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1.
Hematol Oncol ; 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32101329

RESUMO

Overexpression of bcl-2 and c-myc are defining features of double-expressor-lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c-myc and bcl-2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first-line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5-fold and 13-fold higher 5-year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN-IPI. DEL improved the discriminatory capability of the NCCN-IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN-IPI significantly improved the score's discriminatory potential both toward progression-free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple-to-use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN-IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.

2.
J Thromb Haemost ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32073229

RESUMO

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication of cancer. Elevated D-Dimer is associated with an increased risk of cancer-associated VTE. Whether changes in D-Dimer over time harbor additional prognostic information that may be exploited clinically for dynamic prediction of VTE is unclear. OBJECTIVES: To explore the potential role of longitudinal D-Dimer trajectories for personalized prediction of cancer-associated VTE. PATIENTS/METHODS: 167 patients with active malignancy were prospectively enrolled (gastrointestinal: n=59 (35%), lung: n=56 (34%), brain: n=50 (30%), others: n=2 (1%); metastatic disease: n=74 (44%)). D-Dimer (median=0.8µg/mL [25th -75th percentile: 0.4-2.0]) was measured at baseline and during 602 monthly follow-up visits. Joint models of longitudinal and time-to-event data were implemented to quantify the association between D-Dimer trajectories and prospective risk of VTE. RESULTS: VTE occurred in 20 patients (250-day VTE risk=12.1%, 95%CI: 7.8-18.5). D-Dimer increased by 34%/month (0.47µg/mL/month, 95%CI: 0.22-0.72, p<0.0001) in patients who developed VTE, but remained constant in patients who did not develop VTE (change/month=-0.06µg/mL/month, 95%CI: -0.15-0.02, p=0.121). In joint modeling, a doubling of the D-Dimer trajectory was associated with a 2.8-fold increase in the risk of VTE (Hazard ratio=2.78, 95%CI: 1.69-4.58, p<0.0001). This finding was independent of established VTE risk factors. Highly personalized, dynamic predictions of VTE conditional on individual patients' D-Dimer trajectories could be obtained. CONCLUSIONS: D-Dimer increases before the onset of cancer-associated VTE, but remains constant over time in patients without VTE. This study represents proof-of-concept that longitudinal trajectories of D-Dimer may advance the personalized assessment of VTE risk in the oncologic setting.

3.
Thromb Res ; 187: 9-17, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31945589

RESUMO

BACKGROUND: Haemostatic activation and hypercoagulability are frequently observed in patients with metastatic colorectal cancer (mCRC), increase risk of venous thromboembolism (VTE) and have been implicated in tumour proliferation and progression. To date, the association of haemostatic biomarkers with oncologic outcomes including overall survival (OS), progression free survival (PFS) and disease control rate (DCR) is incompletely understood. METHODS: Within the framework of the Vienna Cancer and Thrombosis Study, a prospective observational cohort study, we conducted an exploratory analysis to investigate the association of six known biomarkers of haemostasis with oncologic outcomes in 99 patients with mCRC prior to chemotherapy initiation. RESULTS: Patients with high levels of factor VIII activity (FVIII), D-dimer, prothrombin fragment 1 + 2 (F1 + 2) and fibrinogen (defined as levels >75th percentile) had significantly shorter median OS than patients with lower levels. Elevation of four biomarkers was associated with mortality in multivariable analysis, adjusting for age, sex, number of metastatic sites and VTE (hazard ratio [95% CI] for death per doubling of levels: FVIII: 2.06 [1.28-3.30]; sP-selectin: 1.55 [1.07-2.24]; D-dimer: 1.40 [1.18-1.65]; F1 + 2: 1.64 [1.10-2.46]). Patients with elevated levels had numerically shorter median PFS across all markers and disease control rate (DCR) was significantly smaller in those with high levels of FVIII and F1 + 2 (adjusted odds ratio [95% CI] for DCR per doubling of levels: 0.23 [0.09-0.62] and 0.36 [0.16-0.82]) compared to patients with lower levels. CONCLUSION: Specific elevated haemostatic biomarkers are associated with higher mortality and partially with worse response to chemotherapy in patients with mCRC.

