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1.
J Immunother Cancer ; 9(2)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33589521

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSC), a cornerstone of cancer-related immunosuppression, influence response to therapy and disease outcomes in melanoma patients. Nevertheless, their quantification is far from being integrated into routine clinical practice mostly because of the complex and still evolving phenotypic signatures applied to define the cell subsets. Here, we used a multistep downsizing process to verify whether a core of few markers could be sufficient to capture the prognostic potential of myeloid cells in peripheral blood mononuclear cells (PBMC) of metastatic melanoma patients. METHODS: In baseline frozen PBMC from a total of 143 stage IIIc to IV melanoma patients, we first assessed the relevant or redundant expression of myeloid and MDSC-related markers by flow cytometry (screening set, n=23 patients). Subsequently, we applied the identified panel to the development set samples (n=59 patients undergoing first/second-line therapy) to obtain prognostic variables associated with overall survival (OS) and progression-free survival (PFS) by machine learning adaptive index modeling. Finally, the identified score was confirmed in a validation set (n=61) and compared with standard clinical prognostic factors to assess its additive value in patient prognostication. RESULTS: This selection process led to the identification of what we defined myeloid index score (MIS), which is composed by four cell subsets (CD14+, CD14+HLA-DRneg, CD14+PD-L1+ and CD15+ cells), whose frequencies above cut-offs stratified melanoma patients according to progressively worse prognosis. Patients with a MIS=0, showing no over-threshold value of MIS subsets, had the best clinical outcome, with a median survival of >33.6 months, while in patients with MIS 1→3, OS deteriorated from 10.9 to 6.8 and 6.0 months as the MIS increased (p<0.0001, c-index=0.745). MIS clustered patients into risk groups also according to PFS (p<0.0001). The inverse correlation between MIS and survival was confirmed in the validation set, was independent of the type of therapy and was not interfered by clinical prognostic factors. MIS HR was remarkably superior to that of lactate dehydrogenase, tumor burden and neutrophil-to-lymphocyte ratio. CONCLUSION: The MIS >0 identifies melanoma patients with a more aggressive disease, thus acting as a simple blood biomarker that can help tailoring therapeutic choices in real-life oncology.

2.
NPJ Breast Cancer ; 6(1): 60, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33298933

RESUMO

We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I-III BC (N = 275,836) between 1989 and 2017 were identified from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04-1.17), and lower compared with stage I BC without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82-0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38 (95% CI = 1.35-1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46-3.13) when not screen-detected. The C-index was 0.52 (95% CI = 0.50-0.54) for invasive CBC prediction in DCIS patients. In conclusion, CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information is needed to differentiate CBC risks among DCIS patients.

3.
Am J Hum Genet ; 107(5): 837-848, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022221

RESUMO

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

4.
Breast Cancer Res Treat ; 181(2): 423-434, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32279280

RESUMO

BACKGROUND: Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). METHODS: We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. RESULTS: The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. CONCLUSIONS: Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making.


Assuntos
Neoplasias da Mama/patologia , Tomada de Decisão Clínica , Segunda Neoplasia Primária/patologia , Medição de Risco/métodos , Adulto , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Agências Internacionais , Mastectomia , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/cirurgia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Fatores de Risco
6.
Breast Cancer Res ; 21(1): 144, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847907

RESUMO

BACKGROUND: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. METHODS: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. RESULTS: In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52-0.74; at 10 years, 0.53-0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62-1.37), and the calibration slope was 0.90 (95% PI: 0.73-1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52-0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Área Sob a Curva , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Mutação em Linhagem Germinativa , Humanos , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/prevenção & controle , Países Baixos/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco
7.
Breast Cancer Res ; 21(1): 90, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391067

