Targeted therapy for lung cancer: Beyond EGFR and ALK.

Precision oncology comprises the set of strategies that aim to design the best cancer treatment based on tumor biology. A recognized subset of patients with non-small cell lung cancer (NSCLC) harbor actionable genomic aberrations that can benefit from targeted therapy. In lung cancer, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are well characterized oncogenic drivers for which the therapeutic use of tyrosine kinase inhibitors has demonstrated improved outcomes compared with chemotherapy. Other druggable targets are also well characterized, and effective inhibitors have been developed and commercialized, leading to a paradigm shift in NSCLC treatment. Here, the authors provide a review of the oncogenic role of the most relevant molecular alterations in NSCLC and emerging treatments in this setting beyond EGFR-driven and ALK-driven diseases.

Detection of multiple types of cancer driver mutations using targeted RNA sequencing in non-small cell lung cancer.

BACKGROUND: DNA-based next-generation sequencing has been widely used in the selection of target therapies for patients with nonsmall cell lung cancer (NSCLC). RNA-based next-generation sequencing has been proven to be valuable in detecting fusion and exon-skipping mutations and is recommended by National Comprehensive Cancer Network guidelines for these mutation types. METHODS: The authors developed an RNA-based hybridization panel targeting actionable driver oncogenes in solid tumors. Experimental and bioinformatics pipelines were optimized for the detection of fusions, single-nucleotide variants (SNVs), and insertion/deletion (indels). In total, 1253 formalin-fixed, paraffin-embedded samples from patients with NSCLC were analyzed by DNA and RNA panel sequencing in parallel to assess the performance of the RNA panel in detecting multiple types of mutations. RESULTS: In analytical validation, the RNA panel achieved a limit of detection of 1.45-3.15 copies per nanogram for SNVs and 0.21-6.48 copies per nanogram for fusions. In 1253 formalin-fixed, paraffin-embedded NSCLC samples, the RNA panel identified a total of 124 fusion events and 26 MET exon 14-skipping events, in which 14 fusions and six MET exon 14-skipping mutations were missed by DNA panel sequencing. By using the DNA panel as the reference, the positive percent agreement and the positive predictive value of the RNA panel were 98.08% and 98.62%, respectively, for detecting targetable SNVs and 98.15% and 99.38%, respectively, for detecting targetable indels. CONCLUSIONS: Parallel DNA and RNA sequencing analyses demonstrated the accuracy and robustness of the RNA sequencing panel in detecting multiple types of clinically actionable mutations. The simplified experimental workflow and low sample consumption will make RNA panel sequencing a potentially effective method in clinical testing.

Long-noncoding RNA LINC00461 promotes proliferation and invasion of nonsmall cell lung cancer cells via targeting miR-518a-3p/WDR1 pathway.

Long noncoding RNAs (lncRNAs) are a class of RNAs participating in many biological processes such as imprinting, alternative splicing and RNA decay. Recently, lncRNAs have drawn a great deal of attention for their critical role in cancer progression. LINC00461, a newly identified lncRNA, has been reported to be significantly overexpressed in breast cancer and markedly expedited breast cancer progression. However, the specific role of LINC00461 in nonsmall cell lung cancer (NSCLC) remains unknown. In this study, we for the first time showed the biological functions of LINC00461 in NSCLC. Our results demonstrated that LINC00461 was significantly up-regulated in NSCLC tissues and cell lines. Furthermore, knockdown of LINC00461 inhibited NSCLC cell proliferation and invasion in vitro as well as suppressed tumor growth and metastasis in vivo. We also performed luciferase reporter assays and found that LINC00461 functioned as a sponge for miR-518a-3p and WDR1 was a target of miR-518a-3p. Taken together, we suggested an essential role of LINC00461/miR-518a-3p/WDR1 axis in NSCLC, which could be used as a potential therapeutic target for NSCLC treatment.

The correlation of serum sPD-1 and sPD-L1 levels with clinical, pathological characteristics and lymph node metastasis in nonsmall cell lung cancer patients.

