scholarly journals Global prognostic impact of driver genetic alterations in patients with lung adenocarcinoma: a real-life study

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Panagiotis Paliogiannis ◽  
Maria Colombino ◽  
Maria Cristina Sini ◽  
Antonella Manca ◽  
Milena Casula ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Single Case ◽  
Real Life ◽  
Low Frequency ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Lower Survival ◽  
Global Survival ◽  
Egfr T790m

Abstract Background Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring driver genetic alterations. Methods A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of low-frequency EGFR-T790M mutated alleles at baseline). Results The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18–21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs) agents, had a significantly longer survival in comparison to those without (p < 0.0001); conversely, KRAS mutations were associated with a significantly lower survival (p = 0.0058). Among LAC patients with additional tissue section available for next-generation sequencing (NGS)-based analysis, 26/193 (13.5%) patients found positive for even low-rate EGFR-T790M mutated alleles at baseline were associated with a highly significant lower survival in comparison to those without (8.7 vs. 47.4 months, p < 0.0001). Conclusions In addition to its predictive value for addressing targeted therapy approaches, the assessment of as more inclusive mutation analysis at baseline may provide clues about factors significantly impacting on global survival in advanced LAC patients.

scholarly journals Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yotaro Ochi ◽  
Kenichi Yoshida ◽  
Ying-Jung Huang ◽  
Ming-Chung Kuo ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Genetic Abnormalities ◽  
Prior Use

AbstractBlast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.

Analysis of Philadelphia Negative Clones Detected during Treatment with Tyrosine Kinase Inhibitors: A Study on 63 CML Cases.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4541-4541
Author(s):  
Claudia Haferlach ◽  
Susanne Schnittger ◽  
Alice Fabarius ◽  
Armin Leitner ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Single Case ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Imatinib Treatment ◽  
Prognostic Impact ◽  
Chronic Myeloproliferative Disorder

Abstract The occurrence of Philadelphia chromosome negative (Ph−) clones in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors have been reported in approximately 5% of cases. The pathogenesis of this phenomenon still remains unclear. The clinical relevance of these new clones remains to be clarified, as only occasional reports describe the presence of hematological dysplastic features or development of overt disease such as MDS or AML. We found 63 patients with CML that developed Ph− clones and performed in total 281 chromosome analyses (median: 4 analyses per case; range, 1–18). In total, 66 clonal abnormalities were detected. 60 cases showed only one aberration, in the remaining 3 cases 2 abnormalities were detected. Remarkably, no complex aberrant karyotypes were observed. Most frequent aberrations were gains and losses of whole chromosomes: +8 (n=35, 55.6%), +Y (n=3, 4.8%), +11 (n=2, 3.2%), +X (n=1, 1.6%), −Y (n=9, 14.3%), −7 (n=6, 9.5%). The following abnormalities were only observed in a single case: inv(Y)(p11.1q11.2); +1,der(1;7)(q10;p10); del(5)(q13q33); der(7)del(7)(p13)del(7)(q11.2); del(7)(q11q22); der(7;15)(q10;q10); t(8;11)(q22;q23); del(12)(p11p13); del(20)(q11q13). The majority of aberrations were unbalanced, only 2 balanced rearrangements were observed. No clonal evolution was found. Although this pattern of abnormalities resembles closest the pattern observed in MDS or Ph− chronic myeloproliferative disorder, only 1 case with −7 developed a MDS and subsequently an AML. Most frequently in addition to the Ph− clone a Ph+ clone and a normal clone was observed (n=86). In 8 analyses the Ph− clone was the only clone detected and in 60 analyses the Ph− clone was accompanied by a normal clone, in 10 by a Ph+ clone. In one case two different Ph− clones were observed during the course of the disease. For 34 patients detailed clinical data are available. All these patients were treated with imatinib, 7 patients subsequently received dasatinib and 3 nilotinib after imatinib treatment. The Ph− clone was observed after a median of 43 months (mo) after diagnosis and 20.5 mo after start of imatinib treatment, respectively. Dasatinib treatment was started 2, 3, 6, 10 and 12 mo prior to the first detection of the Ph− clone and in 1 case 5 mo after occurrence of the Ph− clone. Nilotinib treatment was started 6, 7 and 11 mo prior to the first detection of the Ph− clone. In 15 cases imatinib treatment was started within the first 4 mo after diagnosis. In these cases the Ph− clone was observed in median 13 mo after start of imatinib treatment (range: 4–64). Overall the 34 cases were monitored for 428 mo after occurrence of the Ph− clone (median=11.5 mo). In 6 cases the Ph− clone was lost during follow-up (in one case after allogeneic SCT). In conclusion: Ph− clones are stable over time in most cases. In the majority of cases only single, usually unbalanced abnormalities are observed. The size of the Ph− clone fluctuates and can also disappear. In most cases the Ph− clones seem to have no clinical impact. Longer follow-up is necessary to clarifiy the prognostic impact. So far the available data do not imply that the occurrence of Ph− clones per se should lead to changes in treatment strategy. However, close cytogenetic monitoring is recommended.

