Phase II study of carboplatin plus weekly paclitaxel with bevacizumab for non-squamous, non-small cell lung cancer with idiopathic interstitial pneumonia (Hanshin Cancer Group IP002).

BACKGROUND: There is an increased risk of acute exacerbation of idiopathic interstitial pneumonia when treating patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. There is no standard optimal treatment regimen for patients with lung cancer complicated with idiopathic interstitial pneumonia. We aimed to evaluate the efficacy and safety of carboplatin (CBDCA), bevacizumab (Bmab) and weekly paclitaxel (PXT) in patients with idiopathic interstitial pneumonia. METHODS: This phase 2 study involved chemotherapy-naïve patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. Patients received CBDCA (area under the curve: 5 on day 1), PXT (70 mg/m2 on days 1, 8 and 15) and Bmab (15 mg/kg on day 1) every 4 weeks. The primary endpoint was the overall response rate. RESULTS: Twenty-one patients were enrolled between January 2013 and October 2018 and received at least one course of the protocol treatment. The study was terminated before enrolling the planned number of patients because of poor accrual. The median patient age was 69 (range: 62-79) years, and 19 (90.5%) patients were men. The overall response rate was 61.9% (95% confidence interval [CI], 38.4-81.9), meeting the primary endpoint. The median progression-free survival, time to treatment failure, and overall survival were 9.69 (95% CI, 5.78-11.63), 8.21 (95% CI, 3.75-11.63) and 20.93 (95% CI, 13.17-29.83) months, respectively. There was no acute exacerbation or treatment-related death during protocol treatment. CONCLUSION: The results indicate that patients with advanced non-squamous, non-small cell lung cancer with idiopathic interstitial pneumonia could be effectively and safely treated using a combination of CBDCA, PXT and Bmab.

Analysis of Methylome of Different Forms of Basal Cell Hyperplasia and Squamous Cell Metaplasia of Bronchial Epithelium.

Squamous cell lung cancer (SCLC) occurs as a result of dysregenerative changes in the bronchial epithelium: basal cell hyperplasia (BCH), squamous cell metaplasia (SM), and dysplasia. We previously suggested that combinations of precancerous changes detected in the small bronchi of patients with SCLC may reflect various "scenarios" of the precancerous process: isolated BCH→stopping at the stage of hyperplasia, BCH+SM→progression of hyperplasia into metaplasia, SM+dysplasia→progression of metaplasia into dysplasia. In this study, DNA methylome of various forms of precancerous changes in the bronchial epithelium of SCLC patients was analyzed using the genome-wide bisulfite sequencing. In BCH combined with SM, in contrast to isolated BCH, differentially methylated regions were identified in genes of the pathogenetically significant MET signaling pathway (RNMT, HPN). Differentially methylated regions affecting genes involved in inflammation regulation (IL-23, IL-23R, IL12B, IL12RB1, and FIS1) were detected in SM combined with dysplasia in comparison with SM combined with BCH. The revealed changes in DNA methylation may underlie various "scenarios" of the precancerous process in the bronchial epithelium.

Response to Abemaciclib and Immunotherapy Rechallenge with Nivolumab and Ipilimumab in a Heavily Pretreated TMB-H Metastatic Squamous Cell Lung Cancer with CDKN2A Mutation, PIK3CA Amplification and TPS 80%: A Case Report.

Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is considerably more frequent in squamous cell lung cancer (SqCLC) than in other subtypes of lung cancer and may be a promising target for this histology. Here, we present the course of diagnosis and treatment of a patient with advanced SqCLC, harboring not only CDKN2A mutation but also PIK3CA amplification, Tumor Mutational Burden-High (>10 mutations/megabase), and a Tumor Proportion Score of 80%. After disease progression on multiple lines of chemotherapy and immunotherapy, he responded favorably to treatment with the CDK4/6i Abemaciclib and later achieved a durable partial response to immunotherapy rechallenge with a combination of anti-PD-1 and anti-CTLA-4, nivolumab, and ipilimumab.