BACKGROUND: Significant advances have been achieved in immunotherapy for the treatment of lung cancer. It is known that tumor cells and cells in the tumor microenvironment express high amounts of programmed cell death ligand 1 (PD-L1). These PD-L1s interact with programmed cell death protein 1 (PD-1), causing immunosuppression. The aim of our study is to examine the correlation between the serum sPD-1 and sPD-L1 levels and clinicopathological characteristics in patients with nonsmall cell lung cancer. We also compared our results with the healthy population (control group). METHODS: Thirthy-seven nonsmall cell lung cancer (NSCLC) patients who were operated in our clinic were included in our study. The control group included fifteen healthy patients. The sPD-1 and sPD-L1 levels were measured in serum samples by using the ELISA method. RESULTS: The preoperative sPD-1 and sPD-L1 levels were significantly higher in the study group compared to the control group (44.12 ± 22.25 pg/mL vs. 18.54 ± 6.56 pg/mL; p = 0.001 and 26.15 ± 18.03 pg/mL vs. 10.29 ± 3.08 pg/mL; p = 0.001, respectively). There was a statistically significant decline in serum sPD-1 and sPD-L1 levels at the preoperative and postoperative 1st, 7th, and 30th days following surgical resection (44.12 ± 22.25 pg/mL, 37.86 ± 18.02 pg/mL, 36.33 ± 18.36 pg/mL, 34.14 ± 13.71 pg/mL; p = 0.007 and 26.15 ± 18.03 pg/mL, 20.60 ± 15.50 pg/mL, 18.31 ± 14.04 pg/mL, 13.64 ± 10.60 pg/mL; p = 0.001, respectively).There was a positive correlation between the preoperative and postoperative 30th day serum sPD-1 levels and the tumor size (p = 0.031, r = 0.352; p = 0.024, r = 0.371; respectively). We also found a positive correlation between the preoperative and postoperative 30th day serum sPD-L1 levels and pleural invasion (p = 0.001, p = 0.001; respectively), and the N category (p = 0.015, p = 0.013; respectively). DISCUSSION: We think that sPD-1 and sPD-L1 levels may be used as a potential biomarker for lung cancer screening, prediction of the stage, and besides to detect recurrences and/or metastases following resection in NSCLC following validation with multicenter and larger-scale prospective trials.

Baicalein enhances the antitumor efficacy of docetaxel on nonsmall cell lung cancer in a ß-catenin-dependent manner.

The side effects of docetaxel have limited its antitumor performances in the treatment of nonsmall cell lung cancer (NSCLC). To address the problem, baicalein, a bioactive flavone that exhibits antitumor activity, was combined with docetaxel so as to achieve better efficacy and lower toxicity. The combination treatment enhanced the stabilization of microtubules and halted the cell-cycle progression, thus synergistically inhibiting the proliferation and inducing the apoptosis of A549 cells and Lewis lung carcinoma cells. The decreased expression of Cyclin-dependent kinase 6 and Cyclin B1 confirmed its regulation in cell cycle, with ß-catenin being an important upstream effector, as evidenced by the decreased expression in the cytoplasm and nucleus as well as the attenuated aggregation in the nucleus. Furthermore, baicalein plus docetaxel evinced better antitumor efficacy by the suppressed tumor growth, increased apoptosis, and decreased tumor angiogenesis in vivo, with no increased toxicity discovered in both tumor-bearing and non-tumor-bearing mice, and an improvement in therapeutic index. This study has demonstrated that baicalein plus docetaxel is an appropriate combination simultaneously with augmented antitumor efficacy and acceptable safety, which might be a promising strategy for patients with advanced NSCLC.

MicroRNA-105 promotes epithelial-mesenchymal transition of nonsmall lung cancer cells through upregulating Mcl-1.