4.
Transl Res ; 215: 41-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525325

RESUMO

A prothrombotic state is frequently observed in patients with cancer and contributes to the risks of venous thromboembolism (VTE), arterial thromboembolism (ATE), tumor progression, and death. Altered ex vivo properties of plasma clot formation and lysis have been observed in patients with cancer. The aim of this prospective study was to comprehensively characterize the relationship between plasma clot properties, inflammation, hypercoagulability, thrombotic complications, and mortality in patients with cancer using a tissue-factor-based turbidimetric assay of clot formation and lysis. Turbidity parameters were determined in 815 patients with newly-diagnosed or recurrent cancer and 97 healthy controls. Patients were followed-up for 2 years and rates of VTE (n = 72 events), ATE (n = 21 events), and death (n = 304 events) were assessed. Compared to controls, cancer patients' turbidity profiles showed an increased clot formation potential and higher resistance toward fibrinolysis. Elevated biomarkers of inflammation and hemostasis, such as C-reactive protein, FVIII, and thrombin generation explained substantial amounts of variation in turbidity parameters. In a prospective analysis, altered parameters of clot formation identified cancer patients at high risk of ATE (Hazard ratio [HR] per doubling of peak absorbance: 4.43, 95% CI: 1.50-13.07, P = 0.007) and death (HR per doubling of peak absorbance: 2.73, 2.00-3.72, P< 0.0001); these findings were independent of other prognostic covariates. Contrarily, turbidity parameters were not associated with risk of VTE (HR per doubling of peak absorbance: 1.15, 0.66-2.01, P = 0.62). We conclude that patients with cancer have altered ex vivo properties of clot formation which predict risks of ATE and mortality but not VTE.

5.
Anticancer Res ; 39(10): 5589-5596, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570454

RESUMO

BACKGROUND/AIM: To quantify the prognostic impact of age on relapse and mortality in patients with metastatic testicular germ cell tumors (TGCT). PATIENTS AND METHODS: Electronical medical records of 1,225 TGCT patients who were treated at a single academic center between 1994 and 2015 were reviewed. RESULTS: Higher age did not predict for worse progression-free survival (PFS) or for higher progression risk. The corresponding 5-year PFS estimates were 85% in patients younger than 40 years and 83% in the elderly population. Although not statistically significant, higher age was numerically associated with worse overall survival (OS) (univariate HR per five years increase in age=1.18, 95%CI=0.99-1.41). This was explained in regression analysis where age predicted for significantly higher risk of treatment-related death (p=0.022). CONCLUSION: Elderly patients with metastatic TGCT can achieve high cure rates similar to younger patients if they tolerate risk-adapted chemotherapy.


Assuntos
Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/patologia , Adulto , Fatores Etários , Progressão da Doença , Humanos , Masculino , Prognóstico , Intervalo Livre de Progressão , Recidiva , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
6.
Cancers (Basel) ; 11(8)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416207

RESUMO

The aim of this study was to assess the prognostic and predictive value of an untargeted assessment of tumor fractions in the plasma of metastatic breast cancer patients and to compare circulating tumor DNA (ctDNA) with circulating tumor cells (CTC) and conventional tumor markers. In metastatic breast cancer patients (n = 29), tumor fractions in plasma were assessed using the untargeted mFAST-SeqS method from 127 serial blood samples. Resulting z-scores for the ctDNA were compared to tumor fractions established with the recently published ichorCNA algorithm and associated with the clinical outcome. We observed a close correlation between mFAST-SeqS z-scores and ichorCNA ctDNA quantifications. Patients with mFAST-SeqS z-scores above three (34.5%) showed significantly worse overall survival (p = 0.014) and progression-free survival (p = 0.018) compared to patients with lower values. Elevated z-score values were clearly associated with radiologically proven progression. The baseline CTC count, carcinoembryonic antigen (CEA), and cancer antigen (CA)15-5 had no prognostic impact on the outcome of patients in the analyzed cohort. This proof of principle study demonstrates the prognostic impact of ctDNA levels detected with mFAST-SeqS as a very fast and cost-effective means to assess the ctDNA fraction without prior knowledge of the genetic landscape of the tumor. Furthermore, mFAST-SeqS-based ctDNA levels provided an early means of measuring treatment response.