Phase I/II study of nedaplatin and nab-paclitaxel for patients with previously untreated advanced squamous cell lung cancer: Kanto Respiratory Disease Study Group (KRSG) 1302.

BACKGROUND: Nedaplatin and nab-paclitaxel are each efficacious in the treatment of squamous cell lung cancer. PATIENTS AND METHODS: Eligibility criteria were: no prior chemotherapy, advanced squamous cell lung cancer; performance status 0-1, age > 20 years but < 75 years, and adequate hematologic, hepatic and renal function. Patients received escalating doses of nab-paclitaxel under a fixed dose of nedaplatin (100 mg/m2, day 1) every 3 weeks in phase I. The initial nab-paclitaxel dose was 100 mg/m2 on days 1 and 8 (level 1), and the next dose was 100 mg/m2 on days 1, 8, and 15 (level 2). In phase II, patients received the recommended doses. The primary endpoint was tumor response rate. RESULTS: In phase I, three patients at level 1 experienced no dose-limiting toxicities (DLTs) and two patients at level 2 experienced DLTs. Level 1 was thus determined as the recommended dose. Twenty-three patients were enrolled in phase II. The 3 patients in level 1 and 23 patients in phase II were included together for analyses. Three of these 26 patients were excluded from response analysis due to pneumonia and patient refusal. Response rate was 91.3% (95% confidence interval, 72.0-98.9%). Toxicities observed during all cycles were tolerable. CONCLUSIONS: The recommended dose for this combination was nedaplatin at 100 mg/m2 on day 1 and nab-paclitaxel at 100 mg/m2 on days 1 and 8 every 3 weeks. The combination of nedaplatin and nab-paclitaxel appears safe and efficacious in patients with untreated advanced squamous cell lung cancer.

Changes in the Level of Methylation of a Group of microRNA Genes as a Factor in the Development and Progression of Non-Small Cell Lung Cancer.

We studied changes in the level of methylation of a number of microRNA genes hypermethylated in non-small cell lung cancer and its histological subtypes as well as the relationship of methylation of a group of microRNA genes with clinical and morphological features of the tumor with smoking status. A significantly high level of methylation of 7 genes (MIR124-1/3, MIR125B-1, MIR129-2, MIR137, MIR1258, and MIR339) was revealed in adenocarcinoma and squamous cell lung cancer in comparison with samples of adjacent histologically unchanged lung tissue. In squamous cell lung cancer, a significantly high level of methylation of the MIR124-2 gene in the tumor was also shown. In addition, differences in the methylation profile of adenocarcinoma and squamous cell carcinoma at stages III-IV of the oncological process were revealed. A high level of methylation of the MIR137 and MIR1258 genes was shown for adenocarcinoma and MIR339, MIR129-2, and MIR124-2 for squamous cell carcinoma. Significant differences in the level of methylation of MIR124-2 and MIR375 genes were revealed for smoking patients with squamous cell lung cancer.

DDX56 modulates post-transcriptional Wnt signaling through miRNAs and is associated with early recurrence in squamous cell lung carcinoma.

BACKGROUND: Early recurrence is a major obstacle to prolonged postoperative survival in squamous cell lung carcinoma (SqCLC). The molecular mechanisms underlying early SqCLC recurrence remain unclear, and effective prognostic biomarkers for predicting early recurrence are needed. METHODS: We analyzed primary tumor samples of 20 SqCLC patients using quantitative proteomics to identify differentially-expressed proteins in patients who experienced early versus late disease recurrence. The expression and prognostic significance of DDX56 was evaluated using a SqCLC tumor tissue microarray and further verified using different online databases. We performed in vitro and in vivo experiments to obtain detailed molecular insight into the functional role of DDX56 in SqCLC. RESULTS: We found that DDX56 exhibited increased expression in tumors of patients who experienced early versus late disease recurrence. Increased DDX56 expression in SqCLC tumors was subsequently confirmed as an independent prognostic factor of poor recurrence-free survival in independent SqCLC cohorts. Functionally, DDX56 promotes SqCLC cell growth and migration in vitro, and xenograft tumor progression in vivo. Mechanistically, DDX56 post-transcriptionally promotes expression of multiple Wnt signaling pathway-related genes, including CTNNB1, WNT2B, and represses a subset of miRNAs, including miR-378a-3p, a known suppressor of Wnt signaling. Detailed analysis revealed that DDX56 facilitated degradation of primary miR-378a, leading to down-regulation of mature miR-378a-3p and thus derepression of the target gene WNT2B. CONCLUSION: We identified DDX56 as a novel independent prognostic biomarker that exerts its oncogenic effects through miRNA-mediated post-transcriptional regulation of Wnt signaling genes to promote early SqCLC recurrence. DDX56 may assist in identifying SqCLC patients at increased risk of early recurrence and who could benefit from Wnt signaling-targeted therapies.

