGFR gene mutations. For these advanced NSCLC patients, EGFR-TKIs are currently preferred for their superior activity and survival benefits over platinum-based chemotherapy. However, therapeutic efficacy is quite different in patients with EGFR exon 20 insertion (ex20ins) mutations versus common mutations. Patients with ex20ins mutations are insensitive to EGFR-TKIs and have poor prognosis. Some drugs targeting EGFR ex20ins mutations have been approved. Here, we systematically reviewed the recent clinical research of and treatments used for EGFR ex20ins mutations, summarized the latest data on emerging therapies, and discussed future prospects and treatments.

Apatinib with etoposide capsules as a third- or further-line therapy for extensive-stage small cell lung cancer: an open-label, multicenter, single-arm phase II trial.

BACKGROUND: Patients with extensive-stage small-cell lung cancer (ES-SCLC) have a particularly poor prognosis. And the treatment options for patients with relapsed or refractory ES-SCLC are limited. Thus, we conducted an open-label, multicenter, single-arm phase II clinical trial to assess the efficacy and safety of apatinib plus etoposide capsules as the third- or further-line treatment in ES-SCLC patients. METHODS: Patients with ES-SCLC who experienced disease progression following 2 to 3 previous therapies from 11 medical centers in China were enrolled to receive apatinib (250 mg/d, continuously) and etoposide capsules (50 mg/d, on day 1-21, per 28 days). The treatment continued until disease progression, treatment intolerance, or death. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. RESULTS: Fifty-six patients with relapsed or refractory ES-SCLC were enrolled from January 2018 to February 2020 and 53 of them were eventually included in the evaluation population. The median follow-up was 9.8 months. At the data cut-off time (March 5, 2020), 39 patients (74%) had died and 44 (83%) had progressed. The median PFS was 3.0 months (95% CI, 2.1-3.9) and the median OS was 5.0 months (95% CI, 3.6-6.4). No complete responses were seen. Eleven patients (21%) showed a best response of partial response and 37 (70%) patients achieved stable disease. The ORR was 20.8% (11/53), and the disease control rate (DCR) was 90.6% (48/53). The 6-month OS rate was 40.1% (95% CI, 26.2-54). After 12 months, the OS rate was 18.4% (95% CI, 4.7-32.1). Possible treatment-related grade III/IV adverse events included leukopenia [8 (15.1%)], neutropenia [7 (13.2%)], anemia [4 (7.4%)], and hand-foot syndrome [2 (3.8%)]. During the study, no mortality occurred as a consequence of treatment. CONCLUSIONS: Apatinib combined with etoposide capsules exhibits efficacy and has an acceptable safety profile. It could be used as a later-line treatment for ES-SCLC patients who have been heavily pretreated with standard therapies. Further exploration of apatinib combined with etoposide capsules in phase III trials is warranted.

Treatment Patterns and Survival Outcomes of Non-Small Cell Lung Cancer Patients Initially Diagnosed With Brain Metastases in Real-World Clinical Practice.

BACKGROUND: This study aimed to comprehensively analyze the characteristics, treatment patterns, and survival outcomes of non-small-cell lung cancer (NSCLC) patients initially diagnosed with brain metastases (BMs) in real-world practice. METHODS: We enrolled NSCLC patients initially diagnosed with BMs between Jan 2004 and Jan 2018 in our institution. Patient demographics, treatment modalities, and survival outcomes were then analyzed. Brain localized treatment (BLT) included early brain radiotherapy (EBR), deferred brain radiotherapy (DBR), and surgery. RESULTS: A total of 954 patients were identified. Concerning initial treatment, 525 patients (55.0%) received systemic medication (SM)+BLT, 400 patients (41.9%) received SM only, and 29 patients received BLT only (3.0%). SM+BLT cohort was associated with longer median overall survival (mOS) than the SM only and the BLT only cohorts both in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-negative/unknown patients (15.3 months, 95% confidence interval [CI], 14.2-16.4; 11.1 months, 9.0-13.2; 7.0 months, 5.4-8.6; p<0.001) and in EGFR/ALK-positive patients (33.7 months, 28.5-38.9; 22.1 months, 17.8-26.4; 4.0 months, 3.6-4.4; p < 0.001). As for timing of radiotherapy, SM+EBR (14.1 months, 12.7-15.5) was associated with inferior mOS than SM+DBR (19.4 months, 14.2-24.6) in EGFR/ALK-negative/unknown patients. No significant difference was found in EGFR/ALK-positive patients (28.3 months, 19.1-37.5; 33.3 months, 28.1-38.5). Patients in the EGFR/ALK-negative/unknown cohort treated with first-line pemetrexed with platinum (PP) (15.8 months, 14.0-17.6, p<0.001) had longer mOS than those received non-PP regimens (13.1 months, 11.6-14.6). However, no difference was observed among EGFR/ALK-positive patients who were treated with tyrosine kinase inhibitors (TKIs) (29.5 months, 21.1-37.9; p = 0.140), PP (27.2 months, 21.6-32.8) and non-PP regimens (25.0 months, 16.0-34.0). CONCLUSIONS: Our study confirmed that the use of SM+BLT is associated with superior mOS than those treated with SM only and BLT only. SM+DBR might be a better radiotherapeutic strategy for this patient population. EGFR/ALK-negative/unknown patients showed a survival benefit with PP treatment.