7.
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.

8.
J Thromb Haemost ; 17(8): 1335-1344, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31099477

RESUMO

BACKGROUND: Patients with cancer are at risk of developing arterial thromboembolism (ATE). With the prevalence of cancer and cardiovascular diseases on the rise, the identification of risk factors for ATE in patients with cancer is of emerging importance. OBJECTIVES: As data on the association of potential biomarkers with risk of ATE in patients with cancer are scarce, we conducted a cohort study with the aim to identify blood-based biomarkers for ATE risk prediction in patients with cancer. PATIENTS/METHODS: Overall, 1883 patients with newly diagnosed cancer or progressive disease after complete or partial remission were included and followed for 2 years. Venous blood was drawn at study inclusion for measurement of complete blood count parameters, total cholesterol, d-dimer, and soluble P-selectin (sP-selectin) levels. RESULTS: The 2-year cumulative incidence of ATE was 2.5%. In univariable analysis, red cell distribution width (subdistribution hazard ratio (SHR) per doubling: 4.4, 95% CI: 1.4-14.1), leukocyte count (1.2, 1.1-1.5), neutrophil count (1.6, 1.1-2.3), and sP-selectin levels (1.9, 1.3-2.7) were associated with risk of ATE in patients with cancer; d-dimer was not associated with the risk of ATE (1.1, 0.9-1.4). After adjustment for age, sex, and smoking status the association prevailed for the neutrophil count (adjusted [adj.] SHR per doubling: 1.6, 1.1-2.4), and sP-selectin levels (1.8, 1.2-2.8). CONCLUSIONS: An elevated absolute neutrophil count and higher sP-selectin levels were associated with an increased risk of ATE in patients with cancer. Their role for predicting cancer-related ATE needs to be validated in further studies.

9.
Urol Oncol ; 37(7): 510-518, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31060796

RESUMO

BACKGROUND: To externally validate' BioScore', a biomarker-based scoring system using immunohistochemical tumor expression levels of B7-H1, survivin, and Ki-67, in a single-center cohort of renal cell carcinoma (RCC) patients. Additionally, we investigated the potential benefit of BioScore as compared to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score. MATERIALS AND METHODS: The validation cohort comprised 393 nonmetastatic RCC patients treated with radical nephrectomy or nephron-sparing surgery from 1999 to 2004. Kaplan-Meier estimators, the log-rank test, uni- and multivariable Cox regression models, and measures of discrimination were used to quantify the prognostic performance of BioScore regarding cancer-specific mortality (CSM). RESULTS: During a median follow-up of 7.8 years, 69/132 (52%) deaths were adjudicated to progressive disease. BioScore was weakly associated with CSM in univariable analysis (hazard ratio per 1 point increase = 1.12, 95% confidence interval = 1.02-1.23, P = 0.023). However, this association did not prevail after adjusting for other adverse prognostic factors as represented by the SSIGN score. The discriminative performance of BioScore was very modest (Harrell's C-Index = 0.60) and did not improve the SSIGN score (P = 0.341), which already showed an excellent discrimination, as evidenced by Harrell's C-Index of 0.81. In a sensitivity analysis regarding clear cell RCC patients only, B7-H1 positivity did not emerge as a statistically significant predictor of CSM. CONCLUSION: Although a higher BioScore was significantly associated with a higher CSM, the magnitude of this association was weak and not independent from other prognosticators. Moreover, BioScore did not improve the prognostic accuracy of the SSIGN score.