RESUMO

INTRODUCTION: The presence of tumor-infiltrating lymphocytes (TILs) is correlated with good prognosis and outcome after (immuno)therapy in triple-negative and HER2-positive breast cancer. However, the role of TILs in luminal breast cancer is less clear. Emerging evidence has now demonstrated that genetic aberrations in malignant cells influence the immune landscape of tumors. Phosphatidylinositol 3-kinase (PI3K) is the most common altered pathway in ER-positive breast cancer. It is unknown whether changes in the PI3K pathway result in a different composition of the breast tumor microenvironment. Here we present the retrospective analysis of a prospective randomized trial in ER-positive breast cancer on the prognostic and predictive value of specific tumor-associated lymphocytes in the context of PI3K alterations. METHODS: We included 563 ER-positive tumors from a multicenter trial for stage I to III postmenopausal breast cancer patients, who were randomized to tamoxifen or no adjuvant therapy. The amount of CD8-, CD4-, and FOXP3-positive cells was evaluated by immunohistochemistry and quantified by imaging-analysis software. We analyzed the associations between PIK3CA hotspot mutations, PTEN expression, phosphorylated proteins of the PI3K and MAPK pathway (p-AKT, p-ERK1/2, p-4EBP1, p-p70S6K), and recurrence-free interval after adjuvant tamoxifen or no adjuvant treatment. RESULTS: CD8-positive lymphocytes were significantly more abundant in PIK3CA-mutated tumors (OR = 1.65; 95% CI 1.03-2.68). While CD4 and FOXP3 were not significantly associated with prognosis, patients with tumors classified as CD8-high had increased risk of recurrence (HR = 1.98; 95% CI 1.14-3.41; multivariable model including PIK3CA status, treatment arm, and other standard clinicopathological variables). Lymphocytes were more often present in tumors with increased PI3K downstream phosphorylation. This was most pronounced for FOXP3-positive cells. CONCLUSION: These exploratory analyses of a prospective trial in luminal breast cancer suggest high CD8 infiltration is associated with unfavorable outcome and that PI3K pathway alterations might be associated with the composition of the tumor microenvironment.


Assuntos
Biomarcadores Tumorais , Suscetibilidade a Doenças , Neoplasias/etiologia , Neoplasias/metabolismo , Receptores Estrogênicos/metabolismo , Suscetibilidade a Doenças/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Mutação , Estadiamento de Neoplasias , Neoplasias/mortalidade , Neoplasias/patologia , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Transcriptoma
8.
Oncologist ; 24(7): e467-e474, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30606886

RESUMO

BACKGROUND: The aim was to study the impact of comorbidities and age on breast cancer mortality, taking into account competing causes of death. SUBJECTS, MATERIALS, AND METHODS: Cohort analysis of Dutch and Belgian patients with postmenopausal, early hormone receptor-positive breast cancer included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. This is a randomized controlled trial of patients who had completed local treatment with curative intent and were randomized to receive exemestane for 5 years, or sequential treatment of tamoxifen followed by exemestane for a duration of 5 years. Patients were categorized by number of comorbidities (no comorbidities, 1-2 comorbidities, and >2 comorbidities) and age (<70 years and ≥70 years). Main outcome was breast cancer mortality considering other-cause mortality as competing event; cumulative incidences were calculated using the Cumulative Incidence Competing Risk Methods, and the Fine and Gray model was used to calculate the effect of age and comorbidities for the cause-specific incidences of breast cancer death, taking into account the effect of competing causes of death. RESULTS: Overall, 3,159 patients were included, of which 2,203 (69.7%) were aged <70 years and 956 (30.3%) were aged ≥70 years at diagnosis. Cumulative incidence of breast cancer mortality was higher among patients ≥70 without comorbidities (22.2%, 95% CI, 17.5-26.9) compared with patients <70 without comorbidities (15.6%, 95% CI, 13.6-17.7, reference group), multivariable subdistribution hazard ratio (sHR) 1.49 (95% CI, 1.12-1.97, p = .005) after a median follow-up of 10 years. Use of chemotherapy was lower in older patients (1%, irrespective of the number of comorbidities) compared with younger patients (50%, 44%, and 38% for patients with no, 1-2, or >2 comorbidities, p < .001). CONCLUSION: Older patients without comorbidities have a higher risk of dying due to breast cancer than younger counterparts, even when taking into account higher competing mortality, while use of chemotherapy in this group was low. These findings underline the need to take into account comorbidities, age, and competing mortality in the prognosis of breast cancer for accurate decision making. IMPLICATIONS FOR PRACTICE: Older patients without comorbidity are at increased risk of dying from breast cancer, despite a higher other-cause mortality. This study shows that including age and comorbidity for the assessment of breast cancer mortality and other-cause mortality is indispensable for treatment decision making in older patients. Future prognostic tools for breast cancer prognosis should incorporate these items as well as risk of toxicity of adjuvant chemotherapy to adequately predict outcomes to optimize personalized treatment for older patients with early breast cancer.


Assuntos
Neoplasias da Mama/mortalidade , Causas de Morte/tendências , Fatores Etários , Comorbidade , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa
9.
Breast ; 44: 1-14, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30580169

RESUMO

BACKGROUND: The risk of developing metachronous contralateral breast cancer (CBC) is a recurrent topic at the outpatient clinic. We aimed to provide CBC risk estimates of published patient, pathological, and primary breast cancer (PBC) treatment-related factors. METHODS: PubMed was searched for publications on factors associated with CBC risk. Meta-analyses were performed with grouping of studies by mutation status (i.e., BRCA1, BRCA2, CHEK2 c.1100delC), familial cohorts, and general population-based cohorts. RESULTS: Sixty-eight papers satisfied our inclusion criteria. Strong associations with CBC were found for carrying a BRCA1 (RR = 3.7; 95%CI:2.8-4.9), BRCA2 (RR = 2.8; 95%CI:1.8-4.3) or CHEK2 c.1100delC (RR = 2.7; 95%CI:2.0-3.7) mutation. In population-based cohorts, PBC family history (RR = 1.8; 95%CI:1.2-2.6), body mass index (BMI) ≥30 kg/m2 (RR = 1.5; 95%CI:1.3-1.9), lobular PBC (RR = 1.4; 95%CI:1.1-1.8), estrogen receptor-negative PBC (RR = 1.5; 95%CI:1.0-2.3) and treatment with radiotherapy <40 years (RR = 1.4; 95%CI:1.1-1.7) was associated with increased CBC risk. Older age at PBC diagnosis (RR per decade = 0.93; 95%CI:0.88-0.98), and treatment with chemotherapy (RR = 0.7; 95%CI:0.6-0.8) or endocrine therapy (RR = 0.6; 95%CI:0.5-0.7) were associated with decreased CBC risk. CONCLUSIONS: Mutation status, family history, and PBC treatment are key factors for CBC risk. Age at PBC diagnosis, BMI, lobular histology and hormone receptor status have weaker associations and should be considered in combination with key factors to accurately predict CBC risk.


Assuntos
Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medição de Risco , Fatores de Risco , Carga Tumoral
11.
Eur Urol ; 71(2): 281-289, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27726966

RESUMO

BACKGROUND: The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients. OBJECTIVE: To develop a new model based on real-world patients. DESIGN, SETTING, AND PARTICIPANTS: Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011. INTERVENTION: First-line, platinum-based, combination chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms. RESULTS AND LIMITATIONS: A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p<0.001), white blood cell count (p=0.013), body mass index (p=0.003), ethnicity (p=0.012), lung, liver, or bone metastases (p<0.001), and prior perioperative chemotherapy (p=0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p<0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670). CONCLUSIONS: We developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC. PATIENT SUMMARY: We proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Cisplatino/administração & dosagem , Nomogramas , Neoplasias Urológicas/tratamento farmacológico , Idoso , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/secundário , Feminino , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Distribuição Aleatória , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia , Neoplasias Urológicas/secundário
12.
Stem Cells ; 34(10): 2449-2460, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27301067

RESUMO

Melanoma is a highly heterogeneous tumor for which recent evidence supports a model of dynamic stemness. Melanoma cells might temporally acquire tumor-initiating properties or switch from a status of tumor-initiating cells (TICs) to a more differentiated one depending on the tumor context. However, factors driving these functional changes are still unknown. We focused on the role of cyto/chemokines in shaping TICs isolated directly from tumor specimens of two melanoma patients, namely Me14346S and Me15888S. We analyzed the secretion profile of TICs and of their corresponding melanoma differentiated cells and we tested the ability of cyto/chemokines to influence TIC self-renewal and differentiation. We found that TICs, grown in vitro as melanospheres, had a complex secretory profile as compared to their differentiated counterparts. Some factors, such as CCL-2 and IL-8, also produced by adherent melanoma cells and melanocytes did not influence TIC properties. Conversely, IL-6, released by differentiated cells, reduced TIC self-renewal and induced TIC differentiation while IL-10, produced by Me15888S, strongly promoted TIC self-renewal through paracrine/autocrine actions. Complete neutralization of IL-10 activity by gene silencing and antibody-mediated blocking of the IL-10Rα was required to sensitize Me15888S to IL-6-induced differentiation. For the first time these results show that functional heterogeneity of melanoma could be directly influenced by inflammatory and suppressive soluble factors, with IL-6 favoring TIC differentiation, and IL-10 supporting TIC self-renewal. Thus, understanding the tumor microenvironment (TME) role in modulating melanoma TIC phenotype is fundamental to identifying novel therapeutic targets to achieve long-lasting regression of metastatic melanoma. Stem Cells 2016;34:2449-2460.


Assuntos
Linhagem da Célula/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Melanoma/patologia , Células-Tronco Neoplásicas/patologia , Comunicação Autócrina/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Melanoma/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Testes de Neutralização , Comunicação Parácrina/efeitos dos fármacos , Fenótipo , Receptores de Quimiocinas/metabolismo , Esferoides Celulares/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Vet Res Commun ; 40(2): 81-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27142053

RESUMO

In this study, we investigated the dynamics of Mycoplasma hyopneumoniae infections in 66 pig farms, with different production systems (one-, two-, and three-site systems), and considered different risk factors. Serological assay was used to detect serum antibodies against M. hyopneumoniae and real time polymerase chain reaction (RT-PCR) was performed to detect M. hyopneumoniae DNA in tracheobronchial swabs. Results demonstrated that M. hyopneumoniae infection status was predominantly influenced by the age of the animals and the type of production system. Infection rates were higher in older animals and the prevalence was higher in the one- and two-site systems than in the three-site systems. Dynamics of infection by RT-PCR showed that earlier M. hyopneumoniae infection on one-site farms occurs earlier, while on two- and three-site farms occurs later but spreads faster, suggesting that contact between animals of different age favors the transmission.


Assuntos
Criação de Animais Domésticos , Pneumonia Suína Micoplasmática/imunologia , Pneumonia Suína Micoplasmática/patologia , Pneumonia Suína Micoplasmática/transmissão , Fatores Etários , Animais , Anticorpos Antibacterianos/sangue , Mycoplasma hyopneumoniae/genética , Mycoplasma hyopneumoniae/imunologia , Pneumonia Suína Micoplasmática/sangue , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Soroconversão , Suínos
14.
Pediatr Blood Cancer ; 63(3): 479-85, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26797893

RESUMO

BACKGROUND: The potential impact of diagnostic delays on patients' outcomes is a debated issue in pediatric oncology and discordant results have been published so far. We attempted to tackle this issue by analyzing a prospective series of 351 consecutive children and adolescents with solid malignancies using innovative statistical tools. METHODS: To address the nonlinear complexity of the association between symptom interval and overall survival (OS), a regression tree algorithm was constructed with sequential binary splitting rules and used to identify homogeneous patient groups vis-à-vis functional relationship between diagnostic delay and OS. RESULTS: Three different groups were identified: group A, with localized disease and good prognosis (5-year OS 85.4%); group B, with locally or regionally advanced, or metastatic disease and intermediate prognosis (5-year OS 72.9%), including neuroblastoma, Wilms tumor, non-rhabdomyosarcoma soft tissue sarcoma, and germ cell tumor; and group C, with locally or regionally advanced, or metastatic disease and poor prognosis (5-year OS 45%), including brain tumors, rhabdomyosarcoma, and bone sarcoma. The functional relationship between symptom interval and mortality risk differed between the three subgroups, there being no association in group A (hazard ratio [HR]: 0.96), a positive linear association in group B (HR: 1.48), and a negative linear association in group C (HR: 0.61). CONCLUSIONS: Our analysis suggests that at least a subset of patients can benefit from an earlier diagnosis in terms of survival. For others, intrinsic aggressiveness may mask the potential effect of diagnostic delays. Based on these findings, early diagnosis should remain a goal for pediatric cancer patients.


Assuntos
Neoplasias/diagnóstico , Neoplasias/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/mortalidade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
15.
Urol Oncol ; 33(7): 332.e19-24, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25985712

RESUMO

OBJECTIVES: Approximately one-third of the metastatic germ cell tumors (GCT) in patients are classified as intermediate-risk metastatic GCT, and available guidelines recommend the same treatment of poor-risk cases. Yet the prognosis of these patients is heterogeneous, and consequently refining the intensity of treatment is warranted. We aimed to address the heterogeneity of this category by providing a proof of principle for reclassification attempt. PATIENTS AND METHODS: Data on consecutive patients with intermediate-risk metastatic GCT and who received treatment at Fondazione INT Milano in the time frame between February 1980 and March 2014 were collected. Cox regression analyses were done, evaluating potential prognostic factors for overall survival (OS, primary end point) to first-line therapy. Each factor was evaluated in a multivariable model. Recursive partitioning was performed to define prognostic risk groups. RESULTS: A total of 224 patients were suitable for the present analysis. Median age was 26 years (interquartile range: 22-31), 11 patients (4.9%) had a retroperitoneal primary tumor, 6 yielded seminomatous histology, 85 (37.9%) had lung metastases, and 58 (25.9%) had bulky (i.e.,≥ 10 cm) retroperitoneal lymph nodes. Patients received cisplatin, bleomycin, and etoposide (PEB, n = 199) or vinblastine (PVB, n = 23); however, 2 patients received other treatments. Median follow-up was 135 months (interquartile range: 81-223). Globally, 5-year progression-free survival and OS rates were 72.8% (95% CI: 67.1-79.0) and 86.2% (81.7-91.0), respectively. In the multivariable model for OS, elevated alfa fetoprotein (AFP) level was the only significant prognostic factor (hazard ratio = 1.48, 95% CI: 1.12-1.96). The 2 separate prognostic groups with differential OS outcomes were identified based on the cutoff level of 6,200 IU/ml. The 10-year OS rate was 55.6% (95% CI: 36.6-84.3), and it was 86.7% (95% CI: 82.0-91.7) for those with AFP levels more than (n = 19, 8.5%) and less than (n = 205, 91.5%) the cutoff, respectively. CONCLUSIONS: A small fraction of patients with highly elevated AFP levels have an OS approximating the poor prognostic category, whereas most of them are close to good-risk cases. This might have implications to select outlier patients for clinical trials and molecular characterization.


Assuntos
Neoplasias Embrionárias de Células Germinativas/classificação , Neoplasias Retroperitoneais/classificação , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Projetos de Pesquisa , Neoplasias Retroperitoneais/tratamento farmacológico , Neoplasias Retroperitoneais/mortalidade , Estudos Retrospectivos , Adulto Jovem , alfa-Fetoproteínas/metabolismo
16.
Acta Vet Scand ; 56: 86, 2014 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-25492524

RESUMO

BACKGROUND: Salmonella spp. have been isolated from a wide range of wild animals. Opportunistic wild carnivores such as red foxes (Vulpes vulpes) and badgers (Meles meles) may act as environmental indicators or as potential sources of salmonellosis in humans. The present study characterizes Salmonella spp. isolated from the intestinal contents of hunted or dead red foxes (n = 509) and badgers (n = 17) in northern Italy. FINDINGS: Thirty-one strains of Salmonella belonging to 3 Salmonella enterica subspecies were isolated. Fourteen different serovars of S. enterica subsp. enterica were identified, among which were serovars often associated with human illness. CONCLUSIONS: Wild opportunistic predators can influence the probability of infection of both domestic animals and humans through active shedding of the pathogen to the environment. The epidemiological role of wild carnivores in the spread of salmonellosis needs to be further studied.


Assuntos
Raposas , Mustelidae , Salmonelose Animal/epidemiologia , Salmonella/classificação , Salmonella/isolamento & purificação , Animais , Feminino , Itália/epidemiologia , Masculino , Prevalência , Salmonelose Animal/microbiologia
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