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Lung Cancer

Lung cancer is one of the most common types of cancer. The lungs are a pair of cone-shaped organs situated inside the chest, they bring oxygen into the body and take out waste carbon dioxide. There is a strong link between smoking and lung cancer. There are two main categories of lung cancer; Small Cell Lung Cancer (SCLC) , and Non-Small Cell Lung Cancer (NSCLC). World-wide over 1 million people are diagnosed with lung cancer each year.

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Information for Patients and the Public
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Latest Research Publications
Non-Small Cell Lung Cancer
Small Cell Lung Cancer
Risk Factors and Prevention of Lung Cancer

Information Patients and the Public (19 links)

Information for Health Professionals / Researchers (17 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Duregon E, Senetta R, Bertero L, et al.
Caveolin 1 expression favors tumor growth and is associated with poor survival in primary lung adenocarcinomas.
Tumour Biol. 2017; 39(2):1010428317694311 [PubMed] Related Publications
Despite the consolidated clinico-pathological correlates of Caveolin 1 expression in non-small cell lung cancer, the available data on the role of Caveolin 1 in relation to proliferation, migration, and metastasis in lung adenocarcinoma cells is still scant. Here, we aimed to confirm whether Caveolin 1 may act as a promoter of cell growth in human lung adenocarcinoma using in vitro and in vivo models, supported by a survival analysis of Caveolin 1 expression in a series of 116 primary lung adenocarcinomas. The silencing of endogenous Caveolin 1 expression in H522 lung adenocarcinoma cells through stable shRNA transfection significantly inhibited cellular proliferation in vitro and in vivo, in a lung adenocarcinoma xenograft mouse model. The bioluminescence imaging analysis revealed that tumors derived from Caveolin 1 shRNA-transfected cells grew slower than control xenografts. However, this difference progressively diminished over time and was definitively lost after 21 days. This was consistent with a progressive Caveolin 1 re-expression, which started at day 7. The association between the restored expression of Caveolin 1 and the restart of tumor growth in vivo supports the booster role of Caveolin 1 in lung adenocarcinoma progression. To further confirm this role, Caveolin 1 expression was assessed by immunohistochemistry in a series of 116 human lung adenocarcinomas. Positive Caveolin 1 tumors accounted for 20% of cases and were associated with a significantly worse overall survival compared to Caveolin 1-negative cancers. Taken together, these data highlight that Caveolin 1 expression confers a proliferative advantage in lung adenocarcinoma cells, thus fostering increased tumor aggressiveness.

Fiala O, Pesek M, Skrickova J, et al.
Thyroid transcription factor 1 expression is associated with outcome of patients with non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.
Tumour Biol. 2017; 39(2):1010428317691186 [PubMed] Related Publications
Pemetrexed is an antifolate cytostatic agent targeting several folate-dependent enzymatic pathways, widely used in the treatment of locally advanced or metastatic stage non-small cell lung cancer. Aside from the non-squamous histology, there is still no available molecular biomarker predicting treatment efficacy of pemetrexed-based chemotherapy. The aim of our retrospective study was to evaluate the association of thyroid transcription factor 1 expression with outcome of a large cohort of patients with non-squamous non-small cell lung cancer treated with pemetrexed. We retrospectively analysed clinical data of 463 patients with advanced-stage non-small cell lung cancer (IIIB or IV) treated with pemetrexed-based chemotherapy. Thyroid transcription factor 1 expression was assessed using indirect immunohistochemical detection in formalin-fixed paraffin-embedded tumour tissue at the time of diagnosis. Thyroid transcription factor 1 expression was detected in the tumour tissue from 76.0% of patients, and tumours from 24.0% of patients were thyroid transcription factor 1 negative. The median progression-free survival and overall survival for patients with thyroid transcription factor 1 positive tumours were 4.8 and 11.8 months compared to 2.8 and 8.3 months for those with thyroid transcription factor 1 negative tumours (p = 0.001 and p < 0.001). The multivariable Cox proportional hazards model revealed that thyroid transcription factor 1 expression was significantly associated with progression-free survival (hazard ratio = 1.57, p < 0.001) and also with overall survival (hazard ratio = 1.73, p < 0.001). In conclusion, the results of the conducted retrospective study suggest that the thyroid transcription factor 1 expression was independently associated with progression-free survival and overall survival in patients with advanced-stage non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

Shi J, Yuan M, Wang ZD, et al.
Comprehensive profiling and quantitation of oncogenic mutations in non-small cell lung carcinoma using single-molecule amplification and re-sequencing technology.
Tumour Biol. 2017; 39(2):1010428317691413 [PubMed] Related Publications
The carcinogenesis of non-small cell lung carcinoma has been found to associate with activating and resistant mutations in the tyrosine kinase domain of specific oncogenes. Here, we assessed the type, frequency, and abundance of epithelial growth factor receptor, KRAS, BRAF, and ALK mutations in 154 non-small cell lung carcinoma specimens using single-molecule amplification and re-sequencing technology. We found that epithelial growth factor receptor mutations were the most prevalent (44.2%), followed by KRAS (18.8%), ALK (7.8%), and BRAF (5.8%) mutations. The type and abundance of the mutations in tumor specimens appeared to be heterogeneous. Thus, we conclude that identification of clinically significant oncogenic mutations may improve the classification of patients and provide valuable information for determination of the therapeutic strategies.