Recombinant human endostatin combined with chemotherapy for advanced squamous cell lung cancer: a meta-analysis.

BACKGROUND: This paper aims to compare the efficacy and safety of recombinant human endostatin combined with chemotherapy in patients with squamous cell lung cancer (SqCLC). METHODS: We searched the Cochrane Library, PubMed, Embase, CNKI, Wanfang database, Metstr, VIP, and others and manually searched books and magazines until 2019 for articles about the efficacy and safety of recombinant human endostatin combined with chemotherapy in patients with SqCLC. A second search was conducted on the review literature. According to the criteria of the literature screen, the relevant randomized controlled trials (RCTs) and nonrandomized controlled trials (non-RCTs) of recombinant human endostatin combined with chemotherapy and chemotherapy alone in the treatment of SqCLC were included. After the data were extracted and analyzed, RevMan 5.3 software was used for meta-analysis for the outcome indicators. Then, heterogeneity tests and sensitivity analyses were carried out, and the publication bias of this study was tested in Stata 13.0 software. Six RCTs and eight non-RCTs were included. In total, 821 patients with SqCLC were included. RESULTS: The response rate (RR) was 2.12 (95% CI: 1.57-2.85, p < 0.00001). The disease control rate (DCR) was 2.38 (95% CI: 1.70-3.32, p < 0.00001). The difference between the two groups was statistically significant. Regarding safety, the incidence rates of the adverse reactions cardiotoxicity, leukopenia, thrombocytopenia, and gastrointestinal reactions were not significantly different between the two groups (OR = 1.70, 95% CI: 0.79-3.68; OR = 0.93, 95% CI: 0.61-1.42; OR = 1.08, 95% CI: 0.71-1.64; OR = 0.86, 95% CI: 0.56-1.30, respectively). CONCLUSION: The combined treatment had a better therapeutic effect than chemotherapy alone. It did not increase the incidence of adverse reactions in the course of treatment.

Discriminant Profiles of Volatile Compounds in the Alveolar Air of Patients with Squamous Cell Lung Cancer, Lung Adenocarcinoma or Colon Cancer.

The objective of the present work was to analyze volatile compounds in alveolar air in patients with squamous cell lung cancer, lung adenocarcinoma or colon cancer, to prepare algorithms able to discriminate such specific pathological conditions. The concentration of 95 volatile com-pounds was measured in the alveolar air of 45 control subjects, 36 patients with lung adenocarci-noma, 25 patients with squamous cell lung cancer and 52 patients with colon cancer. Volatile compounds were measured with ion molecule reaction mass spectrometry (IMR-MS). An iterat-ed least absolute shrinkage and selection operator multivariate logistic regression model was used to generate specific algorithms and discriminate control subjects from patients with differ-ent kinds of cancer. The final predictive models reached the following performance: by using 11 compounds, patients with lung adenocarcinoma were identified with a sensitivity of 86% and specificity of 84%; nine compounds allowed us to identify patients with lung squamous cell car-cinoma with a sensitivity of 88% and specificity of 84%; patients with colon adenocarcinoma could be identified with a sensitivity of 96% and a specificity of 73% using a model comprising 13 volatile compounds. The different alveolar profiles of volatile compounds, obtained from pa-tients with three different kinds of cancer, suggest dissimilar biological-biochemistry condi-tions; each kind of cancer has probably got a specific alveolar profile.

