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1.
Ther Adv Med Oncol ; 13: 17588359211029125, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367342

RESUMO

Background: Molecular diagnosis has become an established tool in the characterisation of adult soft-tissue sarcomas (STS). FoundationOne® Heme analyses somatic gene alterations in sarcomas via DNA and RNA-hotspot sequencing of tumour-associated genes. Methods: We evaluated FoundationOne® Heme testing in 81 localised STS including 35 translocation-associated and 46 complex-karyotyped cases from a single institution. Results: Although FoundationOne® Heme achieved broad patient coverage and identified at least five genetic alterations in each sample, the sensitivity for fusion detection was rather low, at 42.4%. Nevertheless, potential targets for STS treatment were detected using the FoundationOne® Heme assay: complex-karyotyped sarcomas frequently displayed copy-number alterations of common tumour-suppressor genes, particularly deletions in TP53, NF1, ATRX, and CDKN2A. A subset of myxofibrosarcomas (MFS) was amplified for HGF (n = 3) and MET (n = 1). PIK3CA was mutated in 7/15 cases of myxoid liposarcoma (MLS; 46.7%). Epigenetic regulators (e.g. MLL2 and MLL3) were frequently mutated. Conclusions: In summary, FoundationOne® Heme detected a broad range of genetic alterations and potential therapeutic targets in STS (e.g. HGF/MET in a subset of MFS, or PIK3CA in MLS). The assay's sensitivity for fusion detection was low in our sample and needs to be re-evaluated in a larger cohort.

2.
Soc Sci Med ; 284: 114220, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34273870

RESUMO

INTRODUCTION: Doctors and patients influence each other when interacting and, as a result, can become similar to each other in affect and behavior. In the current work, we examine whether they also become similar to each other on a moment-to-moment basis in their physiological responses. Specifically, we examine physiological linkage-how much a doctor's (or patient's) physiological response predicts a patient's (or doctor's) response at a subsequent time interval-and whether this changes over the course of doctor-patient relationships (measured as the number of consultations held for each unique doctor-patient dyad). METHODS: We collected interbeat interval responses (IBI) continuously during consultations between oncologists and patients undergoing cancer treatment (N = 102 unique doctor-patient interactions) at a hospital in Austria. RESULTS: Physiological linkage varied by an interaction between role (doctor vs. patient) and relationship length (in a non-linear, quadratic pattern). Patients showed significant positive linkage to their doctors (i.e., doctors' physiological responses positively, significantly predicted patients' responses) in relationships that spanned three to eight consultations together. Patients were not linked to their doctors in shorter or longer relationships. Doctors were never significantly linked to their patients, meaning that patients' physiological responses never predicted doctors' responses. CONCLUSION: These results reveal that, by influencing patients' physiological responses on a moment-to-moment basis, doctors may have even more influence over patients' physiology than previously known.


Assuntos
Neoplasias , Médicos , Áustria , Humanos , Neoplasias/terapia , Relações Médico-Paciente , Encaminhamento e Consulta , Inquéritos e Questionários
3.
Br J Cancer ; 124(11): 1795-1802, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33762716

RESUMO

BACKGROUND: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences. METHODS: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint. RESULTS: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation. CONCLUSION: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

4.
Cancers (Basel) ; 12(8)2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32824580

RESUMO

BACKGROUND: Biomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. METHODS: We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort (n = 90), confirm these findings in an external validation cohort (n = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively. RESULTS: In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16-1.63, p < 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18-1.71, p < 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51-0.92, p = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15-1.30, p < 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14-154.54, p = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83-0.99, p = 0.036), respectively. CONCLUSION: These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.

5.
Ann Surg Oncol ; 26(13): 4274-4283, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31452052

RESUMO

BACKGROUND: Assessing the residual cancer burden (RCB) predictive performance, the potential subgroup effects, and time-dependent impact on breast cancer patients who underwent neoadjuvant therapy in a developer's independent cohort is essential for its usage in clinical routine. METHODS: Between 2011 and 2016, the RCB scores of 184 female breast cancer patients were prospectively collected, and subsequent clinicopathological and follow-up data were obtained retrospectively. Recurrence-free survival (RFS), overall survival (OS), as well as subgroup analysis, and time-dependent variables were calculated with multivariate, complex, or linear statistical models. RESULTS: A total of 184 patients (HER2 33%, TNBC 27%), with a mean follow-up time of 4 years, treated with neoadjuvant systemic therapy (92% anthracycline-taxane based) were analyzed revealing 43 events (38 recurrences, 28 deaths). High RCB scores were associated with recurrence (median index: 2.34 vs. 1.39 points, rank-sum p < 0.0001), decreased RFS (hazard ratio [HR] = 1.80, 95% confidence interval [CI] 1.44-2.24, p < 0.0001) and reduced OS (HR 1.96, 95% CI 1.49-2.59, p < 0.0001). The RCB score showed proportionality of hazards (interaction HR with linear follow-up time = 1.00, p = 0.896) and good discriminating power (Harrell's c index 0.7). CONCLUSIONS: Our results confirm the RCB score as externally valid prognostic marker and being independent of molecular subtype for RFS and OS in a clinical setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Terapia Neoadjuvante/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
6.
Breast Cancer Res ; 21(1): 20, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30709367

RESUMO

BACKGROUND: Non-coding RNAs and especially microRNAs have been discovered to act as master regulators of cancer initiation and progression. The aim of our study was to discover and characterize the function of yet functionally uncharacterized microRNAs in human breast carcinogenesis. METHODS: In an unbiased approach, we utilized an established model system for breast cancer (BC) stem cell formation ("mammosphere assay") to identify whole miRNome alterations in breast carcinogenesis. Clinical samples of BC patients were used to evaluate the human relevance of the newly identified miRNA candidates. One promising candidate, miR-1287-5p, was further explored on its impact on several hallmarks of cancer. The molecular mode of action was characterized by whole transcriptome analysis, in silico prediction tools, miRNA-interaction assays, pheno-copy assays, and drug sensitivity assays. RESULTS: Among several other microRNAs, miR-1287-5p was significantly downregulated in mammospheres and human BC tissue compared to normal breast tissue (p < 0.0001). Low expression levels were significantly associated with poor prognosis in BC patients. MiR-1287-5p significantly decreased cellular growth, cells in S phase of cell cycle, anchorage-independent growth, and tumor formation in vivo. In addition, we identified PIK3CB as a direct molecular interactor of miR-1287-5p and a novel prognostic factor in BC. Finally, PI3Kinase pathway chemical inhibitors combined with miR-1287-5p mimic increased the pharmacological growth inhibitory potential in triple negative BC cells. CONCLUSION: Our data identified for the first time the involvement of miR-1287-5p in human BC and suggest a potential for therapeutic interventions in difficult to treat triple negative BC.


Assuntos
Carcinogênese/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Animais , Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Clin Chem Lab Med ; 57(5): 740-744, 2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-30307891

RESUMO

Background Platelets are a major cellular component of blood and their interaction with cancer cells is well-established to influence cancer progression and metastases. The physical size of platelets may have a critical impact on the interaction with cancer cells. In this study, we explored the potential prognostic role of platelet size measured by the determination of the mean platetlet volume (MPV) in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Data from 527 patients with PDAC diagnosed and treated between 2004 and 2015 at a single center were evaluated retrospectively. Associations between MPV and baseline covariates were assessed with Wilcoxon's rank-sum tests, χ2-tests, and Fisher's exact tests. Median follow-up was estimated with a reverse Kaplan-Meier estimator according to Schemper and Smith. Analysis of time-to-death was performed with Kaplan-Meier estimators, log-rank tests and uni- and multivariable Cox proportional hazards models. Results The median MPV was 10.5 femto liter (fL) [9.8-11.3], ranged from 5.9 to 17.7 fL. A large platelet volume was associated with high-grade G3/4 tumors (p=0.004) and worse overall survival (OS) in patients with metastatic disease in univariable analysis (hazard ratio [HR] per fL increase in MPV=1.13 [95% CI: 1.04-1.23, p=0.005]). In multivariable analysis of metatatic PDAC patients, the adverse association between large platelets and a higher risk-of-death prevailed (adjusted HR per doubling of MPV=2.00; 95% CI: 1.10-3.62, p=0.02). Conclusions Large platelets represent a negative prognostic factor and add an independent prognostic information to well-established factors in PDAC patients. MPV should be considered for future individual risk assessment in patients with stage IV PDAC.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Volume Plaquetário Médio , Neoplasias Pancreáticas/diagnóstico , Idoso , Plaquetas/patologia , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
8.
ESMO Open ; 3(4): e000381, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018811

RESUMO

Purpose: TrasGEX is a second-generation monoclonal antibody of trastuzumab, glyco-optimised to enhance antibody-dependent cellular cytotoxicity while fully retaining trastuzumab's antigen-binding properties to human epidermal growth factor receptor 2 (HER2). A phase I dose-escalation study was conducted to establish the optimal TrasGEX dose and regimen for phase II studies and to define the safety, pharmacokinetics (PK) and preliminary antitumour activity of TrasGEX. Patients and methods: A total of 37 patients with advanced HER2-positive carcinomas and progressive disease received TrasGEX intravenously every 3 weeks until disease progression in doses of 12-720 mg in a three-plus-three dose escalation design, including an expansion cohort at the highest dose. Results: No dose limiting toxicity was observed, and no maximum tolerated dose was reached. Drug-related adverse events were mainly infusion-related reactions occurring during the first infusion in 51% of patients; all but two were mild-to-moderate. Compared with trastuzumab, the PK parameters were dose dependent, with a mean terminal half-life (t1/2) of 263±99 hours for the 720 mg dose. Clinical benefit in 15 out of 30 (50%) evaluable patients included one ongoing complete response, two partial remissions lasting 16 and 77 weeks and disease stabilisation (SD) in 12 patients lasting a median (range) of 17 (7-26) weeks; three of them had SD of 24, 25 and 26 weeks, respectively. Conclusion: TrasGEX was safe, well-tolerated and showed antitumour activity in 50% of evaluable patients, all with progressive disease at study entry. Infusions at an interval of 2-3 weeks should achieve clinically relevant trough levels for future studies (NCT01409343).

9.
Virchows Arch ; 472(4): 589-598, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29520483

RESUMO

Squamous cell and adenocarcinomas of the lung develop different mechanisms during carcinogenesis to evade attacks of the immune system. Besides the well-known check-point control programmed death 1 and its ligand, many more mechanisms, acting either tumoricidal or in favor of tumor progression, exist. Analysis of the immune cell profiles in resected tissues and bronchoalveolar lavage samples and correlation between them and with overall survival data was performed. In all tumor samples in this study, cells of the immune system expressed a tumor-cooperating phenotype. High numbers of regulatory T cells, or alternatively expression of Vista on lymphocytes was present. Tumoricidal dendritic cells were absent in tumor tissue, and barely present in bronchoalveolar lavage, whereas tumor-friendly monocytoid and plasmocytoid dendritic cells were seen in both. Alveolar macrophages were predominantly differentiated into tumor-cooperating M2 types, whereas tumoricidal M1 macrophages were absent or rare. The expression of PDL1 on tumor cells did not correlate with any other immune cells. Expression of PD1 on lymphocytes was frequently encountered. None of analyzed immune cells showed correlation with overall survival. Immune cells in bronchoalveolar lavage and tissue did not correlate. For the first time, a tissue-based analysis of different immune cells in squamous cell and adenocarcinomas of the lung is provided, trying to explain their potential role in tumor development and progression. Discordant numbers of cells with bronchoalveolar lavage are most probably due to the fact that bronchoalveolar lavage reflects the situation in the whole lung, where chronic obstructive lung disease and other conditions are present.


Assuntos
Adenocarcinoma/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias Pulmonares/imunologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino
10.
Oncotarget ; 8(54): 92483-92496, 2017 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-29190932

RESUMO

Blood-based biomarkers such as circulating tumor cells (CTCs) provide dynamic real-time assessment of molecular tumor characteristics beyond the primary tumor. The aim of this study was to evaluate the feasibility of a size-based microfilter to assess multigene methylation analysis of enriched CTCs in a prospective proof-of principle study. We examined the quantitative methylation status of nine genes (AKR1B1, BMP6, CST6, HOXB4, HIST1H3C, ITIH5, NEUROD1, RASSF1, SOX17) in enriched CTCs from metastatic breast cancer patients. Feasibility and clinical performance testing were assessed in a test set consisting of 37 patients and 25 healthy controls. With established cut-off values from the healthy control group, methylation of enriched CTCs was detected in at least one gene in 18/37 patients (48.6%), while 97.8% of all control samples were unmethylated. Patients with CTCs unmethylated for CST6, ITIH5, or RASSF1 showed significantly longer PFS compared to patients with corresponding enriched methylated CTCs. This proof-of-principle study shows the feasibility of a size-based microfilter to enrich and analyze multigene methylation profile of CTCs from metastatic breast cancer patients. For the first time, we report that multigene methylation analysis of enriched CTCs provides prognostic information in metastatic breast cancer patients.

11.
PLoS One ; 12(11): e0187814, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29121666

RESUMO

SOX9 has been previously shown to be involved in hepatocellular carcinoma (HCC) and other types of cancer. However, prognostic studies so far involved rather small cohorts or lack external validation and experimental data. In this study, we firstly determined the histological expression pattern of SOX9 in human HCC by immunohistochemistry (n = 84) and evaluated its prognostic value. External cohorts of publicly available datasets were used to validate its prognostic relevance in HCC (n = 359) and other types of cancer including breast (n = 3951), ovarian (n = 1306), lung (n = 1926) and gastric cancer (n = 876). Functional SOX9 knock-down studies using siRNA and cancer stem cell models were generated in a panel of liver and breast cancer cell lines. High level of SOX9 was associated with poor survival even after adjustment for other prognostic factors in multivariate analysis (HR = 2.103, 95%CI = 1.064 to 4.156, p = 0.021). SOX9 prevailed a poor prognostic factor in all cancer validation cohorts (p<0.05). Reduced SOX9 expression by siRNA decreased the growth of liver cancer cells (p<0.05). SOX9 expression was associated with stem cell features in all tested cell lines (p<0.05). In conclusion, this study demonstrated in a large number of patients from multiple cohorts that high levels of SOX9 are a consistent negative prognostic factor.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/patologia , Fatores de Transcrição SOX9/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição SOX9/genética
12.
Sci Rep ; 7(1): 10040, 2017 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-28855609

RESUMO

The cancer stem cell (CSC) and epithelial-to-mesenchymal transition (EMT) models have been closely associated and used to describe both the formation of metastasis and therapy resistance. We established a primary lung cell culture from a patient in a clinically rare and unique situation of primary resistant disease. This culture consisted of two biologically profoundly distinct adenocarcinoma cell subpopulations, which differed phenotypically and genotypically. One subpopulation initiated and sustained in spheroid cell culture (LT22s) whereas the other subpopulation was only capable of growth and proliferation under adherent conditions (LT22a). In contrast to our expectations, LT22s were strongly associated with the epithelial phenotype, and expressed additionally CSC markers ALDH1 and CD133, whereas the LT22a was characterized as mesenchymal with lack of CSC markers. The LT22s cells also demonstrated an invasive behavior and mimicked gland formation. Finally, LT22s were more resistant to Cisplatin than LT22a cells. We demonstrate a primary lung adenocarcinoma cell culture derived from a patient with resistant disease, with epithelial aggressive subpopulation of cells associated with stem cell features and therapy resistance. Our findings challenge the current model associating CSC and disease resistance mainly to mesenchymal cells and may have important clinical implications.


Assuntos
Adenocarcinoma/patologia , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/patologia , Antígeno AC133/genética , Antígeno AC133/metabolismo , Adulto , Família Aldeído Desidrogenase 1 , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Galinhas , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Células Tumorais Cultivadas
13.
Clin Cancer Res ; 23(17): 5255-5266, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28533224

RESUMO

Purpose: miR-196b-5p has been previously implicated in malignant transformation; however, its role in colorectal cancer has not been fully explored. In this study, we examine the clinical and biological relevance of miR-196b-5p, and the molecular pathways regulated by miR-196b-5p in colorectal cancer.Experimental Design: miR-196b-5p expression was quantitated by qRT-PCR in 2 independent cohorts composed of 292 patients with colorectal cancer in total, to explore its biomarker potential. Transient and stable gain- and loss-of-function experiments were conducted in a panel of colorectal cancer cell lines and mice, to evaluate the impact of miR-196b-5p on proliferation, chemosensitivity, migration/invasion, and metastases formation in vitro and in vivo The molecular pathways influenced by miR-196b-5p were characterized using whole transcriptome profiling, in silico target prediction tools, luciferase interaction assays, and phenocopy/rescue gene knockdown experiments.Results: Low miR-196b-5p expression was significantly associated with metastases and poor outcomes in 2 independent colorectal cancer patient cohorts (P < 0.05, log-rank test). miR-196b-5p inhibition led to significantly increased colorectal cancer cell migration/invasion and metastases formation in mice, whereas ectopic overexpression showed the opposite phenotype. Molecular profiling and target confirmation identified an interaction between miR-196b-5p and HOXB7 and GALNT5, which in turn regulated colorectal cancer cell migration.Conclusions: The association of low levels of miR-196b-5p and poor prognosis in patients with colorectal cancer can be explained by its influence on cancer cell migration and metastases formation. miR-196b-5p has an impact on colorectal cancer progression pathways through direct interaction with genes involved in cancer cell migration. Clin Cancer Res; 23(17); 5255-66. ©2017 AACR.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Homeodomínio/genética , MicroRNAs/genética , N-Acetilgalactosaminiltransferases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Lancet Oncol ; 12(7): 631-41, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21641868

RESUMO

BACKGROUND: Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid. METHODS: ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3.6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing. FINDINGS: At a median follow-up of 62 months (range 0-114.4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0.68, 95% CI 0.51-0.91; p=0.009), although the difference was not significant in the tamoxifen (HR 0.67, 95% CI 0.44-1.03; p=0.067) and anastrozole arms (HR 0.68, 95% CI 0.45-1.02; p=0.061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0.67, 95% CI 0.41-1.07; p=0.09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1.08, 95% CI 0.81-1.44; p=0.591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1.75, 95% CI 1.08-2.83; p=0.02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121). INTERPRETATION: Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer. FUNDING: AstraZeneca; Novartis.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Adulto , Anastrozol , Antineoplásicos Hormonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nitrilas/uso terapêutico , Pré-Menopausa , Tamoxifeno/uso terapêutico , Resultado do Tratamento , Triazóis/uso terapêutico , Ácido Zoledrônico
16.
J Clin Oncol ; 29(19): 2653-9, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21555684

RESUMO

PURPOSE: Aromatase inhibitors are effective as endocrine treatment for patients with hormone receptor-positive breast cancer. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial. PATIENTS AND METHODS: ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg subcutaneously every 28 days) in combination with anastrozole or tamoxifen with or without zoledronic acid (4 mg intravenously every 6 months) in premenopausal women with endocrine-responsive breast cancer. BMI was calculated using the prospectively collected data on patients' height and weight at study entry. BMI categories have been differentiated according to the WHO definition. RESULTS: Overweight patients treated with anastrozole had a 60% increase in the risk of disease recurrence (hazard ratio [HR], 1.60; 95% CI, 1.06 to 2.41; P = .02) and more than a doubling in the risk of death (HR, 2.14; 95% CI, 1.17 to 3.92; P = .01) compared with normal weight patients treated with anastrozole. In the overweight group, patients treated with anastrozole had a nearly 50% increase in the risk of disease recurrence (HR, 1.49; 95% CI, 0.93 to 2.38; P = .08) and a three-fold increase in the risk of death (HR, 3.03; 95% CI, 1.35 to 6.82; P = .004) compared with patients treated with tamoxifen. CONCLUSION: BMI significantly impacts on the efficacy of anastrozole plus goserelin in premenopausal patients with breast cancer, probably through influencing aromatase availability and/or ovarian suppression by goserelin.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Gosserrelina/administração & dosagem , Nitrilas/administração & dosagem , Triazóis/administração & dosagem , Adulto , Anastrozol , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Índice de Massa Corporal , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Menopausa , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Risco , Tamoxifeno/farmacologia , Resultado do Tratamento
17.
Case Rep Oncol ; 3(2): 287-93, 2010 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-21347195

RESUMO

Desmoid tumors, also known as aggressive fibromatosis, are tumors of intermediate dignity, which grow slowly but are locally aggressive. These tumors do not metastasize but can be potentially life threatening when infiltrating vital structures. The therapy strategy consists of surgery, radiation and systemic therapy with non-steroidal anti-inflammatory drugs, antiestrogen compounds and cytotoxic chemotherapy. We report on a 40-year-old male patient with advanced fibromatosis of the neck who has been treated with 7 cycles of polychemotherapy (adriablastin, ifosfamide and dacarbazine) followed by targeted therapy with imatinib. Tumor response was evaluated clinically and by magnetic resonance imaging. The tumor decreased significantly after the first cycle of chemotherapy and tumor-related symptoms declined. The response continued after switching to targeted therapy with imatinib, which is currently ongoing. The best treatment for this rare tumor remains under discussion. Doxorubicin and dacarbazine are frequently used agents. We included ifosfamide in our therapy, which is standard in the treatment of soft tissue tumors. The tyrosine kinase inhibitor imatinib seems to offer new possibilities and is currently investigated in randomized trials. We conclude that combination chemotherapy including doxorubicin, ifosfamide and dacarbazine in the treatment of aggressive fibromatosis should be considered for patients suffering from unresectable, advanced disease and clinical symptoms which require a rapid response to therapy.

18.
BMC Cancer ; 6: 1, 2006 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-16390557

RESUMO

BACKGROUND: Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. CASE PRESENTATION: We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m2 of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. CONCLUSION: To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Plasmaferese/métodos , Antineoplásicos/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/sangue , Feminino , Perda Auditiva/induzido quimicamente , Humanos , Fígado/enzimologia , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Insuficiência Renal/induzido quimicamente , Fatores de Tempo , Vômito/induzido quimicamente
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