Brown J, Lee TJ, Joiner T, Wrightson W
Using Electromagnetic Navigation Bronchoscopy and Dye Injection to Aid in Video-Assisted Lung Resection.
Am Surg. 2016; 82(11):1052-1054 [PubMed] Related Publications
Small (2 cm) peripheral lung lesions and ground glass opacities remain a difficult subset of lung lesions for the diagnosis and management of lung cancer. Surgical biopsy is more difficult for these lesions because intraoperative localization has to be made without the aid of direct visualization or manual palpation. Electromagnetic navigation bronchoscopy can be used in the operating room to identify a small peripheral lesion and marked using an injection of methylene blue, which can be seen on the visceral pleura of the lung. We present our initial experience using this technique. The sample was eight patients who had peripheral lesions with an average size of 19 mm. Surgical wedge biopsy was diagnostic in all cases, with an average procedure time of 28 minutes. There were no complications from this procedure. In conclusion, these data suggest that electromagnetic navigation bronchoscopy can be performed safely with high diagnostic accuracy by the operating thoracic surgeon, but further data are needed to establish its utility and safety.

Okada T, Kurabayashi A, Akimitsu N, Furihata M
Expression of Cadherin-17 Promotes Metastasis in a Highly Bone Marrow Metastatic Murine Breast Cancer Model.
Biomed Res Int. 2017; 2017:8494286 [PubMed] Free Access to Full Article Related Publications
We previously established 4T1E/M3 highly bone marrow metastatic mouse breast cancer cells through in vivo selection of 4T1 cells. But while the incidence of bone marrow metastasis of 4T1E/M3 cells was high (~80%) when injected intravenously to mice, it was rather low (~20%) when injected subcutaneously. Therefore, using 4T1E/M3 cells, we carried out further in vitro and in vivo selection steps to establish FP10SC2 cells, which show a very high incidence of metastasis to lungs (100%) and spines (85%) after subcutaneous injection into mice. qRT-PCR and western bolt analysis revealed that cadherin-17 gene and protein expression were higher in FP10SC2 cells than in parental 4T1E/M3 cells. In addition, immunostaining revealed the presence of cadherin-17 at sites of bone marrow and lung metastasis after subcutaneous injection of FP10SC2 cells into mice. Suppressing cadherin-17 expression in FP10SC2 cells using RNAi dramatically decreased the cells' anchorage-independent growth and migration in vitro and their metastasis to lung and bone marrow in vivo. These findings suggest that cadherin-17 plays a crucial role in mediating breast cancer metastasis to bone marrow.

Sone K, Oguri T, Nakao M, et al.
CYFRA 21-1 as a Predictive Marker for Non-small Cell Lung Cancer Treated with Pemetrexed-based Chemotherapy.
Anticancer Res. 2017; 37(2):935-939 [PubMed] Related Publications
BACKGROUND: Pretreatment serum tumor marker levels predict outcome in non-small cell lung cancer (NSCLC). However, little is known about the clinical value of such measurements for patients treated with pemetrexed plus a platinum-derivative.
PATIENTS AND METHODS: We retrospectively screened 100 chemotherapy-naïve patients with advanced non-squamous NSCLC treated with pemetrexed plus a platinum-derivative in relation to the pretreatment level of cytokeratin 19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA).
RESULTS: Sixty one patients with a high CYFRA 21-1 level had statistically shorter progression-free and overall survival than 39 patients with a normal CYFRA 21-1 level (median progression-free survival=127 days vs. 191 days, respectively; p=0.046; median overall survival=360 days vs. 781 days, respectively, p<0.001). Serum CEA level was not related to survival.
CONCLUSION: Serum CYFRA 21-1 level is a predictive and prognostic marker in patients with NSCLC treated with pemetrexed plus a platinum-derivative.

Yamasaki M, Murakami I, Nakano K, et al.
Carboplatin plus Weekly Paclitaxel Combined with Bevacizumab as First-line Treatment for Non-small Cell Lung Cancer.
Anticancer Res. 2017; 37(2):923-928 [PubMed] Related Publications
AIM: We aimed to evaluate the efficacy and safety of carboplatin plus weekly paclitaxel with bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC).
PATIENTS AND METHODS: Patients with stage IIIB/IV or postoperative recurrent NSCLC (n=33) were treated with carboplatin (area under the curve of 6) on day 1; paclitaxel (80 mg/m(2)) on days 1, 8, and 15; and bevacizumab (15 mg/kg) on day 1 repeated every 4 weeks, for four to six cycles; followed by maintenance bevacizumab (15 mg/kg) every 3 weeks.
RESULTS: The overall response rate was 76%. The median progression-free survival and overall survival were 8.4 months and 22.2 months, respectively. Grade 3-4 toxicities included neutropenia in 55% of patients, anemia in 18%, febrile neutropenia in 12%, and anorexia in 9%. No treatment-related deaths were observed.
CONCLUSION: Carboplatin plus weekly paclitaxel with bevacizumab was effective and well tolerated by patients with advanced NSCLC.

Toyokawa G, Kozuma Y, Matsubara T, et al.
Radiological Features of the Surgically Resected Small-sized Small-cell Lung Cancer on Computed Tomography.
Anticancer Res. 2017; 37(2):877-881 [PubMed] Related Publications
BACKGROUND/AIM: Surgical resection can be applied in cases of early-stage small-cell lung cancer (SCLC). Predicting the histology of SCLC and discriminating SCLC from other histologies would be useful for determining the optimal treatment strategies for small pulmonary nodules that have not been preoperatively diagnosed.
MATERIALS AND METHODS: The study population included 17 patients with resected SCLC and 296 patients with adenocarcinoma (ADC) whose preoperative CT were available. The tumors of all patients were smaller than 3.0 cm.
RESULTS: Univariate and multivariate analyses demonstrated that SCLC was significantly associated with the presence of notching and the absence of surrounding ground glass opacity, air bronchogram, pleural indentation, and spiculation in comparison to ADC.
CONCLUSION: The CT scans of patients with SCLC of less than 3.0 cm in size showed notching more frequently than those of patients with ADC, whereas surrounding GGO, air bronchogram, pleural indentation and spiculation were observed less frequently compared to ADC.