Identification of dynamic signatures associated with smoking-related squamous cell lung cancer and chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a risk factor for the development of lung cancer. The aim of this study was to identify early diagnosis biomarkers for lung squamous cell carcinoma (SQCC) in COPD patients and to determine the potential pathogenetic mechanisms. The GSE12472 data set was downloaded from the Gene Expression Omnibus database. Differentially co-expressed links (DLs) and differentially expressed genes (DEGs) in both COPD and normal tissues, or in both SQCC + COPD and COPD samples were used to construct a dynamic network associated with high-risk genes for the SQCC pathogenetic process. Enrichment analysis was performed based on Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathway analysis. We used the gene expression data and the clinical information to identify the co-expression modules based on weighted gene co-expression network analysis (WGCNA). In total, 205 dynamic DEGs, 5034 DLs and one pathway including CDKN1A, TP53, RB1 and MYC were found to have correlations with the pathogenetic progress. The pathogenetic mechanisms shared by both SQCC and COPD are closely related to oxidative stress, the immune response and infection. WGCNA identified 11 co-expression modules, where magenta and black were correlated with the "time to distant metastasis." And the "surgery due to" was closely related to the brown and blue modules. In conclusion, a pathway that includes TP53, CDKN1A, RB1 and MYC may play a vital role in driving COPD towards SQCC. Inflammatory processes and the immune response participate in COPD-related carcinogenesis.

[The role of the immunohistochemical marker p40 in the differential diagnosis of adenocarcinoma and nonkeratinizing squamous cell cancer of the lung]. / Rol' immunogistokhimicheskogo markera p40 pri differentsial'noi diagnostike adenokartsinomy i ploskokletochnogo neorogovevayushchego raka legkogo.

Lung cancer is one of the main causes of cancer death. It is a heterogeneous group of malignant neoplasms, the treatment tactics for which directly depends on tumor morphology and genetic characteristics. However, the pathomorphological differential diagnosis of adenocarcinoma and squamous cell cancer of the lung is difficult in some cases and an immunohistochemical (IHC) study is needed to verify these tumors; moreover, the IHC panel should include both squamous cell and pneumocyte markers. Fifty surgical and biopsy specimens underwent morphological and IHC studies using antibodies against p40, p63, CK5/6, CK7, and TTF1. In this investigation, p40 showed a higher specificity than another squamous cell differentiation marker, such as p63; this confirms the data that it is advisable to use the marker p40 to verify squamous cell lung carcinoma. If there is a small amount of material for an IHC study in the differential diagnosis of adenocarcinoma from squamous cell cancer of the lung, the optimal solution is to limit the IHC panel to two markers, such as p40 and TTF1.

Expression of selected miRNA, RARß and FHIT genes in BALf of squamous cell lung cancer (squamous-cell carcinoma, SCC) patients: a pilot study.

Two suppressor genes which often undergo epigenetic silencing during the early stages of lung carcinogenesis are those encoding retinoic acid receptor-ß (RARß) and Fhit protein (FHIT). RARß expression is regulated by miRNA-34a and miRNA-141, and FHIT expression by miRNA-143 and miRNA-217. The aim of the study was to assess how selected miRNAs regulate the expression of their targeted genes in bronchoalveolar lavage fluid (BALf), obtained from patients with SCC of the lung. It also examines the relationship between the genetic findings and the clinical and pathomorphological features of the tumor. A total of 50 BALf samples were taken: 25 from patients with SCC and 25 from healthy donors. The expression (RQ) of the selected genes was analyzed by qPCR, as well as the miRNA level, with a particular emphasis on the relationship between the expression of the genes themselves and their corresponding miRNAs; in addition, the expression of the genes and miRNAs were compared with the pathomorphological features of the tumor and the clinical features of patients. Analysis of the RQ values showed downregulation of RARß, FHIT and miRNA-34a and increased expression of miRNA-141, miRNA-143 and miRNA-217 in all BALf samples (P > 0.05). No correlation was found between the expression of the selected genes and corresponding miRNAs, history of smoking, cancer stage, age and sex of the patients. The presence of the selected genes and miRNAs in BALf material does not seem to have diagnostic potential in patients with SCC; however, the results should be verified on a larger group of patients.