10.
Sci Rep ; 9(1): 5548, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944390

RESUMO

Whether 2nd-line-chemotherapy (2LCTX) + best-supportive-care (BSC) benefits patients with advanced biliary tract cancer (aBTC) more than BSC alone is unclear. We therefore conducted a propensity-score-based comparative effectiveness analysis of overall survival (OS) outcomes in 80 patients with metastatic, recurrent, or inoperable aBTC, of whom 38 (48%) were treated with BSC + 2LCTX and 42 (52%) with BSC alone. After a median follow-up of 14.8 months and 49 deaths, the crude 6-, 12-, and 18-month Kaplan-Meier OS estimates were 77%, 53% and 23% in the BSC + 2LCTX group, and 29%, 21%, and 14% in patients in the BSC group (p = 0.0003; Hazard ratio (HR) = 0.36, 95%CI:0.20-0.64, p = 0.001). An inverse-probability-of-treatment-weighted (IPTW) analysis was conducted to rigorously account for the higher prevalence of favorable prognostic variables in the 2LCTX + BSC group. After IPTW-weighting, the favorable association between 2LCTX and OS prevailed (adjusted HR = 0.40, 95%CI: 0.17-0.95, p = 0.037). IPTW-weighted 6-, 12-, and 18-month OS estimates were 77%, 58% and 33% in the BSC + 2LCTX group, and 39%, 28% and 22% in the BSC group (p = 0.037). Moreover, the benefit of 2LCTX was consistent across several clinically-relevant subgroups. Within the limitations of an observational study, these findings support the concept that 2LCTX + BSC is associated with an OS benefit over BSC alone in aBTC.

11.
Res Pract Thromb Haemost ; 3(2): 207-216, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31011705

RESUMO

Background: Exposure to vitamin K antagonists (VKA) has been suggested to accelerate progression of chronic kidney disease (CKD) but robust clinical data are currently lacking. Methods: We retrospectively evaluated the impact of VKA exposure on kidney function in patients with atrial fibrillation (AF) and CKD stage 3/4. Patients were prospectively followed within a primary care electronic database (median follow-up of 1.45 years). The kidney function trajectory over time, defined as the annualized change in estimated glomerular filtration rate (eGFR), was analyzed with linear mixed-effects regression including propensity score adjustment. Results: 14 432 patients (median age 78 years, median CHA 2 DS 2-VASc score 4 points) contributed 97 792 eGFR measurements (mean 6.8 measurements/patient; range: 1-197). Mean baseline eGFR was 50.3 mL/min/1.73 m2; and declined by 1.10 mL/min/1.73 m2/year (95% CI: 0.91-1.28, P < 0.0001). In 7409 patients with VKA exposure, CKD progression was significantly faster compared to patients without VKA exposure (5-year absolute eGFR loss from baseline: 6.0 mL/min/1.73 m2 vs 4.5 mL/min/1.73 m2, for an absolute 5-year excess eGFR decline with VKA exposure of 1.5 mL/min/1.73 m2 (95% CI: 0.4-2.7, P = 0.002). These results prevailed upon adjusting for CHA 2 DS 2-VASc score and other potential imbalances in prognostic variables, and in several sensitivity analyses. In the group without documented VKA exposure, 1775 VKA patients (24%) and 1012 patients (14%) developed a 30% decline in eGFR during follow-up (P < 0.0001). Conclusions: In patients with AF and CKD, VKA use is associated with accelerated eGFR decline. Within the limitations of a retrospective analysis, this finding supports the "VKA-renal-calcification hypothesis." However, although statistically significant, the excess loss in eGFR over 5 years with VKA was modest.

12.
Br J Haematol ; 186(2): 311-320, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30968400

RESUMO

Prior studies indicate that neutrophil extracellular traps (NETs) are associated with arterial thromboembolism (ATE) and mortality. We investigated the association between NET formation biomarkers (citrullinated histone H3 [H3Cit], cell-free DNA [cfDNA], and nucleosomes) and the risk of ATE and all-cause mortality in patients with cancer. In this prospective cohort study, H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients with newly diagnosed cancer or progressive disease after remission were followed for 2 years for ATE and death. Nine-hundred and fifty-seven patients were included. The subdistribution hazard ratios for ATE of H3Cit, cfDNA and nucleosomes were 1·0 per 100 ng/ml increase (95% confidence interval [95% CI]: 0·7-1·4, P = 0·949), 1·0 per 100 ng/ml (0·9-1·2, P = 0·494) increase and 1·1 per 1-unit increase (1·0-1·2, P = 0·233), respectively. Three-hundred and seventy-eight (39·5%) patients died. The hazard ratio (HR) for mortality of H3Cit and cfDNA per 100 ng/ml increase was 1·1 (1·0-1·1, P < 0·001) and 1·1 (1·0-1·1, P < 0·001), respectively. The HR for mortality of nucleosome levels per 1-unit increase was 1·0 (1·0-1·1, P = 0·233). H3Cit, cfDNA and nucleosome levels were not associated with the risk of ATE in patients with cancer. Elevated H3Cit and cfDNA levels were associated with higher mortality in patients with cancer.

13.
Blood Adv ; 3(5): 769-776, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30837214

RESUMO

Lupus anticoagulant (LA) has been associated with pregnancy complications and pregnancy loss. Identification of predictive factors could aid in deciding on therapeutic management. To identify risk factors for adverse pregnancy outcomes in high-risk women with persistently positive LA, we prospectively followed 82 women of childbearing age, of whom 23 had 40 pregnancies within the Vienna Lupus Anticoagulant and Thrombosis Study. Pregnancy complications occurred in 28/40 (70%) pregnancies, including 22 (55%) spontaneous abortions (<10th week of gestation [WOG]: n = 12, 10th to 24th WOG: n = 10) and 6 deliveries <34th WOG (15%, 3 due to severe preeclampsia/HELLP [hemolysis, elevated liver enzymes, and a low platelet count] syndrome, 3 due to placental insufficiency). One abortion was followed by catastrophic antiphospholipid syndrome. Neither a history of pregnancy complications nor of thrombosis, or prepregnancy antiphospholipid antibody levels were associated with adverse pregnancy outcomes. In logistic regression analysis, higher age was associated with a lower risk of adverse pregnancy outcome (per 5 years' increase: odds ratio [OR] = 0.41, 95% confidence interval [CI]: 0.19-0.87), a high Rosner index (index of circulating anticoagulant) predicted an increased risk (OR = 4.51, 95% CI: 1.08-18.93). Live birth rate was 15/28 (54%) in women on the combination of low-molecular-weight heparin and low-dose aspirin and 3/12 (25%) in those with no treatment or a single agent. We conclude that the risk of severe, even life-threatening pregnancy complications and adverse pregnancy outcomes is very high in women with persistent LA. A high Rosner index indicates an increased risk. Improved treatment options for women with persistently positive LA are urgently needed.

