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1.
Vet Res Commun ; 48(3): 1611-1620, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38413536

RESUMO

The advancement of nanotechnology and the widespread use of nanoparticles (NPs) in various industries have highlighted the importance of studying the potential harmful effects of nanomaterials on organisms. This study aimed to evaluate the lethal toxicity thresholds of Copper Oxide Nanoparticles (CuO-NPs). The investigation focused on examining the sub-lethal toxicity effects of CuO-NPs on blood parameters, as well as their influence on the gill tissue and liver of goldfish (Carassius auratus). Goldfish were exposed to varying concentrations of CuO-NPs (10, 20, 30, 40, 60, 80, and 100 mg/L) for 96 h. The Probit software was employed to determine the LC50 (lethal concentration causing 50% fish mortality) by monitoring and documenting fish deaths at 24, 48, 72, and 96-hour intervals. Subsequently, sub-lethal concentrations of 5% LC50 (T1), 10% LC50 (T2), and 15% LC50 (T3) of CuO-NPs were administered based on the LC50 level to investigate their effects on haematological parameters, encompassing the number of red blood cells and white blood cells, hematocrit and haemoglobin levels, mean corpuscular volume, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration. Additionally, histopathological examinations were conducted on the gill and liver tissues of the studied fish. Results indicated concentration-response of fish mortalities. In general, changes in the blood biochemical parameters of fish exposed to sub-lethal concentrations of CuO-NPs included a significant decrease in leukocyte count and glucose level and an increase in protein and triglyceride levels. Furthermore, an escalation in tissue damage such as gill apical and basal hyperplasia, lamellae attachment, squamous cell swelling, blood cell infiltration, and cellular oedema in gills tissue. and bleeding, increased sinusoidal space, necrosis, lateralization of the nucleus, cell swelling, and water retention in the liver. The findings showed dose-dependent increasing toxicity in goldfish specimens exposed to CuO-NPs.


Assuntos
Cobre , Brânquias , Carpa Dourada , Nanopartículas Metálicas , Animais , Carpa Dourada/sangue , Cobre/toxicidade , Brânquias/efeitos dos fármacos , Brânquias/patologia , Nanopartículas Metálicas/toxicidade , Dose Letal Mediana , Fígado/efeitos dos fármacos , Fígado/patologia , Poluentes Químicos da Água/toxicidade , Relação Dose-Resposta a Droga
2.
HPB (Oxford) ; 26(3): 444-450, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38142182

RESUMO

PURPOSE: To evaluate tolerability, pathologic response, and disease outcomes utilizing pre-operative stereotactic body radiation therapy (SBRT) followed by consolidation chemotherapy (CHT) prior to orthotopic liver transplant (OLT) in unresectable cholangiocarcinoma (CCA). METHODS: This was a retrospective chart review of patients treated on OLT protocol at a single tertiary center from 2012 to 2019. Patients received pre-operative SBRT (40-50 Gy in 5 fractions) followed by CHT until progression or OLT. Progression-free survival (PFS) and overall survival (OS) were compared via log-rank test and Cox proportional hazards regression. RESULTS: 26 patients (84.6% hilar, 15.4% intrahepatic) were identified for analysis. Eight patients (30.8%) patients developed acute toxicity after SBRT, mostly grade 1 nausea. Nine (34.6%) patients underwent OLT of which 4 (44.4%) achieved a pathologic complete response (pCR). Five (55.6%) OLT patients, including 2 pCR, developed recurrence at a median time of 49.9 weeks after OLT. 3-year OS for the OLT and dropout cohort was 75% and 9%, respectively (p < 0.0001). OS in hilar tumors only was statistically different for those that achieved a pCR (p = 0.014). CONCLUSIONS: Pre-operative SBRT is a well-tolerated and effective radiation technique as part of OLT protocol for unresectable CCA and conferred in a pCR rate of 44% within our cohort.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Transplante de Fígado , Radiocirurgia , Humanos , Resultado do Tratamento , Estudos Retrospectivos , Transplante de Fígado/efeitos adversos , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Colangiocarcinoma/radioterapia , Colangiocarcinoma/cirurgia , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/radioterapia , Neoplasias dos Ductos Biliares/cirurgia
3.
Hepatology ; 77(3): 774-788, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35908246

RESUMO

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.


Assuntos
Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Biomarcadores Tumorais/análise , Vesículas Extracelulares/química , Proteínas de Membrana , Eletrocardiografia , Glipicanas
5.
Drugs Today (Barc) ; 58(7): 327-334, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35851868

RESUMO

Cholangiocarcinoma (CCA) is a serious and often fatal cancer of the bile ducts of the liver with a 5-year survival rate of 5-15%. At the time of diagnosis, most patients present with advanced or metastatic CCA, which is an aggressive malignancy with a poor prognosis. The standard of care for patients with locally advanced or metastatic CCA includes systemic chemotherapy with gemcitabine and cisplatin. Recently, research in the molecular basis of cancer has led to the discovery of underlying gene alterations, allowing the development of targeted therapies. Here we provide a review of infigratinib, which is an oral small-molecule tyrosine kinase inhibitor targeting fibroblast growth factor receptor (FGFR). On the basis of positive phase II efficacy data, infigratinib received accelerated approval from the U.S. Food and Drug Administration (FDA) for adults with previously treated, unresectable locally advanced or metastatic CCA with an FGFR2 fusion or other rearrangement.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Adulto , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Humanos , Compostos de Fenilureia , Pirimidinas/uso terapêutico , Estados Unidos
6.
Liver Transpl ; 28(2): 200-214, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34664394

RESUMO

Numerous studies in hepatocellular carcinoma (HCC) have proposed tissue-based gene signatures for individualized prognostic assessments. Here, we develop a novel circulating tumor cell (CTC)-based transcriptomic profiling assay to translate tissue-based messenger RNA (mRNA) signatures into a liquid biopsy setting for noninvasive HCC prognostication. The HCC-CTC mRNA scoring system combines the NanoVelcro CTC Assay for enriching HCC CTCs and the NanoString nCounter platform for quantifying the HCC-CTC Risk Score (RS) panel in enriched HCC CTCs. The prognostic role of the HCC-CTC RS was assessed in The Cancer Genome Atlas (TCGA) HCC cohort (n = 362) and validated in an independent clinical CTC cohort (n = 40). The HCC-CTC RS panel was developed through our integrated data analysis framework of 8 HCC tissue-based gene signatures and identified the top 10 prognostic genes (discoidin domain receptor tyrosine kinase 1 [DDR1], enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase [EHHADH], androgen receptor [AR], lumican [LUM], hydroxysteroid 17-beta dehydrogenase 6[HSD17B6], prostate transmembrane protein, androgen induced 1 [PMEPA1], tsukushi, small leucine rich proteoglycan [TSKU], N-terminal EF-hand calcium binding protein 2 [NECAB2], ladinin 1 [LAD1], solute carrier family 27 member 5 [SLC27A5]) highly expressed in HCC with low expressions in white blood cells. The panel accurately discriminated overall survival in TCGA HCC cohort (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.4-2.9). The combined use of the scoring system and HCC-CTC RS panel successfully distinguished artificial blood samples spiked with an aggressive HCC cell type, SNU-387, from those spiked with PLC/PRF/5 cells (P = 0.02). In the CTC validation cohort (n = 40), HCC-CTC RS remained an independent predictor of survival (HR, 5.7; 95% CI, 1.5-21.3; P = 0.009) after controlling for Model for End-Stage Liver Disease score, Barcelona Clinic Liver Cancer stage, and CTC enumeration count. Our study demonstrates a novel interdisciplinary approach to translate tissue-based gene signatures into a liquid biopsy setting. This noninvasive approach will allow real-time disease profiling and dynamic prognostication of HCC.


Assuntos
Carcinoma Hepatocelular , Doença Hepática Terminal , Neoplasias Hepáticas , Transplante de Fígado , Células Neoplásicas Circulantes , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Células Neoplásicas Circulantes/metabolismo , Prognóstico , RNA Mensageiro/genética , Índice de Gravidade de Doença
7.
Lancet Gastroenterol Hepatol ; 6(10): 803-815, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34358484

RESUMO

BACKGROUND: Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10-16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment. METHODS: This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing. FINDINGS: Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2-15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6-32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths. INTERPRETATION: Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting. FUNDING: QED Therapeutics and Novartis.


Assuntos
Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Metástase Neoplásica/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopecia/induzido quimicamente , Alopecia/epidemiologia , Coriorretinopatia Serosa Central/induzido quimicamente , Coriorretinopatia Serosa Central/epidemiologia , Colangiocarcinoma/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Progressão da Doença , Síndromes do Olho Seco/induzido quimicamente , Síndromes do Olho Seco/epidemiologia , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Humanos , Hiperfosfatemia/induzido quimicamente , Hiperfosfatemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Descolamento Retiniano/induzido quimicamente , Descolamento Retiniano/epidemiologia , Segurança , Estomatite/induzido quimicamente , Estomatite/epidemiologia , Resultado do Tratamento , Gencitabina
8.
Adv Mater Technol ; 6(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34212072

RESUMO

Transcriptomic profiling of tumor tissues introduces a large database, which has led to improvements in the ability of cancer diagnosis, treatment, and prevention. However, performing tumor transcriptomic profiling in the clinical setting is very challenging since the procurement of tumor tissues is inherently limited by invasive sampling procedures. Here, we demonstrated the feasibility of purifying hepatocellular carcinoma (HCC) circulating tumor cells (CTCs) from clinical patient samples with improved molecular integrity using Click Chips in conjunction with a multimarker antibody cocktail. The purified CTCs were then subjected to mRNA profiling by NanoString nCounter platform, targeting 64 HCC-specific genes, which were generated from an integrated data analysis framework with 8 tissue-based prognostic gene signatures from 7 publicly available HCC transcriptomic studies. After bioinformatics analysis and comparison, the HCC CTC-derived gene signatures showed high concordance with HCC tissue-derived gene signatures from TCGA database, suggesting that HCC CTCs purified by Click Chips could enable the translation of HCC tissue molecular profiling into a noninvasive setting.

9.
Hepatol Commun ; 4(10): 1527-1540, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33024921

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of mortality. Checkpoint inhibitors of programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown great efficacy, but lack biomarkers that predict response. Circulating tumor cells (CTCs) have promise as a liquid-biopsy biomarker; however, data on HCC CTCs expressing PD-L1 have not been reported. We sought to detect PD-L1-expressing HCC-CTCs and investigated their role as a prognostic and predictive biomarker. Using an antibody-based platform, CTCs were enumerated/phenotyped from a prospective cohort of 87 patients with HCC (49 early-stage, 22 locally advanced, and 16 metastatic), 7 patients with cirrhosis, and 8 healthy controls. Immunocytochemistry identified total HCC CTCs (4',6-diamidino-2-phenylindole-positive [DAPI+]/cytokeratin-positive [CK+]/clusters of differentiation 45-negative [CD45-]) and a subpopulation expressing PD-L1 (DAPI+/CK+/PD-L1+/CD45-). PD-L1+ CTCs were identified in 4 of 49 (8.2%) early-stage patients, but 12 of 22 (54.5%) locally advanced and 15 of 16 (93.8%) metastatic patients, accurately discriminating early from locally advanced/metastatic HCC (sensitivity = 71.1%, specificity = 91.8%, area under the receiver operating characteristic curve = 0.807; P < 0.001). Compared to patients without PD-L1+ CTCs, patients with PD-L1+ CTCs had significantly inferior overall survival (OS) (median OS = 14.0 months vs. not reached, hazard ratio [HR] = 4.0, P = 0.001). PD-L1+ CTCs remained an independent predictor of OS (HR = 3.22, P = 0.010) even after controlling for Model for End-Stage Liver Disease score (HR = 1.14, P < 0.001), alpha-fetoprotein (HR = 1.55, P < 0.001), and overall stage/tumor burden (beyond University of California, San Francisco, HR = 7.19, P < 0.001). In the subset of 10 patients with HCC receiving PD-1 blockade, all 5 responders demonstrated PD-L1+ CTCs at baseline, compared with only 1 of 5 nonresponders, all of whom progressed within 4 months of starting treatment. Conclusion: We report a CTC assay for the phenotypic profiling of HCC CTCs expressing PD-L1. PD-L1+ CTCs are predominantly found in advanced-stage HCC, and independently prognosticate OS after controlling for Model for End-Stage Liver Disease, alpha-fetoprotein, and tumor stage. In patients with HCC receiving anti-PD-1 therapy, there was a strong association with the presence of PD-L1+ CTCs and favorable treatment response. Prospective validation in a larger cohort will better define the utility of PD-L1+ CTCs as a prognostic and predictive biomarker in HCC.

10.
Nat Commun ; 11(1): 4489, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895384

RESUMO

We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%).


Assuntos
Biomarcadores Tumorais/isolamento & purificação , Carcinoma Hepatocelular/diagnóstico , Detecção Precoce de Câncer/métodos , Vesículas Extracelulares/genética , Neoplasias Hepáticas/diagnóstico , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Química Click/instrumentação , Química Click/métodos , Química Computacional , Simulação por Computador , Diagnóstico Diferencial , Dimetilpolisiloxanos/química , Progressão da Doença , Detecção Precoce de Câncer/instrumentação , Feminino , Células Hep G2 , Humanos , Dispositivos Lab-On-A-Chip , Biópsia Líquida/instrumentação , Biópsia Líquida/métodos , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Pessoa de Meia-Idade , Nanoestruturas/química , Nanofios/química , Estadiamento de Neoplasias , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa/instrumentação , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
11.
Int J Reprod Biomed ; 18(8): 591-604, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32923926

RESUMO

BACKGROUND: CATSPER 1 (Cation Channel Sperm Associated 1) and CATSPER2 channels have an important role in sperm motility. In this study, the effects of hyperthyroidism on Catsper1 and 2 genes of seminiferous tubules in mice testes were investigated. OBJECTIVE: The present study was conducted to investigate the effect of hyperthyroidism on the expression of CATSPER1 and CATSPER2 genes in the seminiferous tubules of mice. MATERIALS AND METHODS: This study was conducted on 20 BALB/C male mice divided into two groups - experimental and control. The experimental group was administered with 500 mg/l levothyroxine (L-thyroxine) liquid solution for two months for inducing hyperthyroidism, which was confirmed by radioimmunoassay. On the other hand, the control group was kept in animal houses under a normal condition. The implementation of real-time polymerase chain reaction and immunohistochemical studies was accomplished after the removal of the testes of the mice under anesthesia induced by chloroform. RESULTS: Results showed that there was no significant difference in CATSPER1 (p = 0.45) and CATSPER2 (p = 0.34) gene expression between groups. At the same time, the color intensity showed no significant enhancement in the hyperthyroidism group (CATSPER1 p = 0.17 and CATSPER2 p = 0.22) as compared to the control group. CONCLUSION: Considering the key role of CATSPER in the molecular structure of the sperm, our findings showed that the hyperactivity of the thyroid gland has no significant effects on the function of these components. Therefore, it might be concluded that hyperthyroidism has no considerable effects on the seminiferous tubules.

12.
NPJ Precis Oncol ; 4: 16, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32637655

RESUMO

Somatic copy number alterations (SCNAs) are important genetic drivers of many cancers. We investigated the feasibility of obtaining SCNA profiles from circulating tumor cells (CTCs) as a molecular liquid biopsy for hepatocellular carcinoma (HCC). CTCs from ten HCC patients underwent SCNA profiling. The Cancer Genome Atlas (TCGA) SCNA data were used to develop a cancer origin classification model, which was then evaluated for classifying 44 CTCs from multiple cancer types. Sequencing of 18 CTC samples (median: 4 CTCs/sample) from 10 HCC patients using a low-resolution whole-genome sequencing strategy (median: 0.88 million reads/sample) revealed frequent SCNAs in previously reported HCC regions such as 8q amplifications and 17p deletions. SCNA profiling revealed that CTCs share a median of 80% concordance with the primary tumor. CTCs had SCNAs not seen in the primary tumor, some with prognostic implications. Using a SCNA profiling model, the tissue of origin was correctly identified for 32/44 (73%) CTCs from 12/16 (75%) patients with different cancer types.

13.
Future Oncol ; 16(30): 2375-2384, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32580579

RESUMO

Cholangiocarcinoma is an aggressive malignancy with poor overall survival. Approximately 15% of intrahepatic cholangiocarcinomas contain FGFR alterations. Infigratinib is an oral FGFR 1-3 kinase inhibitor. Favorable results from a Phase II trial of infigratinib in advanced/metastatic FGFR-altered cholangiocarcinomas has led to its further investigation in the front-line setting. In this article we describe the design, objectives and rationale for PROOF 301, a Phase III multicenter, open label, randomized trial of infigratinib in comparison to standard of care gemcitabine and cisplatin in advanced/metastatic cholangiocarcinoma with FGFR2 translocations. The results of this study have the potential to define a new role for a chemotherapy-free, targeted therapy option in the front-line setting for these patients. Clinical Trial Registration: NCT03773302 (ClincalTrials.gov).


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Protocolos Clínicos , Proteínas de Fusão Oncogênica/genética , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Humanos , Terapia de Alvo Molecular , Mutação , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/administração & dosagem , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Projetos de Pesquisa , Translocação Genética , Gencitabina
14.
Surg Oncol Clin N Am ; 28(4): 695-715, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31472914

RESUMO

In the past decade, there has been significant progress in the treatment of primary liver cancer. There has been increasing knowledge of the molecular alterations occurring in these tumors, which is now being translated into patient care. Ongoing clinical trials will further advance the therapeutic options available to patients, including the introduction of molecular targeted therapeutics and immunotherapy approaches. Critical to the success of these new drugs, is the appropriate use of them in the clinic to maximize efficacy and limit toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Imunoterapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/imunologia , Colangiocarcinoma/patologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Prognóstico
15.
Galen Med J ; 8: e1369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-34466503

RESUMO

BACKGROUND: Hyperthyroidism is one of the disorders of the thyroid gland, an organ that controls the cellular and molecular behaviors of the seminiferous tubule basement membrane (BM), and ultimately, influences its evolutionary process. We aimed to investigate the effects of hyperthyroidism on immunohistochemical characteristics and gene expression levels of collagen IV and laminin-α5 in seminiferous tubules BM of Balb/C mice. MATERIALS AND METHODS: Twenty male Balb/C mice were divided into experimental and control groups. The experimental group received 500 mg/l of levothyroxine (L-thyroxine) diluted in drinking water for two months to inducing hyperthyroidism, which was confirmed by radioimmunoassay. At the end of the study, the mice were sacrificed, and their testes were extracted for immunohistochemistry and real-time polymerase chain reaction assays. RESULTS: Although a weak reaction was observed in the experimental specimens, no significant enhancement was noted in color intensity of type IV collagen in the seminiferous tubules BM of the experimental group as compared to the control group (P>0.05). Collagen IV gene expression results in the experimental group were not significantly different from the controls (P>0.05). Thus, there was a significant increase in laminin α5 gene expression compared to the control group (P=0.016). CONCLUSION: Considering the key role of collagen IV and laminin-α5 in the seminiferous tubule BM in the testes, the results of this study indicated that hyperthyroidism has important effects on both structures and functions of these two components.

16.
Lung Cancer ; 123: 91-98, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30089602

RESUMO

OBJECTIVES: This open-label, randomized phase II trial evaluated antitumor efficacy of an antiestrogen, fulvestrant, in combination with human epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Patients with advanced or metastatic NSCLC, ECOG 0-2, previous chemotherapy unless patient refusal, and no prior EGFR-directed therapy were randomized 2:1 to erlotinib 150 mg oral daily plus 500 mg intramuscular fulvestrant on day 1, 15, 29 and every 28 days thereafter or erlotinib alone 150 mg oral daily. The primary end point was objective response rate (ORR); secondary endpoints included progression free survival (PFS) and overall survival (OS). RESULTS: Among 106 randomized patients, 100 received at least one dose of study drug. ORR was 16.4% (11 of 67 patients) for the combination versus 12.1% (4 of 33 patients) for erlotinib (p = 0.77). PFS median 3.5 versus 1.9 months [HR = 0.86, 95% CI (0.52-1.43), p = 0.29] and OS median 9.5 versus 5.8 months [HR = 0.92, 95% CI (0.57-1.48), p = 0.74] numerically favored the combination. In an unplanned subset analysis, among EGFR wild type patients (n = 51), but not EGFR mutant patients (n = 17), median PFS was 3.5 versus 1.7 months [HR = 0.35, 95% CI (0.14-0.86), p = 0.02] and OS was 6.2 versus 5.2 months [HR = 0.72, 95% CI (0.35-1.48), p = 0.37] for combined therapy versus erlotinib, respectively. Notably, EGFR WT patients were more likely to be hormone receptor-positive (either estrogen receptor α- and/or progesterone receptor-positive) compared to EGFR mutant patients (50% versus 9.1%, respectively) (p = 0.03). Treatment was well tolerated with predominant grade 1-2 dermatologic and gastrointestinal adverse effects. CONCLUSION: Addition of fulvestrant to erlotinib was well tolerated, with increased activity noted among EGFR wild type patients compared to erlotinib alone, albeit in an unplanned subset analysis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Cloridrato de Erlotinib/administração & dosagem , Feminino , Fulvestranto/administração & dosagem , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Análise de Sobrevida , Resultado do Tratamento
17.
Liver Transpl ; 24(7): 946-960, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29624843

RESUMO

Current clinicopathologic staging systems and serum biomarkers poorly discriminate tumor biology in hepatocellular carcinoma (HCC), with high recurrence rates following curative-intent surgical resection and liver transplantation (LT). Identification of accurate biomarkers for improved prognostication and treatment selection is a critical unmet need. We sought to develop a novel "liquid-biopsy" assay capable of detecting HCC circulating tumor cells (CTCs) and characterizing phenotypic subpopulations with prognostic significance. Using HCC cell lines, a tissue microarray, and human blood samples, an antibody cocktail targeting the cell-surface markers asialoglycoprotein receptor (ASGPR), glypican-3, and epithelial cell adhesion molecule was optimized for HCC CTC capture using the NanoVelcro CTC Assay. The ability of HCC CTCs and vimentin (VIM)-positive CTCs (a subpopulation expressing an epithelial-to-mesenchymal phenotype) to accurately discriminate tumor stage, recurrence, progression, and overall survival (OS) was evaluated in a prospective study of 80 patients. Multimarker capture detected greater numbers of CTCs than any individual antibody alone for both cell line and patient samples (P < 0.001). HCC CTCs were identified in 59/61 (97%) patients, and HCC (median, 6 CTCs) and non-HCC patients (median, 1 CTC; area under the receiver operating characteristic curve [AUROC] = 0.92; P < 0.001; sensitivity = 84.2%; specificity = 88.5%) were accurately discriminated. VIM-positive CTCs accurately discriminated early-stage, LT eligible patients (median, 0 CTCs) from locally advanced/metastatic, LT ineligible patients (median, 6 CTCs; AUROC = 0.89; P = 0.001; sensitivity = 87.1%; specificity = 90.0%), and predicted OS for all patients (hazard ratio [HR], 2.21; P = 0.001), and faster recurrence after curative-intent surgical or locoregional therapy in potentially curable early-stage HCC (HR, 3.14; P = 0.002). In conclusion, we developed a novel multimarker CTC enrichment assay that detects HCC CTCs with high efficiency and accuracy. A phenotypic subpopulation of VIM-positive CTCs appears to signify the presence of aggressive underlying disease and occult metastases and may have important implications for treatment selection. Liver Transplantation 24 946-960 2018 AASLD.


Assuntos
Bioensaio/métodos , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , Recidiva Local de Neoplasia/diagnóstico , Células Neoplásicas Circulantes/metabolismo , Idoso , Receptor de Asialoglicoproteína/análise , Receptor de Asialoglicoproteína/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Molécula de Adesão da Célula Epitelial/análise , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Glipicanas/análise , Glipicanas/metabolismo , Voluntários Saudáveis , Humanos , Imunoensaio/métodos , Estimativa de Kaplan-Meier , Biópsia Líquida/métodos , Cirrose Hepática/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Microfluídica/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Estudos Prospectivos , Sensibilidade e Especificidade , Análise Serial de Tecidos , Vimentina/metabolismo
18.
J Clin Oncol ; 36(3): 276-282, 2018 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-29182496

RESUMO

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Biomarcadores Tumorais/genética , Colangiocarcinoma/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/mortalidade , Colangiocarcinoma/secundário , Progressão da Doença , Esquema de Medicação , Amplificação de Genes , Fusão Gênica , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Mutação , Fenótipo , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Tempo
19.
Liver Transpl ; 23(9): 1123-1132, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28688158

RESUMO

The objective of this article is to evaluate the utility of preoperative needle biopsy (PNB) grading of hepatocellular carcinoma (HCC) as a biomarker for liver transplantation (LT) candidate selection. Given the prognostic significance of HCC tumor grade, PNB grading has been proposed as a biomarker for LT candidate selection. Clinicopathologic characteristics of HCC LT recipients (1989-2014) with a PNB were analyzed, and the concordance of PNB grade to explant grade and vascular invasion was assessed to determine whether incorporation of PNB grade to accepted transplant criteria improved candidate selection. Of 965 patients undergoing LT for HCC, 234 (24%) underwent PNB at a median of 280 days prior to transplant. Grade by PNB had poor concordance to final explant pathology (κ = 0.22; P = 0.003), and low sensitivity (29%) and positive predictive value (35%) in identifying poorly differentiated tumors. Vascular invasion was predicted by explant pathologic grade (rs= 0.24; P < 0.001) but not PNB grade (rs = -0.05; P = 0.50). Increasing explant pathology grade (P = 0.02), but not PNB grade (P = 0.65), discriminated post-LT HCC recurrence risk. The incorporation of PNB grade to the established radiologic Milan criteria (MC) did not result in improved prognostication of post-LT recurrence (net reclassification index [NRI] = 0%), whereas grade by explant pathology resulted in significantly improved reclassification of risk (NRI = 19%). Preoperative determination of HCC grade by PNB has low concordance with explant pathologic grade and low sensitivity and positive predictive value in identifying poorly differentiated tumors. PNB grade did not accurately discriminate post-LT HCC recurrence and had no utility in improving prognostication compared with the MC alone. Incorporation of PNB to guide transplant candidate selection appears unjustified. Liver Transplantation 23 1123-1132 2017 AASLD.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Transplante de Fígado/normas , Fígado/patologia , Recidiva Local de Neoplasia/epidemiologia , Seleção de Pacientes , Idoso , Biópsia por Agulha , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Fígado/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Cuidados Pré-Operatórios/métodos , Prognóstico , Estudos Prospectivos , Fatores de Risco
20.
AJR Am J Roentgenol ; 209(4): 722-732, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28705059

RESUMO

OBJECTIVE: We compared survival outcomes in 313 patients with unresectable hepatocellular carcinoma (HCC) treated with two different transcatheter arterial chemoembolization (TACE) regimens: triple-drug TACE or single-drug TACE using drug-eluting beads. MATERIALS AND METHODS: In this retrospective study, patient selection criteria were uniform. The triple-drug group (n = 166) underwent TACE using ethiodized oil with doxorubicin, cisplatin, and mitomycin-C with a microsphere embolic. The single-drug group (n = 147) underwent TACE using doxorubicin-eluting beads. Group characteristics were classified and analyzed, and survival was calculated using standard statistical methods. All patients were followed until death. Those undergoing orthotopic liver transplant (OLT) were also followed. RESULTS: There were no significant differences between the two groups in terms of demographics, Child-Pugh class, or Okuda stage. With patients undergoing OLT censored (n = 73), the mean (± standard error) survival in the triple-drug group was 23.49 ± 2.38 months, and the median survival was 16.00 ± 1.51 months. Mean survival in the single-drug bead group was 28.16 ± 2.75 months, and the median survival was 15.00 ± 1.50 months (p = 0.168). With patients undergoing OLT censored, the mean and median survival for the total cohort were 26.25 ± 1.97 and 15.00 ± 1.08 months, respectively. In the entire cohort that did not undergo OLT, patients with Child-Pugh class A disease survived significantly longer than did patients with Child-Pugh class B disease. Elevated α-fetoprotein levels were associated with shorter survival, and patients undergoing TACE with drug-eluting beads had shorter hospital stays. Although a greater percentage annual survival was observed in patients undergoing drug-eluting bead TACE who had Child-Pugh class A, Okuda stage I, and Barcelona Clinic Liver Cancer classes A and B disease starting at 36 months, this suggested survival advantage did not reach statistical significance. CONCLUSION: We found no significant survival difference in patients with unresectable HCC treated with triple-drug TACE compared with single-drug TACE using doxorubicin-eluting beads.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Microesferas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateterismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Adulto Jovem
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