Dynamic changes of acquired T790M mutation and small cell lung cancer transformation in a patient with EGFR-mutant adenocarcinoma after first- and third-generation EGFR-TKIs: a case report.

Epithelial growth factor receptor (EGFR) T790M mutation and small cell lung cancer (SCLC) transformation are well-known resistance mechanisms acquired during treatment with EGFR tyrosine kinase inhibitors (TKIs). Various mechanisms sometimes coexist in patients. Here, we report a 57-year-old female diagnosed with stage IV lung adenocarcinoma, who harbored an EGFR exon 19 deletion mutation. This patient initially received gefitinib and progressed after 14 months. A repeat biopsy was performed, and the original EGFR exon 19 deletion and acquired exon 20 T790M mutation were identified. Then, pemetrexed plus carboplatin was administered as second-line and osimertinib as third-line treatment. Rapid progression and mixed response were observed after 2 months on osimertinib, with stable disease of the primary lung lesion but rapid growth of a right lower chest mass. The progressive chest lesion underwent biopsy, and the SCLC transformation was revealed. Furthermore, the patient was treated with etoposide and cisplatin, and she achieved disease control for 4 months. A fourth biopsy both for the primary lung lesion and the chest mass were finally conducted. Interestingly, the histopathology of the two different lesions showed adenocarcinoma and SCLC, respectively. The patient then rapidly suffered brain metastasis, and no EGFR mutations were detected in her cerebrospinal fluid (CSF). Overall survival (OS) of the patient was 29 months. This patient experienced concomitant resistance mechanisms of T790M mutation and SCLC transformation, which might have resulted from intra-tumor heterogeneity and drug-induced selection. Ultimately, this case reminds us that repeat biopsies are essential for patients receiving EGFR-TKIs in order to make appropriate treatment decisions according to the diverse mechanisms of acquired resistance.

N6-methyladenosine induced miR-143-3p promotes the brain metastasis of lung cancer via regulation of VASH1.

BACKGROUND: Brain metastasis (BM) is one of the principal causes of mortality for lung cancer patients. While the molecular events that govern BM of lung cancer remain frustrating cloudy. METHODS: The miRNA expression profiles are checked in the paired human BM and primary lung cancer tissues. The effect of miR-143-3p on BM of lung cancer cells and its related mechanisms are investigated. RESULTS: miR-143-3p is upregulated in the paired BM tissues as compared with that in primary cancer tissues. It can increase the invasion capability of in vitro blood brain barrier (BBB) model and angiogenesis of lung cancer by targeting the three binding sites of 3'UTR of vasohibin-1 (VASH1) to inhibit its expression. Mechanistically, VASH1 can increase the ubiquitylation of VEGFA to trigger the proteasome mediated degradation, further, it can endow the tubulin depolymerization through detyrosination to increase the cell motility. m6A methyltransferase Mettl3 can increase the splicing of precursor miR-143-3p to facilitate its biogenesis. Moreover, miR-143-3p/VASH1 axis acts as adverse prognosis factors for in vivo progression and overall survival (OS) rate of lung cancer. CONCLUSIONS: Our work implicates a causal role of the miR-143-3p/VASH1 axis in BM of lung cancers and suggests their critical roles in lung cancer pathogenesis.