BACKGROUND: A growing number of microRNAs have been proved to play significant roles in limiting tumor growth and the epithelial-mesenchymal transition (EMT) process of nonsmall cell lung cancer (NSCLC). Present work aims to study the function of microRNA (miR)-105 in EMT of NSCLC cells, which is unrevealed yet. METHODS: Two NSCLC cell lines A549 and Calu-3 were transfected with miR-105 mimic, inhibitor, or scrambled control. And then the effects of miR-105 were evaluated by performing trypan blue staining, transwell assay, ANNEXIN-FITC/propidium iodide (PI) double staining and Western blot analysis. The expression levels of myeloid cell leukemia-1 (Mcl-1) after transfection were tested by real-time quantitative polymerase chain reaction and Western blot analysis. Whether Mcl-1 was a downstream effector of miR-105, and the involvement of mammalian target of Rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways were assessed. RESULTS: The overexpression of miR-105 significantly increased the viability and migration of A549 and Calu-3, but had no impacts on cell apoptosis. Meanwhile, E-cadherin was remarkably downregulated, and N-cadherin, Vimentin, ZEB1, and Snail were upregulated by miR-105 overexpression. Mcl-1 was positively regulated by miR-105, and the effects of miR-105 overexpression on A549 and Calu-3 cells viability, migration and EMT were all flattened by Mcl-1 silence. Both mTOR and p38MAPK pathways were activated in miR-105-overexpressing and Mcl-1-overexpressing cells. Besides, inhibition of mTOR and p38MAPK pathways by using Rapamycin and VX-702 abolished the regulatory effects of Mcl-1 on EMT. CONCLUSION: Our study underlines the importance of miR-105 in modulating NSCLC cells EMT. miR-105 promoted the EMT of NSCLC cells possibly via upregulation of Mcl-1 and thereby activation of mTOR and p38MAPK signaling.

Identifying nonsmall-cell lung tumours bearing the T790M EGFR TKI resistance mutation using PET imaging.

Specific mutations significantly affect response to epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer patients. Identifying patients with these mutations remains a major clinical challenge. EGFR T790M mutation, which conveys resistance to in the present study, [18 F]FEWZ was assessed in vitro to determine efficacy relative to the starting compound and in vivo to measure the biodistribution and specificity of binding to EGFR wild-type, L858R and T790M bearing tumours. [18 F]FEWZ is the first evidence of a radiolabeled third generation anilinopyrimidine-derived tyrosine kinase inhibitor targeting T790M mutation bearing tumours in vivo.

Attenuation of deregulated miR-369-3p expression sensitizes non-small cell lung cancer cells to cisplatin via modulation of the nucleotide sugar transporter SLC35F5.

Deregulation of the microRNAs (miRNAs), a cluster of important posttranscriptional regulators, has been frequently associated with lung cancer (LCa). However, the emerging mechanism for how miRNAs is linked causally in the development of LCa chemoresistance is poorly understood. Herein, we established for the time the up-regulation of miR-369-3p in cisplatin (DDP)-resistant nonsmall cell lung cancer (NSCLC) tissues and cells. Its deregulation was found to be correlated to the magnitude of malignancy in well-characterized LCa cells. Functionally, inhibition of miR-369-3p sensitized LCa cells to DDP and suppressed the invasive capability in the presence of DDP treatment, whereas miR-369-3p overexpression promoted DDP resistance and thereby enhanced LCa cells invasiveness. Mechanistically, bioinformatics coupled with luciferase and gain-of-function, loss-of-function assays revealed that miR-369-3p may regulate DDP chemoresistance by directly targeting the 3' untranslated region (UTR) of human solute carrier 35F5 (SLC35F5), as application of miR-369-3p inhibitors or reintroduction of epigenetically silenced SLC35F5 both individually sensitized LCa cells to DDP, but combined treatment with miR-369-3p inhibitors and SLC35F5 overexpression failed to sensitized LCa cells further to DDP-elicited cell death. Our results provide evidence that the oncomiR effect of miR-369-3p may be mediated through disrupting the nucleotide sugar transportation and that SLC35F5 is a key effector of this chemoresistance-promoting activity.

Different roles of myofibroblasts in the tumorigenesis of nonsmall cell lung cancer.

