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2.
Int J Cancer ; 146(1): 94-102, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199501

RESUMO

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , GTP Fosfo-Hidrolases/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/genética , Proteína Supressora de Tumor p53/genética , Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
3.
Tech Vasc Interv Radiol ; 22(4): 100634, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31864529

RESUMO

Klippel-Trenaunay syndrome or KTS is a complex vascular syndrome associated with overgrowth occurring as a result of somatic mutations in the PIK3CA gene. Patients are diagnosed on the basis of physical findings, sometimes with supportive imaging, of commonly a segmental anomaly with a cutaneous port-wine stain, lymphatic and venous malformations and overgrowth. The severity of the component vascular malformations and the degree of overgrowth varies from patient to patient which demands care given by a multi-professional team with regular follow-up in a specialist clinic. Some patients may present with acute life-threatening problems, often as a result of veno-thromboembolic events (VTEs) especially following surgical and invasive radiological procedures. Awareness of such problems is vital and prophylactic measures to reduce such risks are paramount. The interventional radiologist is vital to the care team as he/she can undertake procedures including endovascular closure of significant venous anomalies which predispose to such VTEs. Although these procedures can be lengthy and complex, they can now provide a minimally invasive means to reduce the risk from life-threatening and sometimes fatal VTEs. The results however from such interventions will require long-term studies which to date are unavailable.


Assuntos
Malformações Arteriovenosas/terapia , Procedimentos Endovasculares , Síndrome de Klippel-Trenaunay-Weber/terapia , Tromboembolia Venosa/prevenção & controle , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/mortalidade , Classe I de Fosfatidilinositol 3-Quinases/genética , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Predisposição Genética para Doença , Hemangioma/diagnóstico , Hemangioma/genética , Hemangioma/terapia , Humanos , Síndrome de Klippel-Trenaunay-Weber/diagnóstico , Síndrome de Klippel-Trenaunay-Weber/genética , Síndrome de Klippel-Trenaunay-Weber/mortalidade , Mutação , Fenótipo , Radiografia Intervencionista , Fatores de Risco , Resultado do Tratamento , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/genética , Tromboembolia Venosa/mortalidade
4.
Expert Opin Ther Pat ; 29(12): 925-941, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31670985

RESUMO

Introduction: PI3Kδ is an important subtype of PI3K kinases, which is mainly expressed in leukocytes and plays an important role in the proliferation, differentiation, maturation and self-reaction of B cells. It is an effective target in the treatment of hematological malignancies and autoimmune diseases such as rheumatoid arthritis. Therefore, many pharmaceutical companies and research institutions have focused on the PI3Kδ subtype in an attempt to develop potent and selective PI3Kδ inhibitors.Areas covered: This review aims to provide an overview of the patented selective PI3Kδ inhibitors in treating cancer from 2015 to present.Expert opinion: Due to the importance of PI3Kδ, the development of selective PI3Kδ inhibitors for the treatment of hematoma and autoimmune diseases is expected. On 23 July 2014, the world's first selective PI3Kδ inhibitor, idelalisib, was approved by the FDA for the treatment of CLL, FL and SLL. Moreover, there are still many small molecule selective PI3Kδ inhibitors at different stages of development. The future research effort for development of PI3Kδ inhibitors is to manage the toxicity and lower the side-effects.


Assuntos
Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Doenças Autoimunes/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Desenvolvimento de Medicamentos , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Patentes como Assunto , Purinas/farmacologia , Quinazolinonas/farmacologia
5.
Science ; 366(6466): 685-686, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31699922
6.
Rinsho Ketsueki ; 60(9): 1212-1220, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597846

RESUMO

It is well known that acute lymphoblastic leukemia (ALL) cells can invade the central nervous system (CNS), but the underlying mechanism of such invasion is still unclear. We discovered the direct routes taken by ALL cells when migrating into CNS in ALL model mice. We observed that ALL cells migrate along the external surface of vessels that pass directly between the vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin. The laminin is recognized by integrin α6, which is expressed by ALL cells. The interaction between integrin α6 and laminin mediated the invasion of ALL cells. Furthermore, the expression of integrin α6 depends on PI3Kδ activity. Mice with ALL xenografts were treated with a PI3Kδ inhibitor, which decreased integrin α6 expression on ALL cells. This resulted in significant reductions in blast counts in the cerebrospinal fluid and in CNS disease symptoms. Our data suggest that the PI3Kδ inhibitor has potential to prevent CNS involvement in ALL.


Assuntos
Sistema Nervoso Central/fisiopatologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Integrina alfa6/metabolismo , Laminina/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Animais , Membrana Basal , Medula Óssea , Camundongos , Espaço Subaracnóideo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Virchows Arch ; 475(6): 727-734, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31372739

RESUMO

Clear cell adenocarcinoma (CCA) of the urinary tract is a rare type of malignancy whose molecular profiles remain undefined. Here we reported an integrated clinicopathologic and molecular profiling analysis of four cases of clear cell adenocarcinoma arising in the urethra or the bladder. Utilizing a clinically validated 130-gene exon-sequencing assay, we identified recurrent pathogenic PIK3CA (p. E545K) and KRAS (p.G12D) variants in three of four (75%) of the cases. In addition, an APC variant (P.S2310X), a TP53 variant (p.R273C), and a MYC amplification event were identified. The only CCA case without either PIK3CA or KRAS variants has a distinct pathogenesis through BK virus, demonstrated by positive BK virus PCR and SV40 immunohistochemistry. The novel finding of recurrent variants in the PI3K/AKT/mTOR pathway provides not only insights into oncogenesis but also potential clinical therapeutic targets for patients with clear cell adenocarcinoma of the urinary tract.


Assuntos
Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Sistema Urinário/patologia , Adulto , Criança , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
11.
Medicine (Baltimore) ; 98(32): e16451, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393349

RESUMO

Early diagnose of bladder cancer could lead to good prognosis and high 5-year-survival rate. Among bladder cancer, about 75% patients with were nonmuscle-invasive bladder cancer (NMIBC). Patients were painful and easily get infected during bladder cancer diagnosis, which mainly depends on invasive cystoscopy and low-sensitivity urine exfoliation cytology. Meanwhile, relapse after surgery was also becoming the major problem for patients. Exploring noninvasive, high-sensitivity, and painless method is very important and meaningful for NMIBC treatment.Firstly, we found potential related gene mutation sites for NMIBC by searching COSMIC database and related study. Urinary sediment cells of patients both in normal group (patients with benign) and NMIMC group were collected before and after operation for potential gene mutation site detecting. Meanwhile, the urinary sediment cells of relapse patients and good prognosis people in NMIBC group after surgery were also collected for further Gene mutation detection and NMIBC relapse after surgery prediction.Fourteen genes (152 mutation sites) were selected between 95 NMIBC patients and 67 control patients, which were FGFR3, TP53, PIK3CA, and others. Compared with control group, mutation ratio of above 14 genes was higher in NMIBC group. NMIBC diagnose model was established by 5 times cross-validation and had a good effects, which included the all mutation site in FGFR3, TP53, PIK3CA, ARID1A, STAG2, and KTM2D. On the contrary, the relapse rate was 30.5% among 95 patients for about 1.5-year follow-up time. Compared with control group, smoking rate and tumor grade were higher in relapse group. Meanwhile, mutation rate of FGFR3, TP53, PIK3CA, ERBB3, and TSC1 in relapse group were higher than that in normal group. According to the mutation sites of FGFR3, TP53, PIK3CA, and ERBB3 and the combination of urinary sediment cells genetic mutation and relapse status, a predicted model for NMIBC relapse was also established, which had 90% accuracy.The diagnosed NMIBC model (based on FGFR3, TP53, PIK3CA, ARID1A, STAG2, and KTM2D gene mutation) and predicted relapse model (based on FGFR3, TP53, PIK3CA, and ERBB3 gene mutation) possess high accuracy and would be applied in early diagnose and early predicting relapse of patients.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia
12.
Anticancer Res ; 39(8): 4003-4010, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366481

RESUMO

Epstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is classified as one of four GC subtypes by comprehensive molecular characterization. Though the mechanism of tumorigenesis by EBV infection has not yet been fully clarified, EBV infection might contribute to the malignant transformation of GC cells by involving various cellular processes and signaling pathways. EBVaGC has shown the following distinct characteristics in contrast to other subtypes: extreme DNA hypermethylation, recurrent phosphatidylinositol 4,5-biphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) mutations, overexpression of programmed cell death ligand 1/2 (PD-L1/2), and occasional immune cell signaling activation. Therefore, using these molecular features as guides, targeted agents need to be evaluated in clinical trials for EBVaGC. Accordingly, this review uses the best available evidence to focus on novel therapeutic approaches using the distinct pathologic characteristics of EBVaGC patients.


Assuntos
Carcinogênese/genética , Infecções por Vírus Epstein-Barr/terapia , Neoplasias Gástricas/terapia , Classe I de Fosfatidilinositol 3-Quinases/genética , Metilação de DNA/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/virologia
13.
Nat Commun ; 10(1): 3412, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363081

RESUMO

Skeletal muscle insulin resistance, decreased phosphatidylinositol 3-kinase (PI3K) activation and altered mitochondrial function are hallmarks of type 2 diabetes. To determine the relationship between these abnormalities, we created mice with muscle-specific knockout of the p110α or p110ß catalytic subunits of PI3K. We find that mice with muscle-specific knockout of p110α, but not p110ß, display impaired insulin signaling and reduced muscle size due to enhanced proteasomal and autophagic activity. Despite insulin resistance and muscle atrophy, M-p110αKO mice show decreased serum myostatin, increased mitochondrial mass, increased mitochondrial fusion, and increased PGC1α expression, especially PCG1α2 and PCG1α3. This leads to enhanced mitochondrial oxidative capacity, increased muscle NADH content, and higher muscle free radical release measured in vivo using pMitoTimer reporter. Thus, p110α is the dominant catalytic isoform of PI3K in muscle in control of insulin sensitivity and muscle mass, and has a unique role in mitochondrial homeostasis in skeletal muscle.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Mitocôndrias/enzimologia , Músculo Esquelético/enzimologia , Animais , Classe I de Fosfatidilinositol 3-Quinases/genética , Homeostase , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , NAD/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo
14.
Nat Commun ; 10(1): 3554, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391455

RESUMO

ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. Here we show that monoallelic loss of ARID1A in the mouse endometrial epithelium is sufficient for vaginal bleeding when combined with PI3K activation. Sorted mutant epithelial cells display gene expression and promoter chromatin signatures associated with epithelial-to-mesenchymal transition (EMT). We further show that ARID1A is bound to promoters with open chromatin, but ARID1A loss leads to increased promoter chromatin accessibility and the expression of EMT genes. PI3K activation partially rescues the mesenchymal phenotypes driven by ARID1A loss through antagonism of ARID1A target gene expression, resulting in partial EMT and invasion. We propose that ARID1A normally maintains endometrial epithelial cell identity by repressing mesenchymal cell fates, and that coexistent ARID1A and PI3K mutations promote epithelial transdifferentiation and collective invasion. Broadly, our findings support a role for collective epithelial invasion in the spread of abnormal endometrial tissue.


Assuntos
Transformação Celular Neoplásica/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Transição Epitelial-Mesenquimal/genética , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinases/genética , Fatores de Transcrição/genética , Animais , Linhagem Celular , Movimento Celular/genética , Cromatina/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Neoplasias do Endométrio/patologia , Endométrio/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Haploinsuficiência , Humanos , Mutação com Perda de Função , Camundongos , Camundongos Transgênicos , Miométrio/patologia , Invasividade Neoplásica/genética , Proteínas Nucleares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo
15.
J Mol Model ; 25(8): 242, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31338599

RESUMO

Phosphoinositide 3-kinases (PI3Ks) are crucial for cell proliferation, metabolism, motility, and cancer progression. Since the selective PI3Kδ inhibitor, idelalisib, was firstly approved by the FDA in 2014, large numbers of selective PI3Kδ inhibitors have been reported, but the detailed mechanisms of selective inhibition to PI3Kδ for idelalisib or its derivatives have not been well addressed. In this study, 3D-QSAR with COMFA, molecular docking, and molecular dynamic (MD) simulations was used to explore the binding modes between PI3Kδ and idelalisib derivatives. Firstly, a reliable COMFA model (q2 = 0.59, ONC = 8, r2 = 0.966) was built and the contour maps showed that the electrostatic field had more significant contribution to the bioactivities of inhibitors. Secondly, two molecular docking methods including rigid receptor docking (RRD) and induced fit docking (IFD) were employed to predict the docking poses of all the studied inhibitors and revealed the selective binding mechanisms. And then, the results of the MD simulation and the binding free energy decomposition verified that the binding of PI3Kδ/inhibitors was mainly contributed from hydrogen bonding and hydrophobic interactions and some key residues for selective binding were highlighted. Finally, based on the models developed, 14 novel inhibitors were optimized and some showed satisfactory predicted bioactivity. Taken together, the results provided by this study may facilitate the rational design of novel and selective PI3Kδ inhibitors. Graphical abstract .


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Modelos Teóricos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Purinas/química , Purinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Quinazolinonas/química , Quinazolinonas/farmacologia , Desenho de Drogas , Ligantes , Termodinâmica
16.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295843

RESUMO

Acquired paclitaxel (PTX) resistance limits its effectiveness and results in advanced cancer progression. This review investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. It was established paclitaxel-resistant cell lines (PTX-R ME180/PTX-R HeLa) and determined the combination index for paclitaxel and PI3K inhibitors (BYL-719/ LY294002) by tetrazolium dye assay. Flow cytometry was used to detect the cell cycle and apoptosis. Migration and invasion were explored by wound healing and transwell assays. Genes related to multiple pathways were assessed by a western blot. It was found that the PI3K pathway was significantly activated in paclitaxel-resistant HeLa and ME180 cells compared to parental cells. PTX + PI3K inhibitor combined therapy showed a synergistic effect by strengthening paclitaxel-induced S and G2M arrest in PTX-R cell sublines by the inactivation of cyclin A1, cyclin B1, cyclin E, and Cdc2 expression. Moreover, combination therapy significantly enhanced drug sensitivity and apoptosis through the activation of Bax, and cleavage of poly-(ADP-ribose) polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasion by targeting ß-catenin and matrix metalloproteinase-2/9. The authors suggest that the combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Paclitaxel/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/genética , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Feminino , Variação Genética , Humanos , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo
17.
World J Gastroenterol ; 25(26): 3408-3425, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31341365

RESUMO

BACKGROUND: Different histological growth patterns (HGPs) of colorectal carcinoma (CRC) liver metastasis are associated with patients' prognosis and response to antiangiogenic therapy. However, the relationship between HGPs of liver metastasis and clinicopathological and genomic characteristics of primary cancer has not been well established. AIM: To assess whether certain clinicopathological and genomic features of primary CRC could predict the HGPs of liver metastasis. METHODS: A total of 29 patients with paired resections of both primary CRC and liver metastasis were divided into two groups: A (15 cases with desmoplastic liver metastasis) and B (14 cases with replacement liver metastasis). Clinical information was obtained from patients' charts. Mismatch repair proteins, BRAFV600E, and PD-L1 were evaluated by immunohistochemistry. Five cases were selected randomly from each group for whole exome sequencing (WES) analysis. RESULTS: In the primary tumor, expanding growth pattern, low tumor budding score (TBS), and Crohn's disease-like response (CDR) were associated with desmoplastic liver metastasis and better overall survival, whereas infiltrating growth pattern alone of primary carcinoma could predict the replacement liver metastasis and worse overall survival (P < 0.05). On WES analysis, primary carcinoma with desmoplastic liver metastasis showed mutations in APC (4/5); TP53 (3/5); KRAS, PIK3CA, and FAT4 (2/5); BRCA-1, BRCA2, BRAF, and DNAH5 (1/5), whereas primary carcinoma with replacement liver metastasis showed mutations in APC and TP53 (3/5); KRAS, FAT4, DNH5, SMAD, ERBB2, ERBB3, LRP1, and SDK1 (1/5). CONCLUSION: The HGPs, TBS, and CDR of primary CRC as well as the presence of specific genetic mutations such as those in PIK3CA could be used to predict the HGPs of liver metastasis, response to therapy, and patients' prognosis.


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Reto/patologia , Estudos Retrospectivos , Sequenciamento Completo do Exoma
18.
Medicine (Baltimore) ; 98(28): e16245, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305404

RESUMO

RATIONALE: Primary splenic angiosarcoma (PSA) is a rare mesenchymal malignancy of the splenic vascular origin often with a dismal prognosis. Genomic profile may provide evidence for the solution of therapy. PATIENT CONCERNS: We reported a case of a 51-year-old woman with splenectomy 4 years ago and the postoperative histopathology diagnosis revealed "splenic hemangioma" with spontaneous rupture. Two years after the operation, the patient's rechecked abdominal computed tomography (CT) showed multiple hepatic occupations. DIAGNOSES: Pathological test suggested PSA hepatic metastasis. INTERVENTIONS: The patient was treated with trans-catheter arterial chemoembolization (TACE) and a pathological diagnosis of PSA was highly suspected in the hepatic biopsy. Four somatic alterations, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), MCL1 apoptosis regulator (MCL1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) were detected in the tumor tissue using a Next generation sequencing (NGS) technology. The results prompted that the patient may get clinical benefit from using some agents for targeted therapy, Everolimus, Temsirolimus, or Copanlisib. OUTCOMES: The patient refused targeted therapy. As a result, the patient passed away within 51 months after splenectomy. LESSONS: PSA is an aggressive disease that often presented with a high propensity for metastasis and rupture hemorrhage. Some of these mutations were first discovered in PSA and these findings added new contents to the genomic mutation profile of PSA.


Assuntos
Hemangiossarcoma/cirurgia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Esplenectomia , Neoplasias Esplênicas/cirurgia , Classe I de Fosfatidilinositol 3-Quinases/genética , Evolução Fatal , Feminino , Hemangiossarcoma/genética , Hemangiossarcoma/patologia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Pessoa de Meia-Idade , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-fos/genética , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/patologia
19.
J Cancer Res Clin Oncol ; 145(8): 2051-2059, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31270600

RESUMO

BACKGROUND: Triple negative breast cancer (TNBC) harbors a heterogeneous group of carcinomas with poor prognosis and high genetic variability. As a potential aim for targeted therapy, genetic mutations leading to an activation of the phosphoinositide 3-kinase pathway in a catalytic subunit (PIK3CA) in breast cancer have been analyzed currently. Little is known about the clinical impact and prognostic or predictive value of this marker in TNBC subtypes. METHODS: Samples from 119 TNBC cases were submitted to immunohistochemical PIK3CA protein expression analysis and scored semi-quantitatively as negative, weak (1 +), or strongly expressed (2 +). Expression scores were correlated to patient's characteristics, imaging features, and TNBC subtypes. TNBC subtypes were categorized into four subtypes: basal like, mesenchymal like, luminal androgen receptor (LAR), and immunomodulatory. RESULTS: We did not observe differences in clinical aspects and imaging features between TNBC with and without PIK3CA expression. PIK3CA expression was in general higher in the LAR subtype. The disease-free survival and overall survival were significantly better in TNBC with PIK3CA protein expression, independent of TNBC subtypes. CONCLUSION: Despite conflicting results in the literature, our study clearly shows a better outcome of PIK3CA-expressing TNBC, independent of TNBC subtypes. PIK3CA expression in TNBC is not associated with specific clinical or diagnostic features. Further molecular studies and meta-analysis are warranted to clarify the prognostic and predictive role of PIK3CA protein expression.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/mortalidade
20.
Drugs ; 79(11): 1249-1253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31256368

RESUMO

Alpelisib (Piqray™)-an orally available phosphatidylinositol 3-kinase (PI3K) inhibitor with specific activity against PI3K alpha (PI3Kα)-is being developed by Novartis for the treatment of breast cancer. Alpelisib has demonstrated efficacy in combination with fulvestrant as treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer in patients with a PIK3CA mutation and was recently approved for this indication in the USA. This article summarizes the milestones in the development of alpelisib leading to this first approval.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Tiazóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Aprovação de Drogas , Feminino , Fulvestranto/administração & dosagem , Humanos , Masculino , Mutação , Receptor ErbB-2/metabolismo , Estados Unidos , United States Food and Drug Administration
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