Prevalence of Burnout and Career Satisfaction Among Oncologists in China: A National Survey.

BACKGROUND: Burnout and career satisfaction has been extensively studied among U.S. and European oncologists, although little is known about the situation among Chinese oncologists. Therefore, we conducted this national survey to investigate the prevalence of burnout and career satisfaction among Chinese oncologists. PATIENTS AND METHODS: Between September 2015 and December 2016, a cross-sectional field survey was conducted through the Chinese Society of Clinical Oncology and the Chinese Committee of Rehabilitation and Palliative Care. The full-length survey consisted of 59 questions investigating personal and professional characteristics and standardized instruments to measure burnout (Maslach Burnout Inventory-Human Service Survey) and career satisfaction. An additional six questions, derived from the National Survey on the Practice of Medicine by Chinese Physicians related to burnout or career satisfaction, were also included. RESULTS: In total, 3,500 oncologists received the questionnaire, and 2,700 (77.1%) responded, of whom 1,620 (46.3%) were eligible for analysis (median age, 36 years; 56.1% male). Overall, 827 oncologists (51.0%) were burned out. Five factors (lower curative rate of patients, more hours devoted to patient care, more nights on call per week, fewer minutes allocated for return outpatient visits, and more weekends rounding per year) were associated with burnout. Meanwhile, burnout was also strongly associated with a negative view of the physician-patient relationship (p < .001; odds ratio [OR], 2.07). Notably, the career satisfaction (34.4% for career and 52.1% for specialty) of Chinese oncologists was far less than U.S. colleagues, which may result from low compensation (p < .001; OR, 1.660). CONCLUSION: The overall prevalence of burnout among oncologists in China was similar to oncologists in the U.S., whereas personal accomplishment and career satisfaction were lower. Interestingly, the reasons were different. Beside high workload, the low curative rate of patients was found to be another factor associated with Chinese physicians' burnout. The ongoing Chinese health care system reform may improve the current situation. IMPLICATIONS FOR PRACTICE: Burnout and career satisfaction has been extensively studied among physicians and oncologists in the U.S. and Europe, but little is known about the situation among Chinese oncologists. This study is the first large-scale national study of Chinese oncologists using standardized instruments to evaluate burnout and career satisfaction. The experience of burnout has been linked to a long list of negative implications. However, this issue has not aroused enough concern in China until now. This study may have a vital significance for the ongoing Chinese health care reform aiming to improve the Chinese health care system.

The efficacy of first-line chemotherapy in recurrent or metastatic nasopharyngeal carcinoma: a systematic review and meta-analysis.

BACKGROUND: The standard first-line chemotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) has not been well established. We conducted a pooled meta-analysis to evaluate the efficacy of commonly used first-line chemotherapy in this disease. METHODS: Electronic databases including PubMed, Embase, and Corchrane library were searched for eligible literatures. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS) were pooled with the 95% confidence interval (CI) using R software. RESULTS: Totally 973 patients were available for analysis from 14 phase II single arm clinical trials and 2 phase III randomized clinical trials. Four regimens were identified including 5-fluorouracil plus platinum (FP), gemcitabine plus platinum (GP), taxanes plus platinum (TP), and triplet combination regimen. Of these four regimens, triplet combination regimen demonstrated best short-term efficacy with a highest ORR (0.74; 95% CI, 0.62-0.87), DCR (0.91; 95% CI, 0.87-0.95), and 6-month PFS rate (0.83; 95% CI, 0.75-0.91), while 1-year OS rate (0.74; 95% CI, 0.61-0.87) was a little lower than TP regimen. Meanwhile, TP regimen showed best prognosis with a highest 1-year OS rate of 0.79 (95% CI, 0.65-0.92) and pretty good short-term efficacy with an ORR of 0.60 (95% CI, 0.48-0.72) and a DCR of 0.92 (95% CI, 0.86-0.98) comparable with triplet combination therapy. FP regimen had the lowest ORR (0.52; 95% CI, 0.38-0.65) and 1-year OS rate (0.63; 95% CI, 0.57-0.69). Efficacy of GP regimen fell between FP and TP regimens with an ORR of 0.54 (95% CI, 0.38-0.65), a DCR of 0.85 (95% CI, 0.71-0.93), a 6-month PFS rate of 0.69 (95% CI, 0.60-0.78) and a 1-year OS rate of 0.71 (95% CI, 0.61-0.80). CONCLUSIONS: Among four commonly used first-line chemotherapy regimens for R/M NPC, triplet combination regimen showed best short-term efficacy but failed to improve prognosis. TP regimen demonstrated fairly good short-term efficacy and best long-term efficacy, followed by GP regimen, while FP regimen was the lowest.