Myofibroblasts play a critical role in the cancer cell growth, invasion, and tumor-associated vascularization during the carcinogenesis of nonsmall cell lung cancer (NSCLC), whereas the underlying molecular bases are not completely understood. We isolated Lin-negative, Sca1-low, and CD49e-high myofibroblasts from the NSCLC tissues of the patients and modified the levels of either transforming growth factor ß 1 (TGFß1) or vascular endothelial growth factor A (VEGF-A) in these cells. We found that coculture with TGFß1-overexpressing myofibroblasts significantly decreased the NSCLC cell growth in an MTT assay through proliferation suppression rather than modulation of cell apoptosis, while significantly increased the NSCLC cell invasiveness in either a transwell migration assay or a scratch wound healing migration assay. However, modulation of TGFß1 levels in myofibroblasts did not significantly alter vessel formation in a human umbilical vein endothelial cells (HUVECs) transwell collagen gel assay. On the other hand, overexpression of VEGF-A in myofibroblasts significantly increased vessel formation in the HUVECs transwell collagen gel assay. Together, these data suggest that myofibroblasts may regulate cancer cell growth and invasion through TGFß1 but modulate cancer-associated neovascularization through VEGF-A. Hence, targeting different signaling pathways in myofibroblasts may delicately control NSCLC growth and invasion.

Roles of osteopontin and matrix metalloproteinase-7 in occurrence, progression, and prognosis of nonsmall cell lung cancer.

BACKGROUND: This study detected osteopontin (OPN) and matrix metalloproteinase-7 (MMP-7) expressions to explore the roles of OPN and MMP-7 in the occurrence, progression, and prognosis of nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: A retrospective study was conducted on NSCLC tissues (n = 152; case group) and adjacent nonneoplastic lung parenchyma (adjacent to tumor >5 cm; n = 152; control group) collected from 152 NSCLC patients. The protein expressions of OPN and MMP-7 were detected by immunohistochemistry. OPN and MMP-7 messenger RNA (mRNA) expressions were detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The protein and mRNA expressions of OPN and MMP-7 in NSCLC tissues were evidently higher than those in adjacent nonneoplastic lung parenchyma (all P < 0.05). OPN protein and mRNA expression were associated with the degree of differentiation, tumor node metastasis (TNM) staging, and lymph node metastasis in NSCLC (all P < 0.05). MMP-7 protein expression was associated with TNM staging and lymph node metastasis (both P < 0.05) while MMP-7 mRNA expression was associated with the degree of differentiation, TNM staging, and lymph node metastasis (all P < 0.05). A significantly positive relativity was revealed between OPN expression and MMP-7 expression (protein: r = 0.789, P < 0.001; mRNA: r = 0.377, P < 0.001). Lymph node metastasis, TNM staging, OPN, and MMP-7 protein expressions were independent risk factors for the prognosis of NSCLC (all P < 0.05). CONCLUSION: High MMP-7 and OPN protein expressions are closely related to the occurrence, progression, and prognosis of NSCLC, and can be served as unfavorable prognostic factors for NSCLC.

Clinical Characteristics, Response to Platinum-Based Chemotherapy and Poly (Adenosine Phosphate-Ribose) Polymerase Inhibitors in Advanced Lung Cancer Patients Harboring BRCA Mutations.

The oncogenic role and clinical relevance of BRCA mutations in NSCLC remain unclear. We aim to evaluate the characteristics and clinical outcomes of patients with NSCLC harboring BRCA mutations treated at Hadassah Medical Center (HMC). We retrospectively assessed all patients with advanced NSCLC who underwent next-generation sequencing (NGS) and were found to have pathogenic somatic BRCA mutations (p-BRCA). We compared clinical outcomes in NSCLC patients with wild-type BRCA (wt-BRCA) matched by age, stage, gender, smoking, PDL-1 and driver mutations. Between 2015 and 2022, we evaluated 598 patients with advanced NSCLC using NGS and found 26 patients with p-BRCA, of whom 17 (65.4%) were carriers of germline BRCA variants and represented 1% of all BRCA carriers HMC. The median age of diagnosis was 67 years old (40-78), 13 patients (50%) had a history of smoking and 9 patients (34.6%) had additional driver mutations (EGFR, ALK, BRAF, MET or ERBB2). Objective response rate and median progression-free survival (PFS) for first-line platinum-based chemotherapy in the p-BRCA group compared to wt-BRCA controls were 72.2% and 16 months (CI 95%, 5-22), compared to 47.4% and 7 months (CI 95%, 5-9), respectively, and HR for PFS was 0.41 (CI 95%, 0.17-0.97). Six patients in the p-BRCA group were treated with advanced-line poly (adenosine-phosphate-ribose) polymerase inhibitors (PARPi), with a durable response observed in four patients (66%). In this cohort, patients with NSCLC harboring p-BRCA exhibit high-sensitivity PARPi and a prolonged response to platinum, suggesting some oncogenic role for BRCA mutations in NSCLC. The results support further prospective trials of the treatment of NSCLC harboring p-BRCA with PARPi.