Upregulation of P21-Activated Kinase 1 (PAK1)/CREB Axis in Squamous Non-Small Cell Lung Carcinoma.

BACKGROUND/AIMS: p21-activated Ser/Thr kinase 1 (PAK1) is essential for the genesis and development of many cancers. The purpose of this study was to investigate the role of the PAK1-cyclic AMP response element-binding (CREB) axis in non-small cell lung cancer (NSCLC) tumorigenesis and its related mechanisms. METHODS: Western blot assay and immunohistochemical staining were employed to investigate the PAK1 and CREB expression in the tissue microarray of human squamous NSCLC. Co-immunoprecipitation and immunofluorescence confocal assays were performed to determine the link between PAK1 and CREB. NSCLC xenograft models were used to study oncogenic function of PAK1 in vivo. RESULTS: We observed that PAK1 and CREB expression levels were significantly elevated in human squamous NSCLC-tissue specimens, compared with those in adjacent normal bronchial or bronchiolar epithelial-tissue specimens, as well as their phosphorylated forms, based on western blotting. We showed in vitro that PAK1 knockdown by small-interfering RNA (siRNA) blocked CREB phosphorylation, whereas plasmid-based PAK1 overexpression resulted in CREB phosphorylation at Ser133, based on western blotting. In addition, PAK1 interacted with CREB in co-immunoprecipitation assays. Additionally, our in vitro findings detected by flow cytometry revealed that PAK1 silencing attenuated cell cycle progression, inducing apoptosis. Inhibition of PAK1 expression reduced tumor sizes and masses by modulating CREB expression and activation in xenograft models. CONCLUSION: These results suggest a novel mechanism whereby the PAK1-CREB axis drives carcinogenesis of squamous-cell carcinomas, and have important implications in the development of targeted therapeutics for squamous-cell lung cancer.

The clinical features of squamous cell lung carcinoma with sensitive EGFR mutations.

BACKGROUND: The process of selecting patients on the basis of epidermal growth factor receptor (EGFR) mutations would likely result in a patient population with greater sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, EGFR mutation status is not routinely examined in patients with squamous cell lung cancer (Sq) because of the low incidence of EGFR mutations and the poor clinical response to EGFR-TKIs. METHODS: We retrospectively reviewed the clinical features of patients at our hospital with Sq who carried EGFR-TKI-sensitive EGFR mutations and assessed their responses to EGFR-TKIs. RESULTS: EGFR mutation status was tested in 23 of 441 patients with Sq (5.2%) admitted to our hospital during the study period. An EGFR mutation (exon 19 deletion 3, L858R 2) was identified in five of the 23 patients (21.7%), all of whom were female never-smokers. Of these five patients, four (4/9; 44.4%) were in the normal lung group, one (1/12; 8.3%) was in the emphysematous lung group, and none (0/2; 0%) in the fibrotic lung group. Two of these five patients with the EGFR mutation received gefitinib and two received afatinib. Although the two patients who were treated with gefitinib did not respond well to treatment (stable disease, 1 patient; progressive disease, 1 patient), the two patients who were treated with afatinib showed a good response (partial response, 2 patients). CONCLUSION: The administration of afatinib to Sq patients after selecting patients using the EGFR mutation test based on their underlying pulmonary disease and smoking status would likely result in a population with a greater sensitivity to afatinib.

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

BACKGROUND: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). METHODS: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. RESULTS: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. CONCLUSIONS: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

[Differential expression of an ensemble of the key genes involved in cell-cycle regulation in lung cancer].