Takeda K, Yamasaki A, Igishi T, et al.
Frequency of Epidermal Growth Factor Receptor Mutation in Smokers with Lung Cancer Without Pulmonary Emphysema.
Anticancer Res. 2017; 37(2):765-771 [PubMed] Related Publications
BACKGROUND: Chronic obstructive pulmonary disease is a smoking-related disease, and is categorized into the emphysema and airway dominant phenotypes. We examined the relationship between emphysematous changes and epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma.
PATIENTS AND METHODS: The medical records for 250 patients with lung adenocarcinoma were retrospectively reviewed. All patients were categorized into the emphysema or non-emphysema group.
RESULTS: Wild-type EGFR was detected in 136 (54%) and mutant EGFR in 48 (19%). Emphysematous changes were observed in 87 (36%) patients. EGFR mutation was highly frequent in the non-emphysema group (p=0.0014). Multivariate logistic regression analysis showed that emphysema was an independent risk factor for reduced frequency of EGFR mutation (Odds Ratio=3.47, p=0.005).
CONCLUSION: Our data showed a relationship between emphysematous changes and EGFR mutation status. There might be mutually exclusive genetic risk factors for carcinogenesis and development of emphysematous changes.

Shoji F, Haratake N, Akamine T, et al.
The Preoperative Controlling Nutritional Status Score Predicts Survival After Curative Surgery in Patients with Pathological Stage I Non-small Cell Lung Cancer.
Anticancer Res. 2017; 37(2):741-747 [PubMed] Related Publications
BACKGROUND: The prognostic Controlling Nutritional Status (CONUT) score is used to evaluate immuno-nutritional conditions and is a predictive factor of postoperative survival in patients with digestive tract cancer. We retrospectively analyzed clinicopathological features of patients with pathological stage I non-small cell lung cancer (NSCLC) to identify predictors or prognostic factors of postoperative survival and to investigate the role of preoperative CONUT score in predicting survival.
PATIENTS AND METHODS: We selected 138 consecutive patients with pathological stage I NSCLC treated from August 2005 to August 2010. We measured their preoperative CONUT score in uni- and multivariate Cox regression analyses of postoperative survival.
RESULTS: A high CONUT score was positively associated with preoperative serum carcinoembryonic antigen level (p=0.0100) and postoperative recurrence (p=0.0767). In multivariate analysis, the preoperative CONUT score [relative risk (RR)=6.058; 95% confidence interval (CI)=1.068-113.941; p=0.0407), increasing age (RR=7.858; 95% CI=2.034-36.185; p=0.0029), and pleural invasion (RR=36.615; 95% CI=5.900-362.620; p<0.0001) were independent prognostic factors. In Kaplan-Meier analysis of recurrence-free survival (RFS), cancer-specific survival (CS), and overall survival (OS), the group with high CONUT score had a significantly shorter RFS, CS, and OS than did the low-CONUT score group by log-rank test (p=0.0458, p=0.0104 and p=0.0096, respectively).
CONCLUSION: The preoperative CONUT score is both a predictive and prognostic factor in patients with pathological stage I NSCLC. This immuno-nutritional score can indicate patients at high risk of postoperative recurrence and death.

Ishikura N, Yanagisawa M, Noguchi-Sasaki M, et al.
Importance of Bevacizumab Maintenance Following Combination Chemotherapy in Human Non-small Cell Lung Cancer Xenograft Models.
Anticancer Res. 2017; 37(2):623-629 [PubMed] Related Publications
BACKGROUND: Bevacizumab in combination with chemotherapeutics has shown significant survival benefit in clinical studies in patients with non-small cell lung cancer (NSCLC). Since bevacizumab was administered as standard treatment until disease progression, the importance of bevacizumab during the maintenance phase was not prospectively investigated in these studies.
MATERIALS AND METHODS: Three human NSCLC cell line xenograft models were used to investigate antitumor effect of bevacizumab and tumor microvessel density (MVD) was analyzed.
RESULTS: In A549 and NCI-H292 models, bevacizumab maintenance following combination with paclitaxel exhibited stronger tumor suppression than its absence. In an NCI-H292 model, bevacizumab maintenance continuously inhibited increase of MVD. In an NCI-H2228 model following induction treatment with pemetrexed and bevacizumab, maintenance with pemetrexed plus bevacizumab, had stronger efficacy than pemetrexed alone and led to lower MVD and level of thymidylate synthase.
CONCLUSION: Continuous suppression of angiogenesis by bevacizumab may contribute to the superior efficacy of maintenance treatment containing bevacizumab.

Rafei H, El-Bahesh E, Finianos A, et al.
Immune-based Therapies for Non-small Cell Lung Cancer.
Anticancer Res. 2017; 37(2):377-387 [PubMed] Related Publications
Lung cancer is the leading cause of cancer-related death worldwide. Treatment of non-small cell lung cancer has evolved tremendously over the past decade. Specifically, immune checkpoint inhibitors have become an increasingly interesting target of pharmacological blockade. These immune inhibitors have shown promising results in front-line therapy and after failure of multiple lines, as well as in monotherapy and combination with other therapies. Vaccination in non-small cell lung cancer is also an emerging field of research that holds promising results for the future of immunotherapy in non-small cell lung cancer. This review presents a concise update on the most recent data regarding the role of checkpoint inhibitors as well as vaccination in non-small cell lung cancer.