Advances in the Treatment of Rare Epidermal Growth Factor Receptor Mutations in Advanced Nonsmall-Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) mutations are common driver genes in nonsmall-cell lung cancer and have different sensitivities to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR is divided into classic mutations and rare mutations. Classic mutations are well known, but the understanding of rare mutations is not sufficient. In this article, we summarize the clinical research and treatment progress of rare mutations for different EGFR-TKIs and provide a basis for clinical treatment decisions.

Case Report: Benefits of a NSCLC Patient With EGFR A289G/F287_G288insHA cis Mutations From Immunotherapy in Combination With Antiangiogenesis and Chemotherapy and Sequential Treatment of EGFR-TKI.

We presented a 67-year-old nonsmoking female lung adenocarcinoma patient with novel epidermal growth factor receptor (EGFR) A289G/F287_G288insHA cis mutations who responded positively to sintilimab combined with regorafenib and albumin paclitaxel, and sequential treatment of icotinib. Gene mutations in patients were detected by next-generation sequencing (NGS) technology, and changes in gene mutations before and after treatments were observed by ctDNA monitoring. We observed the efficacy of the patient through chest computed tomography (CT) imaging and carcinoembryonic antigen (CEA) level and found that the patient benefited from immunotherapy in combination with antiangiogenesis and chemotherapy for more than 1 year, CEA levels initially fell sharply and then rebounded during the treatment period. After changing to EGFR-TKI therapy, the CEA level of the patient does not only decreased sharply at the initial stage of treatment but also rebounded and increased at the later stage of treatment. The patient was tested for genetic mutations after 4 months of sequential EGFR-TKI therapy and was found to have lost all previous EGFR mutations, which may be the cause of resistance to targeted drug icotinib. We believe that our findings have enriched the EGFR mutation spectrum in NSCLC and highlighted the possible choice for patients harboring this mutation by immunotherapy combined with chemotherapy and antivascular therapy, and EGFR-TKI-targeted therapy.

RNA Demethylase ALKBH5 Prevents Lung Cancer Progression by Regulating EMT and Stemness via Regulating p53.

Background: Although N6-methyladenosine (m6A) RNA methylation is the most abundant reversible methylation of mRNA, which plays a critical role in regulating cancer processing, few studies have examined the role of m6A in nonsmall-cell lung cancer-derived cancer stem-like cells (CSCs). Methods: CSCs were enriched by culturing NSCLC cells in a serum-free medium, and stem factors, including CD24, CD44, ALDH1, Nanog, Oct4, and Sox2 were detected by Western blot. ALKBH5 expression was measured by employing a tissue array. Global m6A methylation was measured after ALKBH5 knockdown. Malignances of CSCs were detected by performing CCK-8 assay, invasion assay, cell cycle analysis, and tumor formation in vitro and in vivo. Results: m6A demethylase ALKBH5 is highly expressed in CSCs derived from NSCLC. Knockdown of ALKBH5 increased global m6A level, and also increased E-cadherin, decreased stem hallmarkers, Nanog and Oct4, and inhibited stemness of CSCs. In lung carcinoma, ALKBH5 is found to be positively correlated with p53 by using Gene Expression Profiling Interactive Analysis (GEPIA) online tool. P53 transcriptionally regulates ALKBH5 and subsequently regulates the global m6A methylation level. Knockdown of p53 or inhibition of p53's transcriptional activity by addition of its specific inhibitor PFT-α decreased expression of ALKBH5 and CSCs' malignancies, including proliferation, invasion, and tumor formation ability, indicating that p53 may partially regulate CSC's malignancies via ALKBH5. Furthermore, we also found p53 transcriptionally regulates PRRX1, which is consistent with our previous report. Conclusion: Collectively, our findings indicate the pivotal role of ALKBH5 in CSCs derived from NSCLC and highlight the regulatory function of the p53/ALKBH5 axis in modulating CSC progression, which could be a promising therapeutic target for NSCLC.