Effects of thoracic radiotherapy timing and duration on progression-free survival in limited-stage small cell lung cancer.

Concurrent chemoradiotherapy (CRT) has been recommended and applied widely as the standard treatment for limited-stage small cell lung cancer (LS-SCLC). However, controversies remain regarding the optimal timing and treatment duration of thoracic radiotherapy (TRT), and their effects on patient survival. To evaluate prognostic values of TRT timing and duration on progression-free survival (PFS) in LS-SCLC and their dependence on TRT fractionation and clinicopathological characteristics, we retrospectively analyzed 197 LS-SCLC patients receiving CRT from 2000 to 2016 at Sun Yat-sen University Cancer Center. Based on the optimal cut-off values of TRT timing and duration generated by Cutoff Finder, patients were divided into early TRT/late TRT group and short TRT/long TRT group respectively. Univariate and multivariate Cox analysis were performed to assess correlations of TRT timing, duration, fractionation, and clinicopathological characteristics with PFS. Univariate analysis revealed that early-initiated TRT (P = 2.54 × 10-4 ) and short TRT (P = .001) significantly correlated with longer PFS. Their PFS benefits persisted in patients receiving hyperfractionated TRT and etoposide-cisplatin (EP) chemotherapy, but were less prominent in those receiving once-daily TRT and non-EP chemotherapy. Multivariate analysis further identified early initiated TRT (P = .004) and short TRT (P = .017) as independent prognostic factors for longer PFS in LS-SCLC. Our study confirmed that early-initiated TRT and short TRT had positive prognostic roles in LS-SCLC, especially in patients receiving hyperfractionated TRT and etoposide-cisplatin chemotherapy. TRT fractionation was not an independent prognostic factor in LS-SCLC.

p300 promotes proliferation, migration, and invasion via inducing epithelial-mesenchymal transition in non-small cell lung cancer cells.

BACKGROUND: Histone acetyltransferase p300 is a crucial transcriptional coactivator and has been implicated as a poor prognostic factor in human cancers. However, little is known about the substantial functions and mechanisms of p300 in NSCLC proliferation and distant metastasis. METHODS: We constructed p300 down-regulated and up-regulated cell lines through RNAi and recombinant plasmid transfection. Cell Counting Kit-8 assays were used to test the cell proliferation and confirmed by colony formation assays. Wound healing assays and transwell chamber assays were used to test the migration and invasion ability. Based upon these results, we measured the epithelial markers and mesenchymal markers after regulating p300 expression to explore epithelial-mesenchymal transition as a potential mechanism of p300 promoting NSCLC metastasis. RESULTS: In NSCLC cells NCI-H1975 and NCI-H1993, down-regulation of p300 leads to inhibition of cell proliferation and colony formation. Cells with reduced p300 expression also demonstrate inhibited migration and invasion ability. Contrarily, up-regulation of p300 significantly enhanced the proliferation, colony formation, migration and invasion ability of NCI-H460. Importantly, further investigation shows that decreased p300 expression is associated with reduced expression of mesenchymal markers and increased expression of epithelial markers, while up-regulated p300 expression correlated with decreased expression of epithelial markers and increased expression of mesenchymal markers. CONCLUSIONS: As a crucial tumor promoter, p300 promotes cell proliferation, migration, and invasion in NSCLC cells. Epithelial-mesenchymal transition is a potential mechanism of p300 promoting NSCLC metastasis.

Olanzapine-Based Triple Regimens Versus Neurokinin-1 Receptor Antagonist-Based Triple Regimens in Preventing Chemotherapy-Induced Nausea and Vomiting Associated with Highly Emetogenic Chemotherapy: A Network Meta-Analysis.