Le Rhun E, Taillibert S, Chamberlain MC
Neoplastic Meningitis Due to Lung, Breast, and Melanoma Metastases.
Cancer Control. 2017; 24(1):22-32 [PubMed] Related Publications
BACKGROUND: Neoplastic meningitis, a central nervous system (CNS) complication of cancer metastatic to the meninges and cerebrospinal fluid (CSF), is relevant to oncologists due to the impact of the disease on patient quality of life and survival rates.
METHODS: A review of the literature of articles published in English was conducted with regard to neoplastic meningitis.
RESULTS: The incidence of neoplastic meningitis is increasing because patients with cancer are surviving longer in part because of the use of novel therapies with poor CNS penetration. Up to 5% of patients with solid tumors develop neoplastic meningitis during the disease course (breast cancer, lung cancer, and melanoma being the predominantly causative cancers). The rate of median survival in patients with untreated neoplastic meningitis is 1 to 2 months, although it can be as long as 5 months in some cases. Therapeutic options for the treatment of neoplastic meningitis include systemic therapy (cancer-specific, CNS-penetrating chemotherapy or targeted therapies), intra-CSF administration of chemotherapy (methotrexate, cytarabine, thiotepa) and CNS site-specific radiotherapy. Determining whom to treat with neoplastic meningitis remains challenging and, in part, relates to the extent of systemic disease, the neurological burden of disease, the available systemic therapies, and estimated rates of survival.
CONCLUSIONS: The prognosis of neoplastic meningitis remains poor. The increasing use of novel, targeted therapies and immunotherapy in solid tumors and its impact on neoplastic meningitis remains to be determined and is an area of active research. Thus, well conducted trials are needed.

Koba T, Kijima T, Takimoto T, et al.
Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation: Two Case Reports.
Medicine (Baltimore). 2017; 96(6):e6087 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Most of nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations eventually acquire resistance to the first EGFR-tyrosine kinase inhibitors (TKIs) therapy after varying periods of treatment. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. The effect of systemic chemotherapy on brain metastases after acquisition of EGFR-TKI resistance is limited, and thus far, whole-brain radiation therapy, which may cause the harmful effect on neurocognitive functions, has been the only established therapeutic option for especially symptomatic brain metastases. Osimertinib is a third-generation oral, potent, and irreversible EGFR-TKI. It can bind to EGFRs with high affinity even when the EGFR T790M mutation exists in addition to the sensitizing mutations. Its clinical efficacy for NSCLC patients harboring the T790M mutation has already been shown; however, the evidence of osimertinib on brain metastases has not been documented well, especially in terms of the appropriate timing for treatment and its response evaluation.
PATIENT CONCERNS, DIAGNOSES, AND INTERVENTIONS: We experienced 2 NSCLC patients with the EGFR T790M mutation; a 67-year-old woman with symptomatic multiple brain metastases administered osimertinib as seventh-line chemotherapy, and a 76-year old man with an asymptomatic single brain metastasis administered osimertinib as fifth-line chemotherapy.
OUTCOMES: These patients showed great response to osimertinib within 2 weeks without radiation therapy.
LESSONS: These are the first reports to reveal the rapid response of the brain metastases to osimertinib within 2 weeks. These cases suggest the possibility that preemptive administration of osimertinib may help patients to postpone or avoid radiation exposures. In addition, rapid reassessment of the effect of osimertinib on brain metastases could prevent patients from being too late to receive essential radiotherapy.

Malavasi S, Barone D, Gavelli G, Bevilacqua A
Multislice Analysis of Blood Flow Values in CT Perfusion Studies of Lung Cancer.
Biomed Res Int. 2017; 2017:3236893 [PubMed] Free Access to Full Article Related Publications
Objectives. Tumour heterogeneity represents a key issue in CT perfusion (CTp), where all studies are usually based on global mean or median values of perfusion maps, often computed on whole tumour. We sought to determine whether, and to what extent, such global values can be representative of tumour heterogeneity, with respect to single slices, and could be used for therapy assessment. Materials and Methods. Twelve patients with one primary non-small cell lung cancer lesion were enrolled in this study, for a total amount of 26 CTp examinations and 118 slices. Mean and median blood flow (BF) values, calculated voxel-based, were computed on each slice and the whole tumour. To measure functional heterogeneity, entropy was calculated on BF values as well. Results. Most of the slices were not represented by the global BF values computed on the whole tumour. In addition, there are a number of lesions having equivalent global BF values, but they are composed of slices having very different heterogeneity distributions, that is, entropy values. Conclusions. Global mean/median BF values of the single slices separately should be considered for clinical assessment, only if interpreted through entropy computed on BF values. The numerical equivalence between global BF values of different lesions may correspond to different clinical status, thus inducing possible errors in choice of therapy when considering global values only.