Phase II Trial of Flaxseed to Prevent Acute Complications After Chemoradiation for Lung Cancer.

Background: Thoracic radiotherapy is complicated by acute radiation-induced adverse events such as radiation pneumonitis (RP) and radiation esophagitis (RE). Based on preclinical work and a randomized pilot trial from our laboratory, this single-arm phase II trial investigated administering flaxseed as a radioprotector in patients receiving definitive chemoradiation for nonsmall cell lung cancer (NSCLC). Methods: Between June 2015 and February 2018, 33 patients with locally advanced or metastatic NSCLC with planned definitive chemoradiation were enrolled. Finely-ground Linum usitatissimum L. (Linaceae; flaxseed or linseed) in 40-g packets were provided for daily consumption in any patient-desired formulation 1 week before radiotherapy and throughout radiotherapy as tolerated. The primary outcomes were overall adverse events, with particular focus on Grade ≥3 RP, and flaxseed tolerability. Adverse events were graded according to CTCAE v4.0. Results: Of the 33 patients enrolled, 5 patients (15%) did not receive chemoradiation, 4 (12%) withdrew promptly after enrollment, 4 (12%) did not return a flaxseed consumption log, and 1 patient had irritable bowel syndrome (3%). The remaining 19 patients (57%) had chemoradiation and flaxseed ingestion with a mean completion and standard deviation of the intended flaxseed course of 62% ± 8.3%. Nine (50%) of these 19 patients reported difficulties with flaxseed consumption, citing nausea, constipation, odynophagia, or poor taste or texture. One patient (5%), with unverifiable flaxseed consumption, developed Grade 3 RP. There were no cases of Grade 2 RP. Six patients (32%) developed Grade 2 RE, but no patients developed Grade ≥3 RE. Median overall and progression-free survival were 31 and 12 months, respectively. Conclusions: Despite the low incidence of acute radiation-induced complications reported, significant treatment-related gastrointestinal toxicities and subsequently low flaxseed tolerability inhibit accurate determination of flaxseed effect in patients receiving concurrent thoracic chemoradiation. Thus, further investigations should focus on optimizing flaxseed formulation for improved tolerability and evaluation. ClinicalTrials.gov ID: NCT02475330.

Tofacitinib overcomes an IFNγ-induced decrease in NK cell-mediated cytotoxicity via the regulation of immune-related molecules in LC-2/ad.

BACKGROUND: Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) axis have shown promising results in patients with nonsmall cell lung cancer (NSCLC). One major PD-L1 inducer is IFNγ, which is secreted by T cells and NK cells. Importantly, IFNγ-induced PD-L1 is one of the major mechanisms by which cancer cells escape host immunity. METHODS: Here, we found that the NSCLC cell line, LC-2/ad, has a unique character; the PD-L1 expression in these cells is up-regulated by both IFNγ and epidermal growth factor (EGF). RESULTS: Comparative analysis of the cell signaling pathway showed that IFNγ activates STAT1 signaling, while EGF activates AKT, MAPK, and ribosomal protein S6 kinase in LC-2/ad cells. IFNγ-induced PD-L1, but not EGF-induced PD-L1, was clearly blocked by the JAK-STAT inhibitor tofacitinib. Interestingly, IFNγ decreased the expression of NK cell-activating ligands while increasing the expression of MHC class I molecules, resulting in a phenotype that can easily escape from NK cells, theoretically. Finally, we showed that IFNγ stimuli attenuated NK cell-mediated cytotoxicity in LC-2/ad cells, which was, however, blocked by tofacitinib. CONCLUSIONS: Taken together, our study shows that tofacitinib blocks the IFNγ-induced transformation from an NK cell-sensitive phenotype to an NK cell-resistant one in IFNγ-reacted LC-2/ad cells, thereby implicating that tofacitinib may be a promising agent to overcome IFNγ-induced tumor immune escape, although it may be adapted to the limited number of NSCLC patients.