scholarly journals Detection of EGFR Mutations in Cerebrospinal Fluid of EGFR-Mutant Lung Adenocarcinoma With Brain Metastases

2021 ◽  
Vol 11 ◽  
Author(s):  
Liang Shi ◽  
Junfang Tang ◽  
Hong Tao ◽  
Lili Guo ◽  
Weihua Wu ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Metastases ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Digital Pcr ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Mutation Status ◽  
Egfr T790m

BackgroundWe aimed to investigate the feasibility of detecting epidermal growth factor receptor (EGFR) mutations in cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) and plasma of advanced lung adenocarcinoma (LADC) with brain metastases (BMs) by droplet digital polymerase chain reaction (ddPCR).MethodsThirty advanced LADC patients with BMs were enrolled, and their matched CSF and plasma samples were collected. Droplet digital PCR was used to test cfDNA in CSF and plasma for EGFR mutation status. The clinical response and prognosis were evaluated.ResultsOut of 30 patients, there were 21 females and 9 males, aged 34-75 years. In all of the cases, CSF cytology were negative. In ddPCR assays, 10 patients (33.3%) had EGFR mutation in CSF, including 3 cases of EGFR T790M mutation, and 16 patients (53.3%) had EGFR mutation in plasma, including 6 cases of EGFR T790M mutation. Five patients with activating EGFR mutations in CSF achieved an intracranial partial response (iPR) after combination treatment with the first-generation EGFR-tyrosine kinase inhibitors. Three patients with EGFR T790M mutations in CSF achieved iPR after second-line osimertinib treatment. The median overall survival and intracranial progression-free survival were 17.0 months and 11.0 months, respectively.ConclusionIt was feasible to test EGFR mutation in cerebrospinal fluid and plasma. In LADC patients with brain metastasis, cerebrospinal fluid can be used as a liquid biopsy specimen to guide treatment strategy by monitoring EGFR mutation status.

Relationship of radiometabolic biomarkers to KRAS mutation status and ALK rearrangements in cases of lung adenocarcinoma

2019 ◽  
Vol 105 (6) ◽  
pp. 501-508
Author(s):  
Gulfidan Aras ◽  
Zehra Dilek Kanmaz ◽  
Esin Tuncay ◽  
Erdoğan Çetinkaya ◽  
Esin Yentürk ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Fdg Pet ◽  
Kras Mutation ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Diagnostic Value ◽  
Genetic Alterations ◽  
Alk Rearrangement ◽  
Kras Mutations ◽  
Mutational Status

Purpose: Rapid diagnosis of genetic mutations is important for targeted therapies such as EGFR tyrosine kinase inhibitors. KRAS mutation and ALK rearrangement are also important in determining treatment. The purpose of our study was to evaluate the diagnostic value of 18F-FDG PET to predict KRAS mutation and ALK rearrangement in order to determine the frequency of these genetic markers in our lung adenocarcinoma cases and contribute to forthcoming meta-analysis studies. Methods: A total of 218 patients with lung adenocarcinoma (EGFR analyzed) who were seen at our clinic between 2012 and 2014 were included in the study. The results of the 18 F-FDG-PET scans for each patient were retrospectively recorded with the associated medical documents. ALK rearrangements were analyzed in 166 of the 218 patients, while 50 of the 218 patients were analyzed for KRAS mutational status. SPSS 15.0 for Windows was used for statistical analysis. Results: FDG avidity was higher in cases with KRAS mutations and ALK rearrangements than those without, but the difference was not significant. ALK rearrangements were more common in younger, female, and nonsmoking patients with lung adenocarcinoma. Conclusions: The small numbers of KRAS mutations and ALK rearrangements are the limitation of this study for evaluation of diagnostic imaging. The frequency of these genetic alterations was as reported in the literature. We believe that our work will contribute to future meta-analysis.

scholarly journals EGFR, KRAS, BRAF, ALK, and cMET genetic alterations in 1440 Sardinian patients with lung adenocarcinoma

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Maria Colombino ◽  
◽  
Panagiotis Paliogiannis ◽  
Antonio Cossu ◽  
Davide Adriano Santeufemia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Real Life ◽  
Genetic Alterations ◽  
Driver Genes ◽  
Life Study ◽  
Low Incidence ◽  
Almost All ◽  
Similar Incidence

Abstract Background Lung cancer is one of the most incident neoplastic diseases, and a leading cause of death for cancer worldwide. Knowledge of the incidence of druggable genetic alterations, their correlation with clinical and pathological features of the disease, and their interplay in cases of co-occurrence is crucial for selecting the best therapeutic strategies of patients with non-small cell lung cancer. In this real-life study, we describe the molecular epidemiology of genetic alterations in five driver genes and their correlations with the demographic and clinical characteristics of Sardinian patients with lung adenocarcinoma. Methods Data from 1440 consecutive Sardinian patients with a histologically proven diagnosis of lung adenocarcinoma from January 2011 through July 2016 were prospectively investigated. EGFR mutation analysis was performed for all of them, while KRAS and BRAF mutations were searched in 1047 cases; ALK alterations were determined with fluorescence in situ hybridization in 899 cases, and cMET amplifications in 788 cases. Results KRAS mutations were the most common genetic alterations involving 22.1% of the cases and being mutually exclusive with the EGFR mutations, which were found in 12.6% of them. BRAF mutations, ALK rearrangements, and cMET amplifications were detected in 3.2, 5.3, and 2.1% of the cases, respectively. Concomitant mutations were detected only in a few cases. Conclusions Almost all the genetic alterations studied showed a similar incidence in comparison with other Caucasian populations. Concomitant mutations were rare, and they probably have a scarce impact on the clinical management of Sardinians with lung adenocarcinoma. The low incidence of concomitant cMET amplifications at diagnosis suggests that these alterations are acquired in subsequent phases of the disease, often during treatment with TKIs.

scholarly journals Clinical, Immunophenotypic and Genetic Characteristics of Aggressive (non-Burkitt) B-Cell Lymphoma in a Real Life Cohort

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4122-4122
Author(s):  
Louise Roulin ◽  
Jean-Philippe Jais ◽  
Alina Nicolae ◽  
Elsa Poullot ◽  
Cyrielle Robe ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Real Life ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Indolent Lymphoma ◽  
Partner Gene ◽  
Histological Characteristics ◽  
Travel Grant

Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease characterized by recurrent genetic alterations. Several adverse prognostic factors are well known as International Prognostic Index (IPI) parameters or MYC and BCL2 and/or BCL6 gene rearrangements (High-Grade B-cell Lymphoma double/triple hit, HGBL-DH/TH, according to the 2016 WHO classification). Other factors are controversial as previous history of indolent lymphoma, cell of origin (COO), co-expression of MYC and BCL2 proteins (double expressor (DE) status), MYC partner gene if rearranged. The aim of this study is to describe a « real life » cohort of patients treated in our institution for aggressive (non-Burkitt) B-cell lymphoma and to evaluate the prognostic impact of phenotypic and genetic alterations. Methods: We collected clinical and histological characteristics of patients uniformly treated between January 2009 and June 2017 with rituximab R-CHOP/CHOP-like chemotherapy. Treatment was reinforced with high dose methotrexate in case of central nervous system (CNS) localization or HGBL subtype. All tumor samples were analysed for MYC and BCL2 protein expression by immunohistochemistry. BCL2, BCL6 and MYC break were analysed by Interphase Fluorescence In Situ Hybridization (FISH) with breakapart probes. When MYC was rearranged MYC partner gene was analysed with double fusion probes (MYC/IgH, MYC/IgL, MYC/IgK). Positron Emission Tomography (PET scanner) was performed with maximal Standardized Uptake Value (SUV max) at baseline in all patients except 7. Results: 242 patients were studied. Baseline characteristics were: median age: 61 y (18-88), IPI 3-5: 49.6%, CNS localization: 6.6%. With a median follow-up of 4.4 years, 5y-overall survival (OS) and 5y-progression free survival (PFS) were 72% (66.0-78.5) and 65% (58.5-71.3), respectively. SUV max at baseline was 17,1 (minimum value 2,4 - maximal value 39,3).Histological diagnoses were DLBCL-not otherwise specified (NOS): 57%, transformed DLBCL: 26%, HGBL: 7.9%, primary mediastinal B-cell lymphoma (PMBL): 4.1% and others: 5%. Using Hans algorithm, 48.8% were classified as germinal center (GC), 47.9% as non-GC, 3.3% could not be evaluated and 38% were DE. MYC rearrangement was detected in 36 cases (14.9%) with an immunoglobulin partner gene (IgH, IgL or IgK) in 24 (77.4%) of 31 evaluable cases. BCL2 and BCL6 rearrangement were observed in 45 cases (18.6%) and 62 (25.6%) cases respectively. Fifteen cases were HGBL DH/TH including 7 DH MYC/BCL2, 5 DH MYC/BCL6 and 3 TH MYC/BCL2/BCL6. Four cases were HGBL-NOS. IPI score 3-5 (p<0.0001) and HGBL (p=0.03) were significantly associated with inferior OS. IPI score 3-5 (p<0.0001), DE status (p=0.03), MYC-R (p=0.05) and BCL2-R (p=0.0014) were significantly associated with inferior PFS. Previous indolent lymphoma, COO and MYC partner gene had no impact on OS or PFS. Conclusions: This monocentric study in a large cohort of aggressive B-cell lymphoma patients treated in real life conditions confirms previous reports on the negative prognostic impact of DE status, MYC and BCL2 translocations and HGBL subtype. These genetic and immuno-histological characteristics should have implications in the design and interpretation of future clinical trials. Disclosures Le Bras: Takeda: Research Funding; Pfizer: Other: Travel grant; Jansen: Other: Travel grant. Belhadj:Celgene: Other: personal fees from Celgene, personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, outside the submitted work. Haioun:servier: Honoraria; amgen: Honoraria; janssen cilag: Consultancy; takeda: Consultancy; gilead: Consultancy; novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy.

A framework for risk stratification in EGFR+ lung adenocarcinoma treated with tyrosine kinase inhibitors

2019 ◽  
Author(s):  
P Christopoulos ◽  
M Kirchner ◽  
F Bozorgmehr ◽  
N Magios ◽  
AL Volckmar ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Tyrosine Kinase ◽  
Lung Adenocarcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors

Contamination Lab of Turin (CLabTo)

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Eleonora FIORE ◽  
Giuliano SANSONE ◽  
Chiara Lorenza REMONDINO ◽  
Paolo Marco TAMBORRINI
Keyword(s):  
University Students ◽  
Single Case ◽  
Real Life ◽  
Learning By Doing ◽  
Assessment Data ◽  
Entrepreneurial Skills ◽  
Fields Of Study ◽  
Education Levels ◽  
Positive Effect

Interest in offering Entrepreneurship Education (EE) to all kinds of university students is increasing. Therefore, universities are increasing the number of entrepreneurship courses intended for students from different fields of study and with different education levels. Through a single case study of the Contamination Lab of Turin (CLabTo), we suggest how EE may be taught to all kinds of university students. We have combined design methods with EE to create a practical-oriented entrepreneurship course which allows students to work in transdisciplinary teams through a learning-by-doing approach on real-life projects. Professors from different departments have been included to create a multidisciplinary environment. We have drawn on programme assessment data, including pre- and post-surveys. Overall, we have found a positive effect of the programme on the students’ entrepreneurial skills. However, when the data was broken down according to the students’ fields of study and education levels, mixed results emerged.

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