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1.
Cancer genomics of lung cancer including malignant mesothelioma: A brief overview of current status and future prospects.
Jhanwar, SC, Xu, XL, Elahi, AH, Abramson, DH
Advances in biological regulation. 2020;:100723
Abstract
Cancer as a genetic disease is by now well recognized. Genomic analysis of cancer cells, therefore, has greatly enhanced our ability to identify genetic alterations associated with various cancer types, including both lympho-hematopoietic as well as solid tumors. Chronic myeloid leukemia (CML), based on the specific diagnostic genetic abnormality has served as a prototype disease to clearly demonstrate the significance of the genomic analysis of cancer in identifying targeted therapy. Such a success has provided extra ordinary opportunities to investigate the role of genetic abnormalities and the pathways amenable to targeted therapy, not only in blood cancers but solid tumors such as Lung, Brain, Colon, Renal, Breast cancers as well as other epithelial and mesenchymal tumors. The main focus of this presentation is to illustrate the role of genomic analysis in targeting lung cancer, based on abnormalities or the pathways deregulated in tumor cells from individual patients. Lung cancer is one of the most common epithelial cancers associated with chronic inflammation due to cigarette smoking and other environmental carcinogens, and includes four distinct histologic type; non-small cell lung cancer (NSCLC); small cell lung cancer (SCLC) and squamous cell lung cancer. According to current estimates, 1.3 million cases of lung cancer are expected to be diagnosed worldwide annually, resulting in one million deaths. Since the discovery that patient's tumors with specific mutations in the EGFR may be sensitive to targeted therapeutic approach and the subsequent realization that the such mutations in the gene are not as prevalent, several cancer centers including ours initiated intense efforts to find other mutations or genomic alterations, which may serve as targets of specific therapy. Such efforts have successfully resulted in a battery of genes such as KRAS, ALK, C-MET, HER-2/neu, ROS1, etc., which have helped oncologists to triage the patients for personalized therapies. A significant proportion of patients with lung cancer, however, do not show any of the above genetic abnormalities. Approximately 90% of lung cancers exhibit RB1 mutation/deletion and or KRAS mutations, therefore, the signaling pathways, which regulate multistep tumorigenesis in lung cancer, are important for the treatment of histologic subtypes of lung cancer, which includes NSCLC & SCLC. Equally important was the findings that similar signaling pathways are also shared by other solid tumor types. We have investigated the role of these pathways to target these cancers and develop new strategies to treat lung, brain and related cancers. In addition, our translational studies in other tumor types such as NF2 related malignancies, specifically, Malignant Mesothelioma (MM), in which NF2 related pathway amenable to targeted therapies was identified. Selected examples representing experimental approaches will be discussed to illustrate the critical role of translational research in developing novel therapeutics for the successful and durable responses in some of these cancer types.
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2.
GLS2 is protumorigenic in breast cancers.
Dias, MM, Adamoski, D, Dos Reis, LM, Ascenção, CFR, de Oliveira, KRS, Mafra, ACP, da Silva Bastos, AC, Quintero, M, de G Cassago, C, Ferreira, IM, et al
Oncogene. 2020;(3):690-702
Abstract
Many types of cancers have a well-established dependence on glutamine metabolism to support survival and growth, a process linked to glutaminase 1 (GLS) isoforms. Conversely, GLS2 variants often have tumor-suppressing activity. Triple-negative (TN) breast cancer (testing negative for estrogen, progesterone, and Her2 receptors) has elevated GLS protein levels and reportedly depends on exogenous glutamine and GLS activity for survival. Despite having high GLS levels, we verified that several breast cancer cells (including TN cells) express endogenous GLS2, defying its role as a bona fide tumor suppressor. Moreover, ectopic GLS2 expression rescued cell proliferation, TCA anaplerosis, redox balance, and mitochondrial function after GLS inhibition by the small molecule currently in clinical trials CB-839 or GLS knockdown of GLS-dependent cell lines. In several cell lines, GLS2 knockdown decreased cell proliferation and glutamine-linked metabolic phenotypes. Strikingly, long-term treatment of TN cells with another GLS-exclusive inhibitor bis-2'-(5-phenylacetamide-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) selected for a drug-resistant population with increased endogenous GLS2 and restored proliferative capacity. GLS2 was linked to enhanced in vitro cell migration and invasion, mesenchymal markers (through the ERK-ZEB1-vimentin axis under certain conditions) and in vivo lung metastasis. Of concern, GLS2 amplification or overexpression is linked to an overall, disease-free and distant metastasis-free worse survival prognosis in breast cancer. Altogether, these data establish an unforeseen role of GLS2 in sustaining tumor proliferation and underlying metastasis in breast cancer and provide an initial framework for exploring GLS2 as a novel therapeutic target.