Simultaneous cosegmentation of tumors in PET-CT images using deep fully convolutional networks.

PURPOSE: To investigate the use and efficiency of 3-D deep learning, fully convolutional networks (DFCN) for simultaneous tumor cosegmentation on dual-modality nonsmall cell lung cancer (NSCLC) and positron emission tomography (PET)-computed tomography (CT) images. METHODS: We used DFCN cosegmentation for NSCLC tumors in PET-CT images, considering both the CT and PET information. The proposed DFCN-based cosegmentation method consists of two coupled three-dimensional (3D)-UNets with an encoder-decoder architecture, which can communicate with the other in order to share complementary information between PET and CT. The weighted average sensitivity and positive predictive values denoted as Scores, dice similarity coefficients (DSCs), and the average symmetric surface distances were used to assess the performance of the proposed approach on 60 pairs of PET/CTs. A Simultaneous Truth and Performance Level Estimation Algorithm (STAPLE) of 3 expert physicians' delineations were used as a reference. The proposed DFCN framework was compared to 3 graph-based cosegmentation methods. RESULTS: Strong agreement was observed when using the STAPLE references for the proposed DFCN cosegmentation on the PET-CT images. The average DSCs on CT and PET are 0.861 ± 0.037 and 0.828 ± 0.087, respectively, using DFCN, compared to 0.638 ± 0.165 and 0.643 ± 0.141, respectively, when using the graph-based cosegmentation method. The proposed DFCN cosegmentation using both PET and CT also outperforms the deep learning method using either PET or CT alone. CONCLUSIONS: The proposed DFCN cosegmentation is able to outperform existing graph-based segmentation methods. The proposed DFCN cosegmentation shows promise for further integration with quantitative multimodality imaging tools in clinical trials.

What are the clinical symptoms and physical signs for non-small cell lung cancer before diagnosis is made? A nation-wide multicenter 10-year retrospective study in China.

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.

Osimertinib in the treatment of leptomeningeal disease in T790M-negative, epidermal growth factor receptor-mutated non-small cell lung cancer: a case report.

Leptomeningeal carcinomatosis (LMC) is a terminal event in advanced cancer, its incidence in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is increasing due to recent advances in systemic therapy and prolongation of survival. Osimertinib is a third generation EGFR-tyrosine kinase inhibitor (TKI) with preclinical and early clinical studies showing activity against LMC resistant to previous TKI treatments and acquired T790M mutation. We report a case of osimertinib in the treatment of LMC in a T790M-negative, EGFR-mutated NSCLC with significant clinical benefit and no toxicity. Osimertinib is a potentially effective treatment for LMC associated with EGFR-mutated NSCLC regardless of T790M status and a well-tolerated treatment for poor performance status patients.

Outcomes for patients with synchronous and metachronous primary lung cancer after diagnosis of head and neck cancer.

BACKGROUND: Not-infrequently patients with head and neck cancer are also diagnosed with synchronous lung cancer or metachronous primary lung cancer, which complicates the treatment decisions and prognosis. METHODS: Patients were identified from a database of patients with head and neck cancer with second primary non-small cell lung cancer (NSCLC). RESULTS: Thirty-four eligible patients (15 with synchronous lung cancer and 19 with metachronous lung cancer) were identified. Thirteen of 15 patients with synchronous lung cancer received curative intent treatment for head and neck cancer first. Six of 15 patients were in complete remission, 5 of 15 patients had died, and 4 were alive with progressive disease. Median time between 2 diagnoses was 47 months in the metachronous lung cancer group. Twelve patients had died, 3 were alive with disease, and 4 were lost to follow-up. Median survival from the time of lung cancer diagnosis was 13 months with a trend to better survival with synchronous lung cancer (15 vs 11 months; p = .11). CONCLUSION: Aggressive multidisciplinary management of second primary lung malignancies in patients with head and neck cancer can result in respectable long-term disease control particularly in patients with synchronous lung cancer. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1544-1549, 2017.