Yu N, Xiong Y, Wang C
Bu-Zhong-Yi-Qi Decoction, the Water Extract of Chinese Traditional Herbal Medicine, Enhances Cisplatin Cytotoxicity in A549/DDP Cells through Induction of Apoptosis and Autophagy.
Biomed Res Int. 2017; 2017:3692797 [PubMed] Free Access to Full Article Related Publications
Cisplatin is one of the most active cytotoxic agents for non-small cell lung cancer (NSCLC) treatment. However, the development of cisplatin resistance is common. Bu-Zhong-Yi-Qi decoction (BZYQD), a Chinese traditional herbal medicine, is widely used for the enhancement of antitumor effect in other medications. In this study, we evaluated the effect and drug-resistance reversal mechanism of BZYQD combined with cisplatin on cisplatin-resistant A549/DDP cells. Our results showed that BZYQD exhibited direct cytotoxic and chemosensitizing effects. Cotreatment with BZYQD and cisplatin induced intrinsic apoptotic pathways which were measured by condensed nuclear chromatin, Annexin V/PI apoptosis assay, and apoptosis related proteins expression. In addition, cotreatment with BZYQD and cisplatin also activated autophagy, as indicated by an increase in LC3 puncta, classical autophagosomes and/or autolysosomes, and an accumulation of LC3-II and ATG7 protein. Finally, cotreatment with BZYQD and cisplatin resulted in the generation of ROS and scavenging ROS by NAC almost completely suppressing cell death. These results suggest that cotreatment with BZYQD and cisplatin might reverse cisplatin resistance by inducing ROS accumulation, which activates apoptosis and autophagy by oxidative stress. The combination of BZYQD and cisplatin may represent a novel approach in treatment for NSCLC and thus offer a new target for chemotherapy.

Sano I, Katanuma A, Yane K, et al.
Pancreatic Metastasis from Rectal Cancer that was Diagnosed by Endoscopic Ultrasonography-guided Fine Needle Aspiration (EUS-FNA).
Intern Med. 2017; 56(3):301-305 [PubMed] Related Publications
Pancreatic metastasis from colorectal cancer is rare, and there have been only a few reports of its preoperative diagnosis by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with immunohistochemical staining. We herein describe the case of a 77-year-old woman in whom a solitary mass in the pancreatic tail was detected 11 years after rectal cancer resection. The patient also had a history of pulmonary tumor resection. We performed EUS-FNA and a histopathological examination showed adenocarcinoma with CD20+, CD7-, and CDX2+ (similar to her rectal cancer). EUS-FNA enabled a histopathological examination, including immunohistochemical staining, which helped to confirm the diagnosis of pancreatic and pulmonary metastasis from rectal cancer.

Petrella F, Coccè V, Masia C, et al.
Paclitaxel-releasing mesenchymal stromal cells inhibit in vitro proliferation of human mesothelioma cells.
Biomed Pharmacother. 2017; 87:755-758 [PubMed] Related Publications
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare fatal asbestos-related malignancy originating in the mesothelial cells of the pleura. A platinum-based doublet containing a third-generation antifolate is the front-line standard of care whilst there are no approved second-line treatments for MPM which remains a disease setting to test the efficacy of new therapeutic agents.
METHODS: Bone marrow mesenchymal stromal cells (BM-MSCs) were loaded with pemetrexed (PMX) and paclitaxel (PTX) according to a standardized procedure. Drug release by both PMX- and PTX-primed BM-MSCs (BM-MSCs/PMX and BM-MSCs/PTX) was tested on the in vitro proliferation of a panel of tumor cell lines including NCI-H28 mesothelioma.
RESULTS: The in vitro anticancer activity of pure PTX was significantly higher than that of PMX against all the cell lines tested (14.7 times higher than that of PMX against NCI-H28). Whereas BM-MSCs did not take up and release PMX in amounts effective on mesothelioma, PTX-loaded BM-MSCs dramatically inhibited mesothelioma proliferation.
CONCLUSIONS: PTX-primed mesenchymal stromal cells successfully inhibit the in vitro proliferation of human mesothelioma cells. Further studies and in vivo testing are required to confirm our preliminary in vitro results as a potential new mesothelioma therapy based on cell drug delivery.

Jeong E, Hyun SH, Moon SH, et al.
Relation between tumor FDG uptake and hematologic prognostic indicators in stage I lung cancer patients following curative resection.
Medicine (Baltimore). 2017; 96(5):e5935 [PubMed] Free Access to Full Article Related Publications
Hematologic parameters of systemic inflammation are receiving attention as promising prognostic indicators in cancer patients. Here, we investigated the relation and compared the prognostic values of circulating blood cell-based parameters and tumor F-fluoro-2-deoxyglucose (FDG) uptake in patients with stage I nonsmall cell lung cancers (NSCLC).Subjects were 1034 patients with newly diagnosed stage I NSCLC who underwent FDG positron emission tomography/computed tomography (PET/CT) followed by curative resection. Total white blood cell (WBC) count, absolute neutrophil, lymphocyte and platelet counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were obtained. Tumor FDG uptake was measured as SUVmax.WBC, neutrophil and lymphocyte counts, and NLR demonstrated weak but significant correlation to tumor SUVmax. Using the upper quartile as cutoff, patients with high tumor SUVmax had significantly higher WBC, neutrophil and lymphocyte counts, and greater NLR. There were 144 recurrences (13.9%) over a median follow-up of 29.5 months. On Cox proportional hazards regression analysis, WBC count, tumor SUVmax, age, gender, smoking, cell type, and tumor stage were significant univariate prognostic factors. On multivariate analysis, high tumor SUVmax (HR = 2.22; 95% CI, 1.52-3.25; P < 0.001), tumor stage 1B (HR = 2.11; 95% CI, 1.47-3.01; P < 0.001), and old age (HR = 1.03; 95% CI, 1.01-1.05; P = 0.002) were significant independent predictors of poor survival. Finally, high tumor SUVmax remained a significant predictor of prognosis in both low and WBC count groups.Circulating blood counts showed significant correlation to tumor FDG uptake in early stage NSCLC. WBC count was a significant univariate variable, but tumor FDG uptake was a superior and independent predictor of outcome. Hence, tumor FDG uptake effectively stratified prognosis in patients with low as well as high WBC count.