14.
Int J Cardiol ; 282: 47-52, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777405

RESUMO

BACKGROUND: Chronic kidney disease (CKD), commonly described by estimated glomerular filtration rate (eGFR), is a frequent comorbidity in patients with atrial fibrillation (AF) and associated with thromboembolic and bleeding complications. Instead of single eGFR measurements, kidney function decline over time may better predict clinical outcomes but this has not been studied so far. METHODS: Patients with AF and stage 3/4 CKD were prospectively followed within a primary care electronic database from the United Kingdom (IMS-THIN). The associations between the longitudinal eGFR trajectory of these patients and stroke/systemic embolism, major bleeding, first hospitalization-for-any-cause, and death-from-any-cause were estimated with joint models of longitudinal and time-to-event data. RESULTS: 18,240 patients were included (median age 80.4 years, median CHA2DS2-VASc score 4). In 133,676 eGFR measurements (mean: 6 per patient) median "baseline" eGFR was 49 ml/min/1.73m2 [41-55] and mean eGFR decline was 0.54 ml/min/1.73m2/year (95%CI: 0.47-0.62). During follow-up (median 3.2 years; 50,841 patient-years at risk), 5-year cumulative incidence estimates were 9%, 3%, 32% and 76% for stroke/systemic embolism, major bleeding, hospitalization and death, respectively. In joint modeling, an accelerated decline in kidney function strongly predicted for a higher risk of major bleeding (hazard ratio [HR] 1.09 per ml/min/1.73m2/year increase in eGFR decline), hospitalization (HR 1.06), and death-from-any-cause (HR 1.11; all p < 0.05), but not for stroke/systemic embolism (HR 0.97; p = 0.239). CONCLUSIONS: Declining kidney function is a critical determinant of unfavourable outcomes in patients with AF and CKD. Longitudinal kidney function trajectories may enable a much more individualized prediction of adverse outcomes in this vulnerable patient population.


Assuntos
Fibrilação Atrial/mortalidade , Hemorragia/mortalidade , Hospitalização/tendências , Rim/fisiologia , Insuficiência Renal Crônica/mortalidade , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Feminino , Hemorragia/diagnóstico , Hemorragia/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Mortalidade/tendências , Valor Preditivo dos Testes , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia
15.
Eur J Surg Oncol ; 45(2): 242-248, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30031674

RESUMO

INTRODUCTION: Metastasectomy is hypothesised to improve OS in metastatic STS, but evidence in favour of this approach derives from non-controlled single-arm cohorts affected by selection bias. The objective was to quantify the effect of metastasectomy vs. non-surgical management on overall survival (OS) in patients with metachronous metastases from extremity- and trunk soft tissue sarcoma (STS). MATERIALS AND METHODS: From a population of 1578 STS patients, 135 patients who underwent surgery for localised STS at two European centres between 1998 and 2015 and developed metachronous STS metastases were included. Propensity score analyses with inverse-probability-of-treatment-weights (IPTW) and landmark analyses were performed to control for selection and immortal time bias, respectively. RESULTS: OS was significantly longer in the 68 patients undergoing metastasectomy than in the 67 patients who were treated non-invasively for their metastasis (10-year OS: 23% vs. 4%; hazard ratio (HR) = 0.34, 95% CI: 0.22-0.53, p < 0.0001). This association prevailed after IPTW-weighting of the data to control for the higher prevalence of favourable prognostic factors in the surgery group (adjusted 10-year OS: 17% vs. 3%, log-rank p < 0.0001; HR = 0.33, 95% CI: 0.20-0.52, p < 0.0001). Five-year OS estimates were 27.8% in patients who had and 14.5% in patients who had not undergone metastasectomy within the first 3 months after diagnosis of a metastasis (p < 0.0001). CONCLUSION: In this observational bi-centre study, metastasectomy was associated with prolonged survival in patients with metachronous STS metastases. In the absence of randomized studies, our results indicate that metastasectomy should be considered as an important treatment option for metachronous STS metastases.


Assuntos
Metastasectomia/métodos , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/cirurgia , Sarcoma/patologia , Sarcoma/cirurgia , Idoso , Áustria , Feminino , Humanos , Masculino , Gradação de Tumores , Países Baixos , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
16.
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
17.
Ann Hematol ; 98(2): 313-319, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30467688

RESUMO

Lupus anticoagulants (LA) are a heterogeneous group of antiphospholipid antibodies (aPLAs) that promote thrombosis. Tissue factor (TF)-bearing extracellular vesicles (EVs) might contribute to the prothrombotic state of patients with persistent LA and a history of thrombosis. To investigate if EV-associated TF activity is elevated in a well-defined group of LA-positive patients with a history of thrombosis in comparison to that of healthy controls. Adult patients (n = 94, median age 40.1 years, interquartile range (IQR) 29.9-53.4; 87% females) positive for LA and a history of thrombosis (78% venous thrombosis, 17% arterial thrombosis, 5% venous thrombosis and arterial thrombosis) and healthy age- and sex-matched controls (n = 30, median age 42.9 years, IQR 38.6-45.8, 77% females) were included in this study. EV-TF activity was determined with a factor Xa generation assay and anti-ß2-glycoprotein (anti-ß2GPI) and anticardiolipin (aCL) antibodies by enzyme-linked immunoassays. EV-TF activity did not differ between 94 LA-positive patients with a history of thrombosis (median 0.05 pg/mL, IQR 0.00-0.14) and 30 healthy controls (median 0.06, IQR 0.00-0.11, p = 0.7745). No correlation was found between EV-TF activity and lupus-sensitive activated partial thromboplastin time (aPTT-LA) (rho = 0.034), Rosner index (rho = - 0.056), anti-ß2GPI IgG (rho = 0.05), anti-ß2GPI IgM (rho = - 0.08), aCL IgG (rho = 0.12), and aCL IgM (rho = - 0.11) in LA-positive patients. We found low EV-TF activity levels in LA-positive patients and a history of thrombosis and no correlation with analyzed aPLAs. Our data indicate that circulating TF-bearing EVs do not contribute to the prothrombotic state of patients with LA.


Assuntos
Vesículas Extracelulares/metabolismo , Inibidor de Coagulação do Lúpus/sangue , Trombose Venosa/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Int J Mol Sci ; 19(10)2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30321995

RESUMO

Metastatic testicular germ cell tumors (TGCTs) are a potentially curable disease by administration of risk-adapted cytotoxic chemotherapy. Nevertheless, a disease-relapse after curative chemotherapy needs more intensive salvage chemotherapy and significantly worsens the prognosis of TGCT patients. Circulating tumor markers (ß-subunit of human chorionic gonadotropin (ß-HCG), alpha-Fetoprotein (AFP), and Lactate Dehydrogenase (LDH)) are frequently used for monitoring disease recurrence in TGCT patients, though they lack diagnostic sensitivity and specificity. Increasing evidence suggests that serum levels of stem cell-associated microRNAs (miR-371a-3p and miR-302/367 cluster) are outperforming the traditional tumor markers in terms of sensitivity to detect newly diagnosed TGCT patients. The aim of this study was to investigate whether these miRNAs are also informative in detection of disease recurrence in TGCT patients after curative first line therapy. For this purpose, we measured the serum levels of miR-371a-3p and miR-367 in 52 samples of ten TGCT patients at different time points during disease relapse and during salvage chemotherapy. In our study, miR-371a-3p levels in serum samples with proven disease recurrence were 13.65 fold higher than levels from the same patients without evidence of disease (p = 0.014). In contrast, miR-367 levels were not different in these patient groups (p = 0.985). In conclusion, miR-371a-3p is a sensitive and potentially novel biomarker for detecting disease relapse in TGCT patients. This promising biomarker should be investigated in further large prospective trials.


Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/sangue , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Testiculares/diagnóstico , Regulação para Cima , Adulto , Idoso , Biomarcadores Tumorais/sangue , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Neoplasias Embrionárias de Células Germinativas/sangue , Neoplasias Embrionárias de Células Germinativas/genética , Estudos Prospectivos , Sensibilidade e Especificidade , Neoplasias Testiculares/sangue , Neoplasias Testiculares/genética
19.
Thromb Haemost ; 118(11): 1875-1884, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30296815

RESUMO

Patients with cancer are at risk of developing venous and arterial thromboembolism (VTE and ATE). Elevated platelet-to-lymphocyte (PLR) and neutrophil-to-lymphocyte ratios (NLR) have been suggested as potential biomarkers for cancer-associated chronic inflammation, VTE and mortality. We investigated the association between PLR and NLR with VTE, ATE and mortality in patients with cancer. Within a prospective cohort study, we followed-up patients with newly diagnosed or progressing cancer for objectively confirmed, symptomatic VTE, ATE and death. Fine and Gray competing-risk regression was used to model the risk of VTE and ATE. Overall survival was analysed with Kaplan-Meier estimators. From 2003 to 2013, 1,469 patients with solid cancer (median age: 61 years; 47.3% female) were recruited and followed for 2 years. Overall, 128 (8.7%) patients developed VTE, 41 (2.8%) ATE and 643 (43.8%) patients died. The sub-distribution hazard ratios (SHRs) for VTE per doubling of PLR and NLR were 1.0 (95% confidence interval [CI]: 0.8-1.3, p = 0.899) and 1.2 (1.0-1.4, p = 0.059), respectively. For ATE, the SHR per doubling of PLR and NLR were 1.0 (0.7-1.5, p = 0.940) and 1.2 (0.9-1.6, p = 0.191), respectively. A higher PLR (hazard ratio [HR] per doubling = 1.5, 1.4-1.7, p < 0.001) and a higher NLR (HR per doubling = 1.5, 1.4-1.7, p < 0.001) were associated with an increased risk of mortality after adjusting for age, sex and cancer stage. There was no statistically significant association between NLR and VTE occurrence in patients with cancer. Neither PLR nor NLR were associated with the risk of ATE. Both elevated PLR and NLR were independently associated with a twofold increased risk of mortality.


Assuntos
Plaquetas/patologia , Linfócitos/patologia , Neoplasias/patologia , Neutrófilos/patologia , Tromboembolia/patologia , Biomarcadores/metabolismo , Contagem de Células , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/mortalidade , Prognóstico , Estudos Prospectivos , Risco , Análise de Sobrevida , Tromboembolia/epidemiologia , Tromboembolia/mortalidade
20.
Lancet Haematol ; 5(7): e289-e298, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29885940

RESUMO

BACKGROUND: Venous thromboembolism is a common complication of cancer, but the risk of developing venous thromboembolism varies greatly among individuals and depends on numerous factors, including type of cancer. We aimed to develop and externally validate a clinical prediction model for cancer-associated venous thromboembolism. METHODS: We used data from the prospective Vienna Cancer and Thrombosis Study (CATS) cohort (n=1423) to select prognostic variables for inclusion in the model. We then validated the model in the prospective Multinational Cohort Study to Identify Cancer Patients at High Risk of Venous Thromboembolism (MICA) cohort (n=832). We calculated c-indices to show how the predicted incidence of objectively confirmed venous thromboembolism at 6 months compared with the cumulative 6-month incidences observed in both cohorts. FINDINGS: Two variables were selected for inclusion in the final clinical prediction model: tumour-site risk category (low or intermediate vs high vs very high) and continuous D-dimer concentrations. The multivariable subdistribution hazard ratios were 1·96 (95% CI 1·41-2·72; p=0·0001) for high or very high versus low or intermediate and 1·32 (95% CI 1·12-1·56; p=0·001) per doubling of D-dimer concentration. The cross-validated c-indices of the final model were 0·66 (95% CI 0·63-0·67) in CATS and 0·68 (0·62-0·74) in MICA. The clinical prediction model was adequately calibrated in both cohorts. INTERPRETATION: An externally validated clinical prediction model incorporating only one clinical factor (tumour-site category) and one biomarker (D-dimer) predicted the risk of venous thromboembolism in ambulatory patients with solid cancers. This simple model is a considerable improvement on previous models for predicting cancer-associated venous thromboembolism, and could aid physicians in selection of patients who will likely benefit from thromboprophylaxis. FUNDING: Austrian Science Fund, Austrian National Bank Memorial Fund, and participating hospitals.


Assuntos
Neoplasias/complicações , Neoplasias/epidemiologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Idoso , Áustria/epidemiologia , Biomarcadores , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/terapia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Regressão , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/prevenção & controle
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