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1.
J Cachexia Sarcopenia Muscle ; 12(6): 2034-2044, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34612012

RESUMO

BACKGROUND: Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would support an approach that targets these factors. This trial aimed to assess the feasibility of an exercise and nutrition based rehabilitation programme in people with incurable cancer. METHODS: We randomized community dwelling adults with incurable cancer to either a personalized exercise and nutrition based programme (experimental arm) or standard care (control arm) for 8 weeks. Endpoints included feasibility, quality of life, physical activity (step count), and body weight. Qualitative and health economic analyses were also included. RESULTS: Forty-five patients were recruited (23 experimental arm, 22 control arm). There were 26 men (58%), and the median age was 78 years (IQR 69-84). At baseline, the median BMI was 26 kg/m2 (IQR: 22-29), and median weight loss in the previous 6 months was 5% (IQR: -12% to 0%). Adherence to the experimental arm was >80% in 16/21 (76%) patients. There was no statistically significant difference in the following between trial arms: step count - median % change from baseline to endpoint, per trial arm (experimental -18.5% [IQR: -61 to 65], control 5% [IQR: -32 to 50], P = 0.548); weight - median % change from baseline to endpoint, per trial arm (experimental 1%[IQR: -3 to 3], control -0.5% [IQR: -3 to 1], P = 0.184); overall quality of life - median % change from baseline to endpoint, per trial arm (experimental 0% [IQR: -20 to 19], control 0% [IQR: -23 to 33], P = 0.846). Qualitative findings observed themes of capability, opportunity, and motivation amongst patients in the experimental arm. The mean incremental cost of the experimental arm versus control was £-319.51 [CI -7593.53 to 6581.91], suggesting the experimental arm was less costly. CONCLUSIONS: An exercise and nutritional rehabilitation intervention is feasible and has potential benefits for people with incurable cancer. A larger trial is now warranted to test the efficacy of this approach.


Assuntos
Exercício Físico , Neoplasias , Estado Nutricional , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Humanos , Masculino , Neoplasias/terapia , Qualidade de Vida
2.
Transl Oncol ; 14(12): 101229, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34592589

RESUMO

Tumour metastasis accounts for over 90% of cancer related deaths. The platelet is a key blood component, which facilitates efficient metastasis. This study aimed to understand the molecular mechanisms involved in tumour-platelet cell interactions. The interaction between cancer cells and platelets was examined in 15 epithelial cell lines, representing 7 cancer types. Gene expression analysis of EMT-associated and cancer stemness genes was performed by RT-PCR. Whole transcriptome analysis (WTA) was performed using Affymetrix 2.0ST arrays on a platelet co-cultured ovarian model. Platelet adhesion and activation occurred across all tumour types. WTA identified increases in cellular movement, migration, invasion, adhesion, development, differentiation and inflammation genes and decreases in processes associated with cell death and survival following platelet interaction. Increased invasive capacity was also observed in a subset of cell lines. A cross-comparison with a platelet co-cultured mouse model identified 5 common altered genes; PAI-1, PLEK2, CD73, TNC, and SDPR. Platelet cancer cell interactions are a key factor in driving the pro-metastatic phenotype and appear to be mediated by 5 key genes which have established roles in metastasis. Targeting these metastasis mediators could improve cancer patient outcomes.

3.
Mol Cancer ; 20(1): 59, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33789677

RESUMO

Cancer cells that transit from primary tumours into the circulatory system are known as circulating tumour cells (CTCs). These cancer cells have unique phenotypic and genotypic characteristics which allow them to survive within the circulation, subsequently extravasate and metastasise. CTCs have emerged as a useful diagnostic tool using "liquid biopsies" to report on the metastatic potential of cancers. However, CTCs by their nature interact with components of the blood circulatory system on a constant basis, influencing both their physical and morphological characteristics as well as metastatic capabilities. These properties and the associated molecular profile may provide critical diagnostic and prognostic capabilities in the clinic. Platelets interact with CTCs within minutes of their dissemination and are crucial in the formation of the initial metastatic niche. Platelets and coagulation proteins also alter the fate of a CTC by influencing EMT, promoting pro-survival signalling and aiding in evading immune cell destruction. CTCs have the capacity to directly hijack immune cells and utilise them to aid in CTC metastatic seeding processes. The disruption of CTC clusters may also offer a strategy for the treatment of advance staged cancers. