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1.
Medicine (Baltimore) ; 100(8): e24784, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663095

RESUMO

ABSTRACT: Baseline brain metastasis (BBM) commonly occurs in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. Crizotinib prolongs the survival of patients with ALK rearrangement but lacks significant effect on brain metastasis. It remains unclear whether BBM and local therapy affect therapeutic outcomes and progression patterns during crizotinib treatment.Patients with ALK-positive (immunotherapy) non-small cell lung cancer were screened from West China Hospital between May 2013 and January 2019. A total of 155 patients were enrolled in this research, with entirely recorded statistics to analyze retrospectively.Baseline brain metastasis occurred in 64 patients (55.7%). Thirty-seven patients received local therapy, while 24 patients did not. We observed higher overall response rate in patients receiving local therapy (70.2% vs. 41.7%, P = .026), but no statistical difference was found in median progression free survival (mPFS) (12.0 months vs 13.0 months, P = .633). A significantly shorter mPFS was found in patients not receiving local treatment compared with the 16.5 months mPFS of patients without BBM (P = .029). Intracranial progressions were recorded in 35 patients with BBM (71%) and 16 patients who don't have (30%). As for extracranial progression, there is a higher occurrence rate (75.5%) in patients who had baseline extracranial metastases versus 49.0% in BBM patients. A significantly higher occurrence rate of multiple progression was noted in patients with BBM (14/49 vs. 6/53).Baseline intracranial metastasis changes the location and number of progressions after the first-line crizotinib and results in poor prognosis. There is no evidence that local treatment for brain metastasis had a protective effect on intracranial progression.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Quinase do Linfoma Anaplásico/genética , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos
2.
Zhonghua Bing Li Xue Za Zhi ; 50(3): 194-200, 2021 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-33677881

RESUMO

Objective: To investigate the clinicopathological diagnosis and differential diagnosis of inflammatory myofibroblastic tumor (IMT). Methods: Thirty-two cases of IMT collected at the People's Hospital of Jiangsu Province from May 2010 to May 2020 were evaluated for their clinical, histologic, immunohistochemical and genomic features, and relevant literature was reviewed. Results: There were 19 male and 13 female patients, with age ranging from 5 to 65 years (mean, 37 years). The tumors were located in the lung and mediastinum (10 cases), gastrointestinal tract and mesentery/omentum (12 cases), urinary bladder (5 cases), head and neck (3 cases), somatic soft tissue (1 case), and retroperitoneum (1 case). Four cases of epithelioid inflammatory myofibroblastic sarcoma (EIMS) were all located intra-abdominally. Histologically, the tumor cells were myofibroblasts and fibroblasts arranged in predominantly fusiform pattern, with variably edematous to myxoid background or sclerotic collagenized stroma, and variably mixed chronic or acute inflammatory cells infiltration. EIMS were composed mainly of epithelioid tumor cells, with myxoid stroma and numerous neutrophils. Immunohistochemically, the tumor cells expressed cytoplasmic ALK (25/32, 78%), whereas the four EIMS showed nuclear membrane ALK staining pattern. The tumor cells also expressed CKpan (8/19), SMA (24/32, 75%) and desmin (12/32, 38%); all four EIMS also showed strong positivity for desmin. Fluorescence in situ hybridization (FISH) for ALK gene rearrangement showed split apart signals in 12 of 15 cases, most commonly with atypical signals. Next-generation sequencing (NGS) was performed in three tumors and showed that one case of lower leg IMT harbored a novel CLIP2-ALK fusion, and two cases of EIMS harbored RANBP2-ALK fusion. Follow-up data were available in 29 patients. Twenty-two patients were alive with no evidence of tumor, four patients had tumor recurrences (three patients were treated with crizotinib and were alive with tumor), and three patients died of the disease (including two patients with EIMS). Conclusions: IMTs show a wide morphologic spectrum, and should be differentiated form a variety of benign or malignant tumors. Immunohistochemistry (ALKp80, ALKD5F3) and FISH (ALK break-apart probe) could assist the diagnosis of IMT, with NGS recommended for the atypical cases.


Assuntos
Granuloma de Células Plasmáticas , Sarcoma , Adolescente , Adulto , Idoso , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais , Criança , Pré-Escolar , Feminino , Granuloma de Células Plasmáticas/diagnóstico por imagem , Granuloma de Células Plasmáticas/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Methods Mol Biol ; 2279: 157-164, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33683692

RESUMO

The detection of molecular alterations such as ROS1 and ALK rearrangements is performed as part of the diagnosis of advanced-stage lung adenocarcinoma. These alterations allow the treatments with tyrosine kinase inhibitors. Cytological samples are very useful as up to 40% patients are diagnosed with this type of sample. Here we describe the immunocytochemistry technique usable to reveal the overexpression of ALK or ROS1 tyrosine kinase receptors secondary to ALK and ROS1 rearrangements, respectively.


Assuntos
Adenocarcinoma de Pulmão , Quinase do Linfoma Anaplásico , Rearranjo Gênico , Imuno-Histoquímica , Neoplasias Pulmonares , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo
4.
J Cancer Res Clin Oncol ; 147(2): 323-337, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33387037

RESUMO

The incidence of papillary thyroid cancer (PTC), the major type of thyroid cancer, is increasing rapidly around the world, and its pathogenesis is still unclear. There is poor prognosis for PTC involved in rapidly progressive tumors and resistance to radioiodine therapy. Kinase gene fusions have been discovered to be present in a wide variety of malignant tumors, and an increasing number of novel types have been detected in PTC, especially progressive tumors. As a tumor-driving event, kinase fusions are constitutively activated or overexpress their kinase function, conferring oncogenic potential, and their frequency is second only to BRAFV600E mutation in PTC. Diverse forms of kinase fusions have been observed and are associated with specific pathological features of PTC (usually at an advanced stage), and clinical trials of therapeutic strategies targeting kinase gene fusions are feasible for radioiodine-resistant PTC. This review summarizes the roles of kinase gene fusions in PTC and the value of clinical therapy of targeting fusions in progressive or refractory PTC, and discusses the future perspectives and challenges related to kinase gene fusions in PTC patients.


Assuntos
Fusão Gênica , Proteínas Quinases/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Quinase do Linfoma Anaplásico/genética , Fusão Gênica/efeitos dos fármacos , Fusão Gênica/fisiologia , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptor trkA/genética , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico
5.
Virchows Arch ; 478(1): 45-57, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33389149

RESUMO

This review presents an overview on molecular diagnostic in lung cancer using cytologic samples. Every patient with advanced non-small cell lung cancer (NSCLC) should be tested for targetable driver mutations and gene arrangements. If a mutation is found, this may open an option for targeted therapy. As most of the NSCLC patients in advanced stage of disease are no candidates for surgery, these tests have to be performed on small biopsies or cytology samples. The most common and treatable gene alterations should be tested in every patient: EGFR, ALK, ROS1. A growing number of other genetic changes with targetable mutations may become treatable in the near future. To find patients who might profit from inclusion into clinical studies, relevant additional markers may be tested in an appropriate context. Another important approach for treatment is immunotherapy of lung cancer, which is guided by status of PD-L1 expression on tumour cells. The use of cytology samples carries considerable advantages: often, DNA of high quality is extracted thus enabling easy and precise analysis, and samples may be easily obtained. In case of effusions, effusion fluid seldom is not aspirated for immediate patient relief, so no additional dedicated procedure is needed. Some challenges exist: If the tumour cell count is low, mutations with a low allelic frequency may be missed. In cellblocks formalin-induced DNA, damage may obviate any DNA analysis. In very cellular smears, FISH may be impossible due to massive overlapping of nuclei. Autofluorescence may impede FISH analysis. Although there is no real universal test for genomic profiling for lung cancer, the pathology laboratory must be prepared to offer different assays on different specimens in order to address turnaround time and optimise detections of difficult tumour alterations such as gene fusions. The data from the literature demonstrate that cytology show consistent results, and it is a good alternative for lung cancer molecular testing.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Mutação , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Análise Mutacional de DNA , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo
6.
Biomed Pharmacother ; 133: 111073, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378972

RESUMO

Sepsis is a life-threatening condition often leading to multiple organ failure for which currently no pharmacological treatment is available. Endothelial cells (EC) are among the first cells to respond to pathogens and inflammatory mediators in sepsis and might be a sentinel target to prevent the occurrence of multiple organ failure. Lipopolysaccharide (LPS) is a Gram-negative bacterial component that induces endothelial expression of inflammatory adhesion molecules, cytokines, and chemokines. This expression is regulated by a network of kinases, the result of which in vivo enables leukocytes to transmigrate from the blood into the underlying tissue, causing organ damage. We hypothesised that besides the known kinase pathways, other kinases are involved in the regulation of EC in response to LPS, and that these can be pharmacologically targeted to inhibit cell activation. Using kinome profiling, we identified 58 tyrosine kinases (TKs) that were active in human umbilical vein endothelial cells (HUVEC) at various timepoints after stimulation with LPS. These included AXL tyrosine kinase (Axl), focal adhesion kinase 1 (FAK1), and anaplastic lymphoma kinase (ALK). Using siRNA-based gene knock down, we confirmed that these three TKs mediate LPS-induced endothelial inflammatory activation. Pharmacological inhibition with FAK1 inhibitor FAK14 attenuated LPS-induced endothelial inflammatory activation and leukocyte adhesion partly via blockade of NF-κB activity. Administration of FAK14 after EC exposure to LPS also resulted in inhibition of inflammatory molecule expression. In contrast, inhibition of ALK with FDA-approved inhibitor Ceritinib attenuated LPS-induced endothelial inflammatory activation via a pathway that was independent of NF-κB signalling while it did not affect leukocyte adhesion. Furthermore, Ceritinib administration after start of EC exposure to LPS did not inhibit inflammatory activation. Combined FAK1 and ALK inhibition attenuated LPS-induced endothelial activation in an additive manner, without affecting leukocyte adhesion. Summarising, our findings suggest the involvement of FAK1 and ALK in mediating LPS-induced inflammatory activation of EC. Since pharmacological inhibition of FAK1 attenuated endothelial inflammatory activation after the cells were exposed to LPS, FAK1 represents a promising target for follow up studies.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Inibidores de Proteínas Quinases/farmacologia , Aminopiridinas/farmacologia , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Perfilação da Expressão Gênica , Células HL-60 , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Inflamação/enzimologia , Inflamação/genética , Análise Serial de Proteínas , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Piridonas/farmacologia , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Sulfonas/farmacologia , Fatores de Tempo , Transcriptoma
7.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352665

RESUMO

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Neuroendócrino/patologia , Rearranjo Gênico , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral , Microambiente Tumoral , Adulto , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico
8.
Medicine (Baltimore) ; 99(45): e22631, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157918

RESUMO

RATIONALE: The anaplastic lymphoma kinase (ALK) fusion has been identified to be a driver gene in lung cancer, and serves as important diagnostic and therapeutic targets. Owing to the advanced sequencing technologies, new partner genes of ALK have been constantly detected. PATIENT CONCERNS: A 55-year-old Chinese woman went to our hospital because of cough and expectoration for 1 year. The patient had no fever, chest pain and hemoptysis. DIAGNOSES: She was diagnosed with lung adenocarcinoma. Because she had no operational condition, combination chemotherapy with docetaxel and cisplatin (CP) for 4 cycles was adopted. However, computed tomography (CT) scan indicated progression disease (PD). To explore possibility of targeted therapy, the tumor samples were subjected to next-generation sequencing (NGS), and a rare double ALK fusion variant EML4-ALK and CDK15-ALK was identified. INTERVENTIONS AND OUTCOMES: The patient subsequently received crizotinib treatment, and achieved partial response (PR). No significant drug related adverse reactions were found during crizotinib treatment. The progression-free survival achieved 23 months. LESSONS: Together, we identified a rare double ALK fusion variant, EML4-ALK and CDK15-ALK, in a patient with lung adenocarcinoma. The patient benefited from crizotinib treatment, which could provide a certain reference for the patients with such gene alteration.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/uso terapêutico , Crizotinibe/uso terapêutico , Quinases Ciclina-Dependentes/genética , Proteínas de Fusão Oncogênica/genética , Adenocarcinoma de Pulmão/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
9.
Nat Commun ; 11(1): 5183, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33056981

RESUMO

Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. To better understand neuroblastoma pathogenesis, here we analyze whole-genome, whole-exome and/or transcriptome data from 702 neuroblastoma samples. Forty percent of samples harbor at least one recurrent driver gene alteration and most aberrations, including MYCN, ATRX, and TERT alterations, differ in frequency by age. MYCN alterations occur at median 2.3 years of age, TERT at 3.8 years, and ATRX at 5.6 years. COSMIC mutational signature 18, previously associated with reactive oxygen species, is the most common cause of driver point mutations in neuroblastoma, including most ALK and Ras-activating variants. Signature 18 appears early and is continuous throughout disease evolution. Signature 18 is enriched in neuroblastomas with MYCN amplification, 17q gain, and increased expression of mitochondrial ribosome and electron transport-associated genes. Recurrent FGFR1 variants in six patients, and ALK N-terminal structural alterations in five samples, identify additional patients potentially amenable to precision therapy.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Neuroblastoma/genética , Adolescente , Adulto , Fatores Etários , Quinase do Linfoma Anaplásico/genética , Criança , Pré-Escolar , Estudos de Coortes , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Transporte de Elétrons/genética , Exoma/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Ribossomos Mitocondriais , Mutação , Neuroblastoma/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Ribossômicas/genética , Transcriptoma/genética , Sequenciamento Completo do Genoma , Adulto Jovem
10.
J Cancer Res Ther ; 16(4): 771-779, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930117

RESUMO

Introduction: Lung cancer is the most common malignant disease and is the topmost cause of cancer deaths in the world across all age groups and in both sexes. It is the most common cause of cancer deaths in developed countries and is also rising at an alarming rate in the developing countries. Objective: The present study was undertaken to explore the clinicopathological and molecular profile of bronchogenic carcinoma in northwestern population of India. Materials and Methods: A total of 136 consecutive patients with histologically proven bronchogenic carcinoma, registered between May 2014 and April 2016 at a tertiary care hospital in New Delhi, India, were analyzed. Results: Out of a total of 136 diagnosed cases, 6% were in the third to fourth decade of life, 49% in the fifth to sixth decade, and 45% in the seventh decade and above. Seventy-one percent of patients were male. Smoking was the major risk factor in 65.40% of patients. About 33% of female patients were smokers with a significant overlap in the use of smoking objects. Twenty-one percent of patients had been initially empirically treated with antitubercular therapy. Most common symptoms at presentation were cough, dyspnea, weight loss, and chest pain. Pleural effusion, paraneoplastic phenomenon, clubbing, peripheral lymphadenopathy, and Pancoast syndrome were the major signs at presentation. Twenty-one percent of nonsmokers and 40% of smoker patients presented with ECOG Performance Status 3 or 4. Ninety-three percent of patients presented in stage III or IV. Metastases to skeleton, brain, liver, pleura, adrenals, lung, and distant lymph nodes were present in 30.8%, 16.9%, 15.4%, 15.4%, 14.7%, 13.2%, and 11.8%, respectively. Fiberoptic bronchoscopy was found to be the most efficient diagnostic procedure as compared to transthoracic and thoracoscopic methods. Histologically, squamous cell carcinoma, adenocarcinoma, and small cell carcinoma and its variants were seen in 35.30%, 44.9%, and 15.40% cases, respectively. Nearly 4.4% of patients were diagnosed as poorly differentiated carcinoma. Driver mutations (epidermal growth factor receptor or anaplastic lymphoma kinase) were detected in 48% (25 of 52 tested) of adenocarcinomas and 55.55% (5 of 9 tested) of young, nonsmoker, female squamous cell carcinoma patients. Conclusion: This study highlights that the adenocarcinoma incidence is surpassing squamous cell carcinoma in Indian lung cancer patients also, as observed in Western population. Mean age at diagnosis is about one decade earlier than in the Western population. Driver mutations are more common in India than in the West as also reported in other Asian studies.


Assuntos
Quinase do Linfoma Anaplásico/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Pequenas/epidemiologia , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Receptores ErbB/genética , Feminino , Humanos , Incidência , Índia/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumantes/estatística & dados numéricos , Adulto Jovem
11.
J Cancer Res Ther ; 16(4): 919-921, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930141

RESUMO

An 84-year-old male had a recurrence after surgical resection against Stage IIIA pulmonary adenocarcinoma and was treated with crizotinib due to harboring the anaplastic lymphoma kinase fusion gene. The patient exhibited crizotinib-induced interstitial lung disease (ILD), and alectinib was administered because of progressive disease. However, ILD appeared in both lungs again after alectinib treatment. This is the first case of ILD, resulting from alectinib administration after crizotinib-induced ILD. We should pay careful attention to patients who are treated with alectinib after crizotinib-induced ILD.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Carbazóis/efeitos adversos , Crizotinibe/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Carbazóis/uso terapêutico , Crizotinibe/uso terapêutico , Humanos , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Piperidinas/uso terapêutico , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico
12.
Am J Clin Oncol ; 43(9): 670-675, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889839

RESUMO

During the course of therapy, patients with small cell lung cancer have been noted to develop transformation to non-small cell lung cancer and conversely, patients with non-small cell lung cancer have had transformation to small cell lung cancer or other non-small cell histologies. Transformation may occur after prior tyrosine kinase inhibitors, chemotherapy, immunotherapy or radiation therapy. These changes reflect on the overlapping biology of these cell types and the clinical need for re-biopsy at times of disease progression. The optimum therapy after transformation will depend upon prior therapies received, the functional capacity of the patient, and further research to define the best therapy options.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Transformação Celular Neoplásica , Receptores ErbB/genética , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/terapia
14.
PLoS One ; 15(8): e0236580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756609

RESUMO

Lung cancer is generally treated with conventional therapies, including chemotherapy and radiation. These methods, however, are not specific to cancer cells and instead attack every cell present, including normal cells. Personalized therapies provide more efficient treatment options as they target the individual's genetic makeup. The goal of this study was to identify the frequency of causal genetic mutations across a variety of lung cancer subtypes in the earlier stages. 833 samples of non-small cell lung cancer from 799 patients who received resection of their lung cancer, were selected for molecular analysis of six known mutations, including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK. A SNaPshot assay was used for point mutations and fragment analysis searched for insertions and deletions. ALK was evaluated by IHC +/- FISH. Statistical analysis was performed to determine correlations between molecular and clinical/pathological patient data. None of the tested variants were identified in most (66.15%) of cases. The observed frequencies among the total samples vs. only the adenocarcinoma cases were notable different, with the highest frequency being the KRAS mutation (24.49% vs. 35.55%), followed by EGFR (6.96% vs. 10.23%), PIK3CA (1.20% vs. 0.9%), BRAF (1.08% vs. 1.62%), ALK (0.12% vs. 0.18%), while the lowest was the HER2 mutation (0% for both). The statistical analysis yielded correlations between presence of a mutation with gender, cancer type, vascular invasion and smoking history. The outcome of this study will provide data that helps stratify patient prognosis and supports development of more precise treatments, resulting in improved outcomes for future lung cancer patients.


Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença , Prognóstico , Adenocarcinoma/classificação , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética
15.
Am J Surg Pathol ; 44(9): 1224-1234, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32804454

RESUMO

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.


Assuntos
Adenocarcinoma/genética , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Fusão Gênica , Rearranjo Gênico , Adenocarcinoma/química , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Idoso , Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Análise Mutacional de DNA , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Japão , Metástase Linfática , Masculino , Mutação , Estadiamento de Neoplasias , Fenótipo , Resultado do Tratamento , Estados Unidos
16.
Bull Cancer ; 107(7-8): 779-791, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32532420

RESUMO

Immunotherapy alone or in combination with chemotherapy is now an integral part of the treatment of metastatic NSCLC. This treatment is transforming the management of these cancers, with 20-30% of patients achieving long survival. However, disease progression under treatment is still the rule for the majority of patients, raising problems both in understanding its mechanisms and in subsequent appropriate management. This study examines current therapeutic options and proposes solutions to circumvent resistance to immunotherapy. The mechanisms of resistance to these treatments is also analysed.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Quinase do Linfoma Anaplásico/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase III como Assunto , Terapia Combinada/métodos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/fisiologia , Genes erbB-1 , Humanos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Receptores de Antígenos Quiméricos/uso terapêutico , Translocação Genética
17.
Expert Opin Pharmacother ; 21(13): 1547-1554, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32511029

RESUMO

INTRODUCTION: Approximately 3-7% of advanced non-small cell lung cancers (NSCLC) are driven by an anaplastic lymphoma kinase (ALK) rearrangement. Crizotinib, ceritinib, alectinib, and brigatinib are active ALK inhibitors (ALKi) used to treat this oncogene-driven subset of NSCLC. Resistance occurs with time to ALKi and new therapeutics are being developed. Lorlatinib is an efficacious third-generation ALKi with an ability to overcome resistance mutations that develop with first- or second-generation ALKi. AREAS COVERED: Herein, the authors review the mechanism of action, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of lorlatinib and provide their future perspectives on this drug. EXPERT COMMENTARY: Lorlatinib is a potent ALK and ROS-1 inhibitor that also has activity against many acquired ALK resistance mutations. Clinical trials show the robust systemic and intracranial anti-tumor activity of lorlatinib in ALK rearranged advanced NSCLC. Adverse events of lorlatinib are unique and manageable. These include hypocholesteremia, hypertriglyceridemia, edema, cognitive effects, weight gain, and diarrhea. Loratinib will play an increasing role in the management of ALK-rearranged NSCLC with the optimal sequencing of ALKi undergoing further research.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Quinase do Linfoma Anaplásico/genética , Animais , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias Pulmonares/enzimologia , Resultado do Tratamento
18.
Arkh Patol ; 82(3): 18-23, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32593262

RESUMO

AIM OF STUDY: To determine a diagnostic algorithm for detecting translocation of the ALK gene and its frequency in the Moscow region. MATERIALS AND METHODS: During the priod between 2014 and 2018 (inclusive), 488 patients without activating mutations in the EGFR gene in the Moscow region were tested. To detect translocation of the ALK gene, fluorescence in situ hybridization (FISH) methods, an immunohistochemical method, and, in some cases, a polymerase chain reaction were used. RESULTS: Revealed ALK gene rearrangement in a population of patients with lung adenocarcinoma amounted to an average of 7.6% of cases. With this, the main method that we used was immunohistochemical method, applicable in more than 80% of cases. The use of other methods for verification of abnormalities in the ALK gene was found necessary in rare cases (3.3%). CONCLUSIONS: Using the algorithm presented in the article, it was possible to detect ALK gene rearrangement in a population of patients with lung adenocarcinoma in the Moscow region in an average of 7.6% of cases.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Moscou , Mutação , Receptores Proteína Tirosina Quinases
19.
Rev. cuba. hematol. inmunol. hemoter ; 36(2): e1189, abr.-jun. 2020.
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1149902

RESUMO

Introducción: La leucemia mieloide aguda (LMA) es un grupo heterogéneo de desórdenes clonales con una gran variabilidad en términos de patogénesis, características morfológicas, genéticas e inmunofenotípicas. Las mutaciones en el gen NPM1 representan una de las más comunes en las LMA y está asociada con una respuesta clínica favorable. Por citogenética, la inversión del cromosoma 16 define el subgrupo de las LMA de factor de unión al grupo con un pronóstico favorable. Objetivo: Describir un caso con diagnóstico de LMA en los cuales el estudio molecular del gen NPM1 y de la inv(16) fueron positivos. Caso clínico: A nivel molecular, la hibridación in situ fluorescente fue positivo a la inv(16) y por biología molecular fue positivo tanto a la inv(16) como al gen NPM1-A, elementos de baja frecuencia de aparición. Se le administró a la paciente un esquema de poliquimioterapia no intensiva para mejorarla clínicamente. Después de una mejoría clínica inicial, la paciente comenzó con complicaciones y falleció. Conclusiones: La coexistencia de estas dos mutaciones es muy poco frecuente en pacientes con LMA, y a pesar de ser de buen pronóstico la paciente falleció a los pocos días de tratamiento(AU)


Introduction: Acute myeloid leukemia (AML) is a heterogeneous group of clonal disorders with great variability in terms of pathogenesis, morphological, genetic and immunophenotypic characteristics. NPM1 mutations represent one of the most common in AML and are associated with favorable clinical response. By cytogenetics, chromosome 16 inversion defines, with a favorable prognosis, the core‐binding factor for the subgroup of AMLs Objective: To describe a AML case in which the molecular study of the NPM1 gene and the chromosome 16 inversion were positive. Clinical case: At the molecular level, fluorescent in situ hybridization was positive for chromosome 16 inversion and, by molecular biology, it was positive for both chromosome 16 inversion and for the NPM1-A gene, elements with a low frequency of appearance. The patient was administered a non-intensive combination as part of a chemotherapy regimen to improve her clinical status. After initial clinical improvement, the patient began with complications and died. Conclusions: The coexistence of these two mutations is very rare in patients with AML. Despite presenting a good prognosis, the patient died after a few days of treatment(AU)


Assuntos
Humanos , Feminino , Cromossomos Humanos Par 16/genética , Leucemia Mieloide Aguda/diagnóstico , Mutação/genética , Hibridização in Situ Fluorescente/métodos , Quinase do Linfoma Anaplásico/genética
20.
Nat Commun ; 11(1): 2393, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409712

RESUMO

Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Quinase do Linfoma Anaplásico/genética , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/farmacologia , Lapatinib/uso terapêutico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , RNA-Seq , Análise de Célula Única , Ensaios Antitumorais Modelo de Xenoenxerto
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