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1.
Diagnostics (Basel) ; 11(8)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34441436

RESUMO

Molecular testing of the BCR-ABL1 transcript via real-time quantitative-polymerase-chain-reaction is the most sensitive approach for monitoring the response to tyrosine-kinase-inhibitors therapy in chronic myeloid leukaemia (CML) patients. Each stage of the molecular procedure has been standardized and optimized, including the total white blood cells (WBCs) and RNA isolation methods. Here, we compare the performance of our current manual protocol to a newly semiautomatic method based on the Biomek i-5 Automated Workstations integrated with the CytoFLEX Flow Cytometer, followed by the automatic QIAsymphony system to facilitate high-throughput processing samples and reduce the hands-on time and the risk associated with SARS-CoV-2. The recovery efficiency was investigated in blood samples from 100 adults with CML. We observe a 100% of concordance between the two methods, with similar total WBCs isolated (median 1.137 × 106 for manual method vs. 1.076 × 106 for semiautomatic system) and a comparable quality and quantity of RNA extracted (median 103 ng/µL with manual isolation kit vs. 99.95 ng/µL with the QIAsymphony system). Moreover, by stratifying patients according to their BCR-ABL1 transcript levels, we obtained similar BCR-ABL1/ABL1IS values and ABL1 copies, and matched samples were assigned to the same group of molecular response. We conclude that this newly semiautomatic workflow has a performance comparable to our more laborious standard manual, which can be replaced, particularly when specimens from patients with suspected or confirmed SARS-CoV-2 infection need to be processed.

2.
Nat Commun ; 12(1): 5006, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408135

RESUMO

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.


Assuntos
Tecido Adiposo/citologia , Reprogramação Celular , Neoplasias do Colo/fisiopatologia , Células-Tronco Neoplásicas/citologia , Nicho de Células-Tronco , Tecido Adiposo/metabolismo , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , Células-Tronco/citologia , Células-Tronco/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
3.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299334

RESUMO

Thyroid cancer is the most common malignancy of the endocrine system, encompassing different entities with distinct histological features and clinical behavior. The diagnostic definition, therapeutic approach, and follow-up of thyroid cancers display some controversial aspects that represent unmet medical needs. Liquid biopsy is a non-invasive approach that detects and analyzes biological samples released from the tumor into the bloodstream. With the use of different technologies, tumor cells, free nucleic acids, and extracellular vesicles can be retrieved in the serum of cancer patients and valuable molecular information can be obtained. Recently, a growing body of evidence is accumulating concerning the use of liquid biopsy in thyroid cancer, as it can be exploited to define a patient's diagnosis, estimate their prognosis, and monitor tumor recurrence or treatment response. Indeed, liquid biopsy can be a valuable tool to overcome the limits of conventional management of thyroid malignancies. In this review, we summarize currently available data about liquid biopsy in differentiated, poorly differentiated/anaplastic, and medullary thyroid cancer, focusing on circulating tumor cells, circulating free nucleic acids, and extracellular vesicles.


Assuntos
Biópsia Líquida/métodos , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/patologia , Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , Vesículas Extracelulares/patologia , Humanos , Biópsia Líquida/tendências , Células Neoplásicas Circulantes/patologia , Prognóstico
4.
Clin Cancer Res ; 27(18): 5012-5019, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266890

RESUMO

PURPOSE: This phase I study evaluated safety, tolerability, pharmacokinetics, and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel. PATIENTS AND METHODS: Patients with advanced solid tumors treated with ≤ 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, and 22 (95, 110, or 130 mg according to dose level); carboplatin (AUC5) on day 8 (day 1 following protocol amendment); and paclitaxel at 80 mg/m2 on days 8, 15, and 22 (1, 8, and 15 after amendment), every 28 days. Patients without progressive disease after cycle 6 received maintenance gedatolisib until progression. RESULTS: Seventeen patients were enrolled [11 ovarian (10 clear cell ovarian cancer, CCOC), 4 endometrial, 2 lung cancers]. Median number of prior chemotherapies was 1 (range, 0-2). Median number of administered cycles was 6 (range, 2-16). Dose-limiting toxicities occurred in 4 patients: 2 (cycle 2 delay due to G2-G3 neutropenia) at 110 mg leading to a change in the treatment schedule, 2 at 130 mg (G2 mucositis causing failure to deliver ≥ 75% of gedatolisib at cycle 1). The recommended phase II dose is gedatolisib 110 mg on days 1, 8, 15, and 22 with carboplatin AUC5 on day 1 and paclitaxel 80 mg/m2 on days 1, 8, and 15. The most frequent ≥G3 treatment-related adverse events were neutropenia (35%), anemia (18%), and mucositis (12%). The overall response rate was 65% (80% in CCOC). Pharmacokinetic parameters of gedatolisib were consistent with single-agent results. CONCLUSIONS: Gedatolisib combined with carboplatin and paclitaxel is tolerable, and preliminary efficacy was observed especially in CCOC.

5.
Br J Radiol ; 94(1125): 20201314, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34233456

RESUMO

Radiomics is an emerging field of research that aims to find associations between quantitative information extracted from imaging examinations and clinical data to support the best clinical decision. In the last few years, some papers have been evaluating the role of radiomics in gynecological malignancies, mainly focusing on ovarian cancer. Nonetheless, cervical cancer is the most frequent gynecological malignancy in developing countries and endometrial cancer is the most common in western countries. The purpose of this narrative review is to give an overview of the latest published papers evaluating the role of radiomics in cervical and endometrial cancer, mostly evaluating association with tumor prognostic factors, with response to therapy and with prediction of recurrence and distant metastasis.


Assuntos
Diagnóstico por Imagem/métodos , Neoplasias do Endométrio/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias do Colo do Útero/diagnóstico por imagem , Colo do Útero/diagnóstico por imagem , Endométrio/diagnóstico por imagem , Feminino , Humanos
6.
Front Pharmacol ; 12: 662232, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995085

RESUMO

The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.

7.
Transl Oncol ; 14(8): 101104, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33993096

RESUMO

Over the last quarter century several genetic alterations have been implicated in hereditary breast cancer (HBC). Two papers recently published in the New England Journal of Medicine explored the mutation prevalence in breast cancer predisposition genes across a large population of affected and unaffected subjects. These analyses designated ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C and RAD51D as the core set of genes associated with a significantly increased risk of developing breast cancer. A deeper understanding of the biological role of these genes unearths an intricate mechanism involving DNA repair and cell cycle regulation. Exploiting these inherited alterations for targeted treatments, as is currently the case with PARP inhibitors, may provide additional therapeutic opportunities for HBC patients.

8.
Crit Rev Oncol Hematol ; 162: 103334, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33865994

RESUMO

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is commonly deregulated in many human tumors, including breast cancer. Somatic mutations of the PI3K alpha catalytic subunit (PIK3CA) are the most common cause of pathway hyperactivation. Hence, several PI3K inhibitors have been investigated with one of them, alpelisib, recently approved for the treatment of endocrine sensitive, PIK3CA mutated, metastatic breast cancer. Unfortunately, all patients receiving a PI3K inhibitor eventually develop resistance to these compounds. Mechanisms of resistance include oncogenic PI3K alterations, pathway reactivation through upstream or downstream effectors and enhancement of parallel pro-survival pathways. We review the prognostic and predictive role of PI3K alterations in breast cancer, focusing on resistance to PI3K inhibitors and on biomarkers with potential clinical relevance. We also discuss combination strategies that may overcome resistance to PI3K inhibitors, thus increasing the efficacy of these drugs in breast cancer.


Assuntos
Neoplasias da Mama , Fosfatidilinositol 3-Quinase , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Mutação , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR
9.
Case Rep Oncol Med ; 2021: 6692538, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33728080

RESUMO

Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.

10.
Future Oncol ; 16(1s): 9-13, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31916463

RESUMO

Due to its low incidence, liposarcoma displays a limited number of therapeutic options. However, eribulin recently received approval for the treatment of advanced liposarcoma patients, progressing to at least two chemotherapy lines. We report herein the case of a man initially diagnosed with a leyomiosarcoma, subsequently reclassified as a dedifferentiated liposarcoma, who received eribulin after he failed several therapy lines. Eribulin provided our patient an 8-month disease control and a substantial clinical benefit with no relevant adverse effects, showing a good efficacy and safety profile despite its delayed employ. Additionally, this case strengthens the pivotal importance of molecular profiling in the management of soft tissue sarcomas.


Assuntos
Antineoplásicos/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Leiomiossarcoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais , Diagnóstico Tardio , Erros de Diagnóstico , Furanos/administração & dosagem , Furanos/efeitos adversos , Variação Genética , Humanos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Leiomiossarcoma/diagnóstico , Leiomiossarcoma/etiologia , Leiomiossarcoma/mortalidade , Masculino , Pessoa de Meia-Idade , Retratamento , Tempo para o Tratamento , Tomografia Computadorizada por Raios X
11.
Front Oncol ; 10: 612385, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33604294

RESUMO

Glioblastoma multiforme (GBM) is the most common primary brain malignancy and is often resistant to conventional treatments due to its extensive cellular heterogeneity. Thus, the overall survival of GBM patients remains extremely poor. Insulin-like growth factor (IGF) signaling entails a complex system that is a key regulator of cell transformation, growth and cell-cycle progression. Hence, its deregulation is frequently involved in the development of several cancers, including brain malignancies. In GBM, differential expression of several IGF system components and alterations of this signaling axis are linked to significantly worse prognosis and reduced responsiveness to temozolomide, the most commonly used pharmacological agent for the treatment of the disease. In the present review we summarize the biological role of the IGF system in the pathogenesis of GBM and comprehensively discuss its clinical significance and contribution to the development of resistance to standard chemotherapy and experimental treatments.

12.
Genes (Basel) ; 10(9)2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540307

RESUMO

Thyroid cancer comprises different clinical and histological entities. Whereas differentiated (DTCs) malignancies are sensitive to radioiodine therapy, anaplastic (ATCs) and medullary (MTCs) tumors do not uptake radioactive iodine and display aggressive features associated with a poor prognosis. Moreover, in a majority of DTCs, disease evolution leads to the progressive loss of iodine sensitivity. Hence, iodine-refractory DTCs, along with ATCs and MTCs, require alternative treatments reflective of their different tumor biology. In the last decade, the molecular mechanisms promoting thyroid cancer development and progression have been extensively studied. This has led to a better understanding of the genomic landscape, displayed by thyroid malignancies, and to the identification of novel therapeutic targets. Indeed, several pharmacological compounds have been developed for iodine-refractory tumors, with four multi-target tyrosine kinase inhibitors already available for DTCs (sorafenib and lenvatinib) and MTCs (cabozantib and vandetanib), and a plethora of drugs currently being evaluated in clinical trials. In this review, we will describe the genomic alterations and biological processes intertwined with thyroid cancer development, also providing a thorough overview of targeted drugs already tested or under investigation for these tumors. Furthermore, given the existing preclinical evidence, we will briefly discuss the potential role of immunotherapy as an additional therapeutic strategy for the treatment of thyroid cancer.


Assuntos
Neoplasias da Glândula Tireoide/metabolismo , Antineoplásicos/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética
13.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269742

RESUMO

The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)-comprising papillary (PTC) and follicular (FTC) tumors-respond to radioiodine therapy, while undifferentiated tumors-including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)-are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer.


Assuntos
Carcinogênese/metabolismo , Transdução de Sinais , Somatomedinas/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Humanos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia
14.
Future Oncol ; 11(24 Suppl): 29-33, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26638920

RESUMO

The increasing incidence and the dismal prognosis of malignant pleural mesothelioma calls for the identification of biomarkers that will allow a timely diagnosis; display prognostic value; and, predict the response to pharmacological agents employed for the treatment of the disease. Biomarkers associated with early diagnosis currently include mesothelin in combination with miRNA miR-103a-3p. As for prognostic biomarkers, the Cancer and Leukemia Group B (CALGB) and the European Organization for Research and Treatment of Cancer (EORTC) scores take into account different hematological and clinical parameters that distinguish patients with good prognosis from those with inferior outcomes. Fluorodeoxyglucose-PET, microarray expression data, neutrophil-to-lymphocyte ratios, c-MET expression, Ki-67 ratios and fibulin-3 levels have also been associated with disease outcome. Finally, thymidylate synthase protein cutoffs may predict mesothelioma response to the association of pemetrexed with a platinum derivative.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Mesotelioma/diagnóstico , Mesotelioma/metabolismo , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Mesotelioma Maligno , Neoplasias Pleurais/patologia , Prognóstico
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