Lin PY, Tsai CT, Chuang WL, et al.
Chlorella sorokiniana induces mitochondrial-mediated apoptosis in human non-small cell lung cancer cells and inhibits xenograft tumor growth in vivo.
BMC Complement Altern Med. 2017; 17(1):88 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung cancer is one of the leading causes of cancer related deaths worldwide. Marine microalgae are a source of biologically active compounds and are widely consumed as a nutritional supplement in East Asian countries. It has been reported that Chlorella or Chlorella extracts have various beneficial pharmacological compounds that modulate immune responses; however, no studies have investigated the anti-cancer effects of Chlorella sorokiniana (CS) on non-small cell lung cancer (NSCLC).
METHODS: In this study, we evaluated the anti-cancer effects of CS in two human NSCLC cell lines (A549 and CL1-5 human lung adenocarcinoma cells), and its effects on tumor growth in a subcutaneous xenograft tumor model. We also investigated the possible molecular mechanisms governing the pharmacological function of CS.
RESULTS: Our results showed that exposure of the two cell lines to CS resulted in a concentration-dependent reduction in cell viability. In addition, the percentage of apoptotic cells increased in a dose-dependent manner, suggesting that CS might induce apoptosis in human NSCLC cells. Western blot analysis revealed that exposure to CS resulted in increased protein expression of the cleaved/activated forms of caspase-3, caspase-9, and PARP, except caspase-8. ZDEVD (caspase-3 inhibitor) and Z-LEHD (caspase-9 inhibitor) were sufficient at preventing apoptosis in both A549 and CL1-5 cells, proving that CS induced cell death via the mitochondria-mediated apoptotic pathway. Exposure of A549 and CL1-5 cells to CS for 24 h resulted in decreased expression of Bcl-2 protein and increased expression of Bax protein as well as decreased expression of two IAP family proteins, survivin and XIAP.
CONCLUSIONS: We demonstrated that CS induces mitochondrial-mediated apoptosis in NSCLC cells via downregulation of Bcl-2, XIAP and survivin. In addition, we also found that the tumors growth of subcutaneous xenograft in vivo was markedly inhibited after oral intake of CS.

Zhou X, Wang W, Zhang S, et al.
CACNA1B (Cav2.2) Overexpression and Its Association with Clinicopathologic Characteristics and Unfavorable Prognosis in Non-Small Cell Lung Cancer.
Dis Markers. 2017; 2017:6136401 [PubMed] Free Access to Full Article Related Publications
CACNA1B (Cav2.2) encodes an N-type voltage-gated calcium channel (VGCC) ubiquitously expressed in brain and peripheral nervous system that is important for regulating neuropathic pain. Because intracellular calcium concentration is a key player in cell proliferation and apoptosis, VGCCs are implicated in tumorigenesis. Recent studies have identified CACNA1B (Cav2.2) being overexpressed in prostate and breast cancer tissues when compared to adjacent normal tissues; however, its role in non-small cell lung cancer (NSCLC) has not been investigated. In this study, we determined the mRNA and protein expression of CACNA1B (Cav2.2) in NSCLC tumorous and adjacent nontumorous tissues by quantitative reverse transcription PCR (qRT-PCR) and tissue microarray immunohistochemistry analysis (TMA-IHC), respectively. CACNA1B (Cav2.2) protein expressions in tumorous tissues were correlated with NSCLC patients' clinical characteristics and overall survival. CACNA1B (Cav2.2) mRNA and protein expression levels were higher in NSCLC tumorous tissues than in nontumorous tissues. High CACNA1B (Cav2.2) protein expression was associated with higher TNM stages, and CACNA1B (Cav2.2) protein expression is an independent prognostic marker in NSCLC. Based on our results, we conclude that CACNA1B (Cav2.2) plays a role in NSCLC development and progression. Elucidating the underlying mechanism may help design novel treatment by specifically targeting the calcium regulation pathway for NSCLC, a devastating disease with increasing incidence and mortality in China.

Ding X, Makino T, Koezuka S, et al.
Primary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue with multiple pure ground-glass opacities: a case report.
J Cardiothorac Surg. 2017; 12(1):2 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade B cell lymphoma that is a type of non-Hodgkin lymphoma and a type of primary pulmonary malignant lymphoma. MALT lymphomas affecting the lung show various findings on chest computed tomography, which range from typical nodules or areas of consolidation to findings that are extremely rare in pulmonary MALT lymphomas, such as pure ground-glass opacities throughout the lung.
CASE PRESENTATION: A 35-year-old woman was found to have a few shadows with ground glass opacities on chest computed tomography (CT) in 2012. A shadow in right S10 that was initially very small increased in size over time, and was 14 × 8 mm in 2015. Other shadows also appeared. Because lung adenocarcinoma was suspected, the patient underwent video-assisted thoracoscopic surgery with a right wedge resection of the lower lobe that included the largest nodule in S10 and other nodules. Histopathological examination of the right S10 and other lesions revealed small- or medium-sized lymphocyte-like cells that were located in the alveolar interseptal spaces. The alveolar walls remained intact. Immunohistochemical staining showed that tumor cells were positive for CD20, CD79a, and BCL2 expression. The lesions were diagnosed as extranodal marginal zone B-cell lymphoma of MALT.
CONCLUSIONS: We think that the ground glass opacities on CT were accounted for by MALT lesions that contained intact alveolar air spaces. The patient has remained well during 12 months of follow up after surgery. Although she did not receive chemotherapy because the MALT lymphoma lesions have been stable without progression, the patient is kept under close observation because of potential progression of the disease.