BACKGROUND: The current antiemetic prophylaxis for patients treated with highly emetogenic chemotherapy (HEC) included the olanzapine-based triplet and neurokinin-1 receptor antagonists (NK-1RAs)-based triplet. However, which one shows better antiemetic effect remained unclear. MATERIALS AND METHODS: We systematically reviewed 43 trials, involving 16,609 patients with HEC, which compared the following antiemetics at therapeutic dose range for the treatment of chemotherapy-induced nausea and vomiting: olanzapine, aprepitant, casopitant, fosaprepitant, netupitant, and rolapitant. The main outcomes were the proportion of patients who achieved no nausea, complete response (CR), and drug-related adverse events. A Bayesian network meta-analysis was performed. RESULTS: Olanzapine-based triple regimens showed significantly better no-nausea rate in overall phase and delayed phase than aprepitant-based triplet (odds ratios 3.18, 3.00, respectively), casopitant-based triplet (3.78, 4.12, respectively), fosaprepitant-based triplet (3.08, 4.10, respectively), rolapitant-based triplet (3.45, 3.20, respectively), and conventional duplex regimens (4.66, 4.38, respectively). CRs of olanzapine-based triplet were roughly equal to different NK-1RAs-based triplet but better than the conventional duplet. Moreover, no significant drug-related adverse events were observed in olanzapine-based triple regimens when compared with NK-1RAs-based triple regimens and duplex regimens. Additionally, the costs of olanzapine-based regimens were obviously much lower than the NK-1RA-based regimens. CONCLUSION: Olanzapine-based triplet stood out in terms of nausea control and drug price but represented no significant difference of CRs in comparison with NK-1RAs-based triplet. Olanzapine-based triple regimens should be an optional antiemetic choice for patients with HEC, especially those suffering from delayed phase nausea. IMPLICATIONS FOR PRACTICE: According to the results of this study, olanzapine-based triple antiemetic regimens were superior in both overall and delayed-phase nausea control when compared with various neurokinin-1 receptor antagonists-based triple regimens in patients with highly emetogenic chemotherapy (HEC). Olanzapine-based triplet was outstanding in terms of nausea control and drug price. For cancer patients with HEC, especially those suffering from delayed-phase nausea, olanzapine-based triple regimens should be an optional antiemetic choice.

Establishment of an Adjusted Prognosis Analysis Model for Initially Diagnosed Non-Small-Cell Lung Cancer With Brain Metastases From Sun Yat-Sen University Cancer Center.

BACKGROUND: The current published prognosis models for brain metastases (BMs) from cancer have not addressed the issue of either newly diagnosed non-small-cell lung cancer (NSCLC) with BMs or the lung cancer genotype. We sought to build an adjusted prognosis analysis (APA) model, a new prognosis model specifically for NSCLC patients with BMs at the initial diagnosis using adjusted prognosis analysis (APA). PATIENTS AND METHODS: The model was derived using data from 1158 consecutive patients, with 837 in the derivation cohort and 321 in the validation cohort. The patients had initially received a diagnosis of BMs from NSCLC at Sun Yat-Sen University Cancer Center from 1994 to 2015. The prognostic factors analyzed included patient characteristics, disease characteristics, and treatments. The APA model was built according to the numerical score derived from the hazard ratio of each independent prognostic variable. The predictive accuracy of the APA model was determined using a concordance index and was compared with current prognosis models. The results were validated using bootstrap resampling and a validation cohort. RESULTS: We established 2 prognostic models (APA 1 and 2) for the whole group of patients and for those with known epidermal growth factor receptor (EGFR) genotype, respectively. Six factors were independently associated with survival time: Karnofsky performance status, age, smoking history (replaced by EGFR mutation in APA 2), local treatment of intracranial metastases, EGFR-tyrosine kinase inhibitor treatment, and chemotherapy. Patients in the derivation cohort were stratified into low- (score, 0-2), moderate- (score, 3-5), and high-risk (score 6-7) groups according to the median survival time (16.6, 10.3, and 5.2 months, respectively; P < .001). The results were further confirmed in the validation cohort. CONCLUSION: Compared with recursive partition analysis and graded prognostic assessment, APA seems to be more suitable for initially diagnosed NSCLC with BMs.