Targeted cancer therapy directed at individual targets is often accompanied by the rapid development of drug resistance. The development of a new generation of antitumor drugs involves the search for many targets simultaneously to block or, conversely, restore their activity. In this regard, simultaneous analysis of gene expression in a complex network of interactions, primarily cell cycle control elements, is relevant for the search of specific molecular markers for the differential diagnosis of adenocarcinoma (ADC) and squamous cell lung cancer (SCC), as well as new targets for therapy. In this paper we performed an extended quantitative analysis of the expression of two suppressor genes, CTDSPL and its target RB1, as well as 84 genes of the main participants of the p16^(INK4A)-Cdk/cyclin D1-Rb and p53/p21^(Waf1) signaling pathways in the histological types of non-small-cell lung cancer (NSCLC), i.e., ADC and SCC, using the special panel of the Human Cell Cycle Regulation Panel. The expression profile of some genes shows the specificity to the histological type of NSCLC and the presence of metastases. The genes with a significantly increased expression that affect the activity of Rb (cyclins, cyclin-dependent kinases, their activators, inhibitors, etc.) can serve as potential targets for combined therapy of both ADC and SCC.

PD-L1 Expression in Squamous-cell Carcinoma and Adenocarcinoma of the Lung.

BACKGROUND: With introduction of immunotherapy (IT) into the treatment of advanced non-small-cell lung cancer (NSCLC), a need for predictive biomarker became apparent. Programmed death ligand 1 (PD-L1) protein expression is most widely explored predictive marker for response to IT. We assessed PD-L1 expression in tumor cells (TC) and immune cells (IC) of squamous-cell carcinoma (SCC) and adenocarcinoma (AC) patients. PATIENTS AND METHODS: We obtained 54 surgically resected tumor specimens and assessed PD-L1 expression by immunohistochemistry after staining them with antibody SP142 (Ventana, USA). Clinicopathological characteristics were acquired from the hospital registry database. Results were analyzed according to cut-off values of ≥ 5% and ≥ 10% of PD-L1 expression on either TC or IC. RESULTS: 29 (54%) samples were AC and 25 (46%) were SCC. PD-L1 expression was significantly higher in TC of SCC compared to AC at both cut-off values (52% vs. 17%, p = 0.016 and 52% vs. 14%, p = 0.007, respectively) no difference in PD-L1 expression in IC of SCC and AC was found. In AC alone, PD-L1 expression was significantly higher in IC compared to TC at both cut-off values (72% vs. 17%, p < 0.001 and 41% vs. 14%, p = 0.008, respectively), while no significant difference between IC and TC PD-L1 expression was revealed in SCC. CONCLUSIONS: Our results suggest a significantly higher PD-L1 expression in TC of SCC compared to AC, regardless of the cut-off value. PD-L1 expression in IC is high in both histological subtypes of NSCLC, and adds significantly to the overall positivity of AC but not SCC.

Efficacy and safety of dovitinib in pretreated patients with advanced squamous non-small cell lung cancer with FGFR1 amplification: A single-arm, phase 2 study.

BACKGROUND: Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential driving oncogene in squamous cell cancer (SCC) of the lung. The current phase 2 study evaluated the efficacy and tolerability of dovitinib, an FGFR inhibitor, in patients with advanced SCC of the lung. METHODS: Patients with pretreated advanced SCC of the lung whose tumors demonstrated FGFR1 amplification of > 5 copies by fluorescence in situ hybridization were enrolled. Dovitinib at a dose of 500 mg was administered orally, once daily, on days 1 to 5 of every week, followed by 2 days off. The primary endpoint was overall response. Secondary endpoints were progression-free survival, overall survival, and toxicity. RESULTS: All 26 patients were men with a median age of 68 years (range, 52-80 years). The majority of patients were ever-smokers. The median duration of dovitinib administration (28 days per cycle) was 2.5 months (range, 0.7-8.6 months). The overall response rate was 11.5% (95% confidence interval [95% CI], 0.8%-23.8%) and the disease control rate was 50% (95% CI, 30.8%-69.2%), with 3 patients achieving partial responses. Response durations for the patients with partial responses were ≥4.5 months, ≥ 5.1 months, and 6.1 months, respectively. After a median follow-up of 15.7 months (range, 1.2-25.6 months), the median overall survival was 5.0 months (95% CI, 3.6-6.4 months) and the median progression-free survival was 2.9 months (95% CI, 1.5-4.3 months). The most common grade 3 or higher adverse events were fatigue (19.2%), anorexia (11.5%), and hyponatremia (11.5%) (event severity was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). CONCLUSIONS: Treatment with dovitinib demonstrated modest efficacy in patients with advanced SCC with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in patients with SCC are warranted. Cancer 2016;122:3024-3031. © 2016 American Cancer Society.

Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer.

Objectives Maintenance therapy is a standard therapeutic strategy in non-squamous non-small-cell lung cancer. However, there is no consensus regarding the benefit of maintenance therapy for patients with squamous cell lung cancer. We assessed maintenance therapy with S-1, an oral fluoropyrimidine agent, following induction therapy with carboplatin and S-1 in patients with squamous cell lung cancer. Methods In this phase II trial, chemotherapy-naïve patients with squamous cell lung cancer were enrolled to induction therapy with four cycles of carboplatin (at an area under the curve of 5 on day 1) and S-1 (80 mg/m(2)/day on days 1-14) in a 28-day cycle. Patients who achieved disease control after induction therapy received maintenance therapy with S-1 in a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival after administration of maintenance therapy. Results Fifty-one patients were enrolled in the study. The median progression-free survival from the start of maintenance therapy was 3.0 months (95 % confidence interval, 2.5-3.5). The most common toxicities associated with maintenance therapy were anemia, thrombocytopenia, and fatigue, but they were not severe. Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer.

Loss of ß-arrestin1 expression predicts unfavorable prognosis for non-small cell lung cancer patients.

We aimed to study the expression status of ß-arrestin1 in non-small cell lung cancer (NSCLC) specimens and its clinicopathologic significance. The correlation between ß-arrestin1 and the tumor migration biomarker E-cadherin, as well as smoking index were studied. A total of 152 patients with NSCLC who undergone surgery were enrolled. Altogether, 88 lung squamous cell lung cancer (SCC) specimens and 64 adenocarcinoma (ADC) specimens were tested for immunohistochemistry. Patients' survival was analyzed by the Kaplan-Meier method. Univariate and multivariate analyses were performed to determine independent prognostic factors. Spearman rank correlation test was used to show data associations. For SCC patients, the expression of ß-arrestin1 was either lost (56 of 88, 63.6 %) or low (32 of 88, 36.4 %), which was significantly and negatively associated with E-cadherin expression (P = 0.017). The similar correlation existed between smoking index and ß-arrestin1 expression (P = 0.044). For ADC patients, the deletion of ß-arrestin1 expression was rare (4 of 64, 6.3 %). Loss of ß-arrestin1 expression indicated poorer survival for both SCC (P = 0.026) and ADC patients (P = 0.006). ß-arrestin1 expression was detected in the other ADC specimens but showed no significant correlation with survival. In SCC patients, the loss expression of ß-arrestin1 was frequently observed, and ß-arrestin1 expression was significantly correlated with the smoking index and E-cadherin expression, which all indicated ß-arrestin1's significant clinicopathologic role. However, ß-arrestin1 was expressed in most ADC patients, but its clinicopathologic role seemed to be obscure and might need further exploration.

Understanding immunotherapy for the treatment of non-small cell lung cancer.

Patients diagnosed with advanced non-small-cell lung cancer (NSCLC) (either squamous or non-squamous) have previously had limited treatment options after progression on chemotherapy. With the emergence of new drugs, particularly in the immuno-oncology setting, this is now changing. Recent clinical trial evidence demonstrates that compared with docetaxel, patients who received nivolumab had better overall survival and also significantly fewer grade 3-4 adverse events. This article reviews the clinical trial data for nivolumab and provides an overview of how this drug works. The adverse event profile of nivolumab is assessed and compared to that of docetaxel. The important role that nurses can play in supporting patients on nivolumab is also discussed.