Lee SH, Park MJ, Choi SI, et al.
Reactive oxygen species modulator 1 (Romo1) as a novel diagnostic marker for lung cancer-related malignant effusion.
Medicine (Baltimore). 2017; 96(4):e5975 [PubMed] Free Access to Full Article Related Publications
Reactive oxygen species modulator 1 (Romo1) is a novel protein that plays an important role in intracellular reactive oxygen species generation. Recently, Romo1 has been suggested to have diagnostic and prognostic potential in lung cancer. However, there is no data on the diagnostic value of Romo1 level in malignant pleural effusion. We evaluated the clinical usefulness of Romo1 in pleural fluid for the diagnosis of malignant effusion in lung cancer patients. Pleural fluid Romo1 level was measured using enzyme-linked immunosorbent assay and compared between lung cancer-associated malignant effusion (n = 53; 29 adenocarcinomas and 24 squamous cell carcinomas) and benign pleural effusions (n = 91; 31 tuberculous pleurisy, 30 parapneumonic effusion, and 30 transudate). The discriminative power of Romo1 for lung cancer-associated malignant effusion was determined using receiver operating characteristic (ROC) curve analysis and compared with those of other tumor markers. Median Romo1 level in lung cancer-associated malignant effusion was 99.3 ng/mL, which was significantly higher than that in benign pleural effusions (P < 0.001). The optimal cutoff value of Romo1 to discriminate lung cancer-associated malignant effusion from benign effusions was 67.0 ng/mL with a sensitivity of 73.8% and a specificity of 84.1%. The area under the curve was 0.837 (95% confidence interval [CI]: 0.750-0.886), which was significantly better than that of cytokeratin 19 fragments (P < 0.001). Pleural fluid Romo1 could discriminate lung cancer from benign diseases with considerable sensitivity and specificity. Our findings suggest a diagnostic potential of Romo1 for lung cancer-associated malignant effusion.

Sarfaty M, Moore A, Dudnik E, Peled N
Not only for melanoma. Subcutaneous pseudoprogression in lung squamous-cell carcinoma treated with nivolumab: A case report.
Medicine (Baltimore). 2017; 96(4):e5951 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Pseudoprogression, that is, initial tumor growth followed by subsequent tumor regression, has been well described for immunomodulation therapy in melanoma patients. This phenomenon is not well defined in lung cancer. Nivolumab, an anti-PD-1 monoclonal antibody, was recently approved for nonsmall cell lung cancer (NSCLC) as a second-line therapy.
PATIENT CONCERNS AND DIAGNOSIS: We present a patient with squamous NSCLC, suffering from multiple bone and subcutaneous metastases.
INTERVENTIONS: The patient was treated with nivolumab.
OUTCOMES: A subcutaneous lesion in her upper back grew substantially after the first cycle of nivolumab, and later regressed, with marked improvement in all cancer sites.
LESSONS: Such pseudoprogression may serve to predict subsequent clinical response.

Sun JM, Lee SH, Ahn JS, et al.
Osimertinib for the treatment of non-small cell lung cancer.
Expert Opin Pharmacother. 2017; 18(2):225-231 [PubMed] Related Publications
INTRODUCTION: The T790 M mutation of the epidermal growth factor receptor (EGFR) gene is the most common mechanism underlying resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR TKI, shows robust clinical efficacy in patients with T790 M-mutated lung cancer. Areas covered: We analyzed and reviewed clinical data for which patients who experienced acquired resistance to first- or second-generation EGFR TKIs. In addition, we briefly reviewed the potential role of osimertinib as a first-line therapy. Expert opinion: Osimertinib was recently licensed for use in NSCLC patients with acquired resistance to other EGFR TKIs due to a T790 M mutation. However, unresolved issues surrounding the optimal application of osimertinib remain, specifically the development of a plasma-based mutation test to overcome the difficulty of repeat biopsy, the efficacy of osimertinib for brain or leptomeningeal metastases, the development of resistance to osimertinib, and the use of osimertinib therapy as a first-line treatment. Many ongoing studies are currently exploring these issues.

Zhu WY, Zhang YK, Chai ZD, et al.
Identification of Factors for the Preoperative Prediction of Tumour Subtype and Prognosis in Patients with T1 Lung Adenocarcinoma.
Dis Markers. 2016; 2016:9354680 [PubMed] Free Access to Full Article Related Publications
Aims. Identification of factors that can predict the subtypes of lung adenocarcinoma preoperatively is important for selecting the appropriate surgical procedure and for predicting postoperative survival. Methods. We retrospectively evaluated 87 patients with lung adenocarcinomas ≤30 mm. Results. Preoperative radiological findings, serum CEA level, serum microRNA-183 (miR-183) level, and tumour size differed significantly between patients with adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) and those with invasive adenocarcinoma (IAC). Receiver operating characteristic curves and univariate analysis revealed that patients who were older than 57 years or had a pure solid nodule or a tumour with mixed ground-glass opacity (mGGO), a tumour >11 mm, a serum CEA level >2.12 ng/mL, or a serum miR-183 level >1.233 (2(-ΔΔCt)) were more likely to be diagnosed with IAC than with AIS or MIA. The combination of all five factors had an area under the curve of 0.946, with a sensitivity of 89.13% and a specificity of 95.12%. Moreover, patients with a cut-off value >0.499 for the five-factor combination had poor overall survival. Conclusions. The five-factor combination enables clinicians to distinguish AIS or MIA from IAC, thereby aiding in selecting the appropriate treatment, and to predict the prognosis of lung adenocarcinoma patients.

Kaur G, Nijhawan R, Gupta N, et al.
Pleural fluid cytology samples in cases of suspected lung cancer: An experience from a tertiary care centre.
Diagn Cytopathol. 2017; 45(3):195-201 [PubMed] Related Publications
OBJECTIVE: Pleural effusion is present in some patients with lung carcinoma. This study was undertaken to evaluate the role of pleural fluid cytology in suspected cases of lung carcinoma.
METHODS: In this prospective study, 86 cases of suspected primary lung carcinoma associated with pleural effusion were included. Cytomorphology of conventional smears was combined with LBC smears and a cytomorphological diagnosis was offered. An immunopanel of CK7, CK5/6, p63, TTF1, calretinin, and CD56 was applied on cell blocks. Additional immunochemical markers were performed based on clinical details and cytomorphology, wherever indicated.
RESULTS: The mean age of the patients was 56.8 years. The female to male ratio was 2.1:1. Lung nodule/mass could be detected in 70.9% cases by CECT chest. Cytomorphology was evaluated in all the 86 cases and IHC was used to refine the cytomorphological diagnosis. After IHC along with clinico-radiological details, 61/86 (71%) cases were confirmed as metastasis from lung primary, 5/86 (5.8%) were diagnosed as metastatic adenocarcinoma of extrapulmonary origin, and 6/86 (7%) were metastatic SCC. A diagnosis of adenosquamous carcinoma was suspected in five cases. Other cases included small cell carcinoma (n = 2), large cell carcinoma (n = 2), large cell neuroendocrine carcinoma (n = 3), and mesothelioma (n = 1). One case remained "uncategorized" even after IHC.
CONCLUSIONS: Immunohistochemistry (IHC) performed on the pleural fluid sample can accurately diagnose and subtype primary lung carcinoma even in cases where radiology failed to identify a definite lung lesion. IHC can further help in delineating primary site in tumors of extrapulmonary origin. © 2017 Wiley Periodicals, Inc. Diagn. Cytopathol. 2017;45:195-201. © 2016 Wiley Periodicals, Inc.

Remon J, Le Rhun E, Besse B
Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era.
Cancer Treat Rev. 2017; 53:128-137 [PubMed] Related Publications
Leptomeningeal metastasis is a fatal manifestation seen in advanced cancer patients. Its incidence is increasing, reaching 3.8% in molecularly unselected non-small cell lung cancer patients and up to 5% and 9% in ALK-rearranged and EGFR-mutant lung cancer patients, respectively. The prognosis remains poor despite systemic treatment, intrathecal chemotherapy, radiation therapy and personalized treatments in molecularly selected patients. However, new therapies with improved cerebral-spinal fluid penetration have been developed for subgroups of molecular selected patients indicating they could be promising therapeutic options for managing leptomeningeal disease. Systemic chemotherapy, which may be combined with intrathecal chemotherapy, remains standard treatment for lung cancer patients with leptomeningeal disease and a good-risk profile. We summarize evidence reported in the literature for managing this complication in lung cancer patients. Based on this, we have selected potential therapeutic strategies that could be used in daily clinical practice.

Matikas A, Mistriotis D, Georgoulias V, Kotsakis A
Targeting KRAS mutated non-small cell lung cancer: A history of failures and a future of hope for a diverse entity.
Crit Rev Oncol Hematol. 2017; 110:1-12 [PubMed] Related Publications
Lung cancer remains the leading cause of cancer-related deaths in both men and women. However, the discovery of several oncogenic driver mutations and the development of immune checkpoint inhibitors resulted in improved clinical outcomes for most patients. Although activating KRAS mutations are the most common recurring molecular events in lung adenocarcinoma, little progress has been made during the past decades with no new agents being approved for this indication. The elucidation of the underlying biology of this diverse patient subgroup offers great potential and renewed hope regarding the rational development, rigorous evaluation and subsequent approval of novel targeted agents and combinations which will effectively suppress compensatory escape routes and the emergence of resistance, issues that have plagued previous attempts. Here, we review in a structured manner all aspects of KRAS positive non-small cell lung cancer, including the molecular biology, clinicopathologic characteristics, the prognostic and predictive value of KRAS mutations, as well as previous and contemporary approaches towards the treatment of this elusive target.

Abe Y, Tanaka N
The Hedgehog Signaling Networks in Lung Cancer: The Mechanisms and Roles in Tumor Progression and Implications for Cancer Therapy.
Biomed Res Int. 2016; 2016:7969286 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the most common cause of cancer-related death worldwide and is classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Several gene mutations that contribute to aberrant cell proliferation have been identified in lung adenocarcinoma, a part of NSCLC. Various anticancer drugs that target these mutated molecules have been developed for NSCLC treatment. However, although molecularly targeted drugs are initially effective for patients, the 5-year survival rate remains low because of tumor relapse. Therefore, more effective drugs for lung cancer treatment should be developed. The hedgehog (HH) signaling pathway contributes to organ development and stem cell maintenance, and aberrant activation of this signaling pathway is observed in various cancers including lung cancer. In lung cancer, HH signaling pathway upregulates cancer cell proliferation and maintains cancer stem cells as well as cancer-associated fibroblasts (CAFs). Furthermore, physical contact between CAFs and NSCLC cells induces HH signaling pathway activation in NSCLC cells to enhance their metastatic potential. Therefore, HH signaling pathway inhibitors could be a useful option for lung cancer therapy.

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