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3.
Candida albicans Beta-Glucan Induce Anti- Cancer Activity of Mesenchymal Stem Cells against Lung Cancer Cell Line: An In-Vitro Experimental Study.
Peymaeei, F, Sadeghi, F, Safari, E, Khorrami, S, Falahati, M, Roudbar Mohammadi, S, Roudbary, M
Asian Pacific journal of cancer prevention : APJCP. 2020;(3):837-843
Abstract
OBJECTIVE β-glucan, glucopyranosyl polymers of fungi cell wall, represent an immune stimulating effects with potential anti-cancer activity. Mesenchymal stem cells (MSC) have immunomodulating properties in cancer microenvironment. The aim of this study was to investigate the anti-cancer effect of Candida albicans (C. albicans) beta-glucan on MSCs supernatant for apoptosis assay of lung cancer cells in vitro. METHODS Beta-glucan was extracted from cell wall of C.albicans. MSC isolated from adipose tissue of patients and confirmed using specific surface markers expression which examined by flow cytometry. MSCs treated with various concentrations of β-glucans for 48 hours. Cytotoxic effect of β-glucans was evaluated using MTT assay. MSC and lung cancer line cocultured and treated with β-glucans and apoptosis assay was done by flow cytometry. RESULTS Cytotoxicity findings showed a significant decrease in MSC viability during 48h, however it was dose-dependent (P<0.05). According to the obtained findings, supernatant of mesenchymal stem cells treated with β-glucans increased cancer cells apoptosis (P<0.05). CONCLUSION Beta glucan may highlight a potential and novel promising candidate in future strategies to cause apoptosis of cancer cells and consider as therapeutic agent against tumor growth as well. Definitely, more in vitro and in vivo studies are required to understand its functions.
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4.
Difference in decline in renal function due to cisplatin after a short or long hydration scheme in non-small-cell lung cancer: A retrospective cohort study (HYCIS-XL).
Niggebrugge-Mentink, KL, Beex-Oosterhuis, MM, Ter Horst, PGJ, van de Poll, MEC, Dieleman, HG, van Kesteren, C
Journal of clinical pharmacy and therapeutics. 2020;(5):1153-1158
Abstract
WHAT IS KNOWN AND OBJECTIVE Nephrotoxicity is a frequently occurring side effect of cisplatin, which may be reduced by applying ample hydration. The aim of this study was to determine whether there is a difference in decline in renal function due to cisplatin between a short hydration (SH) and long hydration scheme (LH). METHODS A retrospective, observational, cohort study was conducted in two hospitals. Patients in one hospital received an SH scheme (SH group), whereas patients in the other hospital received an LH scheme (LH group). Other aspects of treatment and hydration were comparable between both patient groups. Consecutive patients (≥18 years) treated for non-small-cell lung cancer with cisplatin-pemetrexed with ≥1 cisplatin dose were included. Patients were excluded when serum creatinine at baseline was <40 μmol/L. Primary outcome was the difference in estimated glomerular filtration rate (eGFR) between baseline and after the last cisplatin cycle for the SH and LH patients, regardless of the number of administered cisplatin courses. RESULTS Fifty patients were included in the SH and LH group. There were no significant differences in baseline characteristics between the two groups. None of the patients had renal failure at baseline. After two cisplatin cycles, the median differences between the baseline eGFR and the eGFR after the last cisplatin dose were 1 (-6 to 5) and -9 (-22 to -2) mL/min/1.73 m2 (interquartile range) for the SH and LH group, respectively (P = .000). Less patients completed the four cycles in the LH group (16%) compared to the SH group (64%), mainly because more LH patients were switched to another treatment and due to nephrotoxicity. However, the difference in eGFR remained statistically significant (P = .027). WHAT IS NEW AND CONCLUSION In this retrospective study, the SH scheme resulted in less decrease in renal function compared with the LH scheme, with a significant and clinically relevant difference. Additionally, more LH patients had to stop this effective treatment prematurely due to nephrotoxicity. Therefore, a short hydration scheme provides adequate and safe hydration, with a lower risk of nephrotoxic side effects and therefore better outcomes for patients and a reduction of healthcare costs.
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5.
Absolute quantification of selenoproteins and selenometabolites in lung cancer human serum by column switching coupled to triple quadrupole inductively coupled plasma mass spectrometry.
Callejón-Leblic, B, Rodríguez-Moro, G, Arias-Borrego, A, Pereira-Vega, A, Gómez-Ariza, JL, García-Barrera, T
Journal of chromatography. A. 2020;:460919
Abstract
One of the most important causes of the high mortality rate and low life expectancy of lung cancer is the detection at advanced stages. Thus, there is an urgent need for early diagnosis and the search of new selective biomarkers. Selenium is an important constituent of selenoproteins and a powerful antioxidant able to protect against cancer. In this work, the absolute quantification of selenium in selenoproteins and the total content in selenometabolites has been performed for the first time in serum from lung cancer patients (LC) and healthy controls (HC). To this end, a method for the simultaneous speciation of selenoproteins using size exclusion chromatography (SEC) and affinity chromatography (AF) with detection by ICP-QQQ-MS, and quantification by isotopic dilution (IDA) (SEC-AF-HPLC-SUID-ICP-QQQ-MS) was developed to determine the selenium concentration in eGPx, SEPP1 and SeAlb, as well as total selenometabolites, to find alterations that may serve as biomarkers of this disease. In the same way, a method based on anion-exchange chromatography coupled to ICP-QQQ-MS was developed to quantify selenometabolites (SeCys2, SeMeSeCys, SeMet, selenite and selenate) in the same LC and HC serum samples. The results showed that the averaged concentrations of selenium in eGPx, SeAlb and selenite were significantly higher in LC patients (LC (eGPx: 21.24 ± 0.77 ng g-1; SeAlb: 49.56 ± 3.16 ng g-1 and Se(IV): 6.20 ± 1.22 ng g-1) than in HC group (eGPx: 16.96 ± 0.53 ng g-1; SeAlb: 38.33 ± 2.66 ng g-1 and Se(IV): 3.56 ± 0.55 ng g-1). In addition, the ratios between selenoproteins and selenometabolites have been calculated for the first to study their potential use as LC biomarkers. The rates eGPx/SEPP1, SEPP1/SeAlb, eGPx/Se(IV) and SEPP1/Se(IV) were significantly different between LC and HC groups.
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6.
Autophagy-related MicroRNAs in chronic lung diseases and lung cancer.
Rezaei, S, Mahjoubin-Tehran, M, Aghaee-Bakhtiari, SH, Jalili, A, Movahedpour, A, Khan, H, Moghoofei, M, Shojaei, Z, R Hamblin, M, Mirzaei, H
Critical reviews in oncology/hematology. 2020;:103063
Abstract
Chronic lung disease has become a leading cause of death in recent years. Despite several attempts to discover and develop new therapeutic approaches, patients often suffer a poor quality of life, and are faced with an increased risk of developing lung cancer. Lung cancer often occurs as an end-stage after years of chronic lung disease. An increased understanding of the pathophysiology of chronic lung disease may be obtained from studying the role of autophagy in its initiation and progression. MicroRNAs (miRNAs) play a critical role in the modulation of autophagy, and their deregulation could be associated with the initiation and progression of several chronic lung diseases. Herein, we documented that up/down regulation of miRNAs can activate or inhibit autophagy in chronic lung diseases including lung cancer. Therefore, theses miRNAs could be a promising therapeutic tool for lung cancer specially in drug-resistance lung cancer cells.
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7.
Circulating tumour cells as a potential biomarker for lung cancer screening: a prospective cohort study.
Marquette, CH, Boutros, J, Benzaquen, J, Ferreira, M, Pastre, J, Pison, C, Padovani, B, Bettayeb, F, Fallet, V, Guibert, N, et al
The Lancet. Respiratory medicine. 2020;(7):709-716
Abstract
BACKGROUND Lung cancer screening with low-dose chest CT (LDCT) reduces the mortality of eligible individuals. Blood signatures might act as a standalone screening tool, refine the selection of patients at risk, or help to classify undetermined nodules detected on LDCT. We previously showed that circulating tumour cells (CTCs) could be detected, using the isolation by size of epithelial tumour cell technique (ISET), long before the cancer was diagnosed radiologically. We aimed to test whether CTCs could be used as a biomarker for lung cancer screening. METHODS We did a prospective, multicentre, cohort study in 21 French university centres. Participants had to be eligible for lung cancer screening as per National Lung Screening Trial criteria and have chronic obstructive pulmonary disease with a fixed airflow limitation defined as post-bronchodilator FEV1/FVC ratio of less than 0·7. Any cancer, other than basocellular skin carcinomas, detected within the previous 5 years was the main exclusion criterion. Participants had three screening rounds at 1-year intervals (T0 [baseline], T1, and T2), which involved LDCT, clinical examination, and a blood test for CTCs detection. Participants and investigators were masked to the results of CTC detection, and cytopathologists were masked to clinical and radiological findings. Our primary objective was to test the diagnostic performance of CTC detection using the ISET technique in lung cancer screening, compared with cancers diagnosed by final pathology, or follow up if pathology was unavailable as the gold standard. This study is registered with ClinicalTrials.gov identifier, number NCT02500693. FINDINGS Between Oct 30, 2015, and Feb 2, 2017, we enrolled 614 participants, predominantly men (437 [71%]), aged 65·1 years (SD 6·5), and heavy smokers (52·7 pack-years [SD 21·5]). 81 (13%) participants dropped out between baseline and T1, and 56 (11%) did between T1 and T2. Nodules were detected on 178 (29%) of 614 baseline LDCTs. 19 participants (3%) were diagnosed with a prevalent lung cancer at T0 and 19 were diagnosed with incident lung cancer (15 (3%) of 533 at T1 and four (1%) of 477 at T2). Extrapulmonary cancers were diagnosed in 27 (4%) of participants. Overall 28 (2%) of 1187 blood samples were not analysable. At baseline, the sensitivity of CTC detection for lung cancer detection was 26·3% (95% CI 11·8-48·8). ISET was unable to predict lung cancer or extrapulmonary cancer development. INTERPRETATION CTC detection using ISET is not suitable for lung cancer screening. FUNDING French Government, Conseil Départemental 06, Fondation UNICE, Fondation Aveni, Fondation de France, Ligue Contre le Cancer-Comité des Alpes-Maritimes, ARC (Canc'Air Genexposomics), Claire de Divonne-Pollner, Enca Faidhi, Basil Faidhi, Fabienne Mourou, Michel Mourou, Leonid Fridlyand, cogs4cancer, and the Fondation Masikini.
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8.
Oral nutritional supplement prevents weight loss and reduces side effects in patients in advanced lung cancer chemotherapy.
Torricelli, P, Antonelli, F, Ferorelli, P, Borromeo, I, Shevchenko, A, Lenzi, S, De Martino, A
Amino acids. 2020;(3):445-451
Abstract
Weight loss in patients with cancer is caused by cancer cachexia and chemotherapy-induced nausea and vomiting. Recent developments in antiemetic drugs have substantially improved nausea and vomiting, but this intervention did not reduce weight loss and other more severe side effects of chemotherapy, like anorexia, weakness, cough, dyspnea, hemoptysis, and pain. This study aimed to investigate the effects of nutrition intervention with a food supplement, during chemotherapy in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Patients received individualized nutrition counseling by a registered dietitian and were provided with oral supplements of Texidrofolico® for 90 days. Bodyweight and the mentioned other side effects were evaluated at baseline and after 90 days of intervention. To assess the effects of this dietary supplement, a total of 30 patients were retrospectively enrolled as controls, and the bodyweight and change in side effects of chemotherapy were compared with those observed in 30 Texidrofolico®-treated patients. After 90-day intervention, by oral supplement of Texidrofolico®, the patients, during the course of cytotoxic chemotherapy, showed an improved quality of life and not significant weight and BMI loss respect the control group. Furthermore, the number of patients, treated with Texidrofolico® who maintained or increased their body weight, after 90 days of treatment was significantly higher than in the control group. The effects of treatment with the food supplement have also been studied from a metabolic point of view. It was possible to find that one of the known markers of tumor growth, plasma polyamines, was reduced after the treatment. A possible relationship between these biogenic amines and the folate cycle is discussed. In conclusion, early intensive nutrition intervention with oral supplements of Texidrofolico® during chemotherapy of NSCLC patients prevents weight loss and it is beneficial for their quality of life.
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9.
Occurrence of abscesses during treatment with pazopanib in metastatic renal cancer: a case report.
Puliafito, I, Russo, A, Sciacca, D, Puglisi, C, Giuffrida, D
Journal of medical case reports. 2020;(1):7
Abstract
BACKGROUND Pazopanib is a multitarget tyrosine kinase inhibitor used in the treatment of renal cancer and soft tissue sarcoma. Its use is commonly associated with a number of side effects, such as hemorrhagic diathesis, neutropenia, leukopenia, thrombocytopenia, nausea, vomiting, abdominal pain, increased serum aspartate aminotransferase, increased serum alanine aminotransferase, decreased serum glucose, increased serum bilirubin, decreased serum phosphate and magnesium, fatigue, hypertension, diarrhea, anorexia, proteinuria, and hypothyroidism. Abscesses of metastases caused by pazopanib administration are rarely reported in the literature. CASE PRESENTATION We report a case of abscesses of lung metastases related to pazopanib in a patient with metastatic renal cancer. The patient was a 53-year-old Caucasian man who developed abscesses of lung metastases during the first 3 months of treatment with pazopanib. The abscesses resolved after 1 month by stopping pazopanib and administering adequate antibiotic therapy. CONCLUSIONS We conclude that abscesses of metastases could be a rare side effect occurring during treatment with pazopanib in patients with renal cancer.
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10.
Treatment sequence in patients with neuroendocrine tumours: a nationwide multicentre, observational analysis of the Swiss neuroendocrine tumour registry.
Kollar, A, Bütikofer, L, Ochsenbein, A, Stettler, C, Trepp, R
Swiss medical weekly. 2020;:w20176
Abstract
BACKGROUND In recent years, several treatment modalities have proved to be effective in the treatment of neuroendocrine tumours (NETs). However, there is currently no consensus on the sequence in which these options are best used. METHODS In this observational study, we analysed the treatment modalities and sequences of all patients included in the Swiss NeuroEndocrine Tumour registry (SwissNET). SwissNET is a national registry, which has prospectively included patients with a NET from all regions of Switzerland since 2008. RESULTS The registry includes 1366 patients; 1063 had documented therapies after the main diagnosis and were included in the analysis. The median follow-up time was 1.86 years. The most common primary site was the small intestine (291 patients, 27%) followed by pancreas (254 patients, 24%), lung (172 patients, 16%) and appendix (163 patients, 15%). A total of 167 different therapy sequences were observed. In 708 (67%) patients, surgery was the only treatment. The sequence of surgery followed by chemotherapy was most frequently documented in poorly (G3) differentiated (24 patients, 60%) and pancreatic (15 patients, 34%) NETs. Tumours treated with surgery followed by biotherapy or followed by peptide receptor radionuclide therapy (PRRT) were predominantly well-differentiated G1 NETs of the small intestine. In patients who were treated with either PRRT or systemic therapy (chemotherapy or molecular therapy) or both, PRRT was used more frequently than systemic therapy in patients with a small intestinal NET (35 patients, 62% vs 30, 54%), whereas the opposite held true in pancreatic (44 patients, 59% vs 56, 70%) and lung NETs (6 patients, 14% vs 40, 97%). If both chemotherapy and molecular therapy were used, chemotherapy was applied prior to molecular therapy in 13 of 19 (68%) patients with a pancreatic NET. CONCLUSION Surgery represents the treatment of choice in most patients with a NET irrespective of tumour stage. In patients receiving additional treatment, an impressive variety of treatment sequences were documented. In small intestinal NETs, patients received PRRT more often than chemotherapy, whereas the opposite holds true for patients with pancreatic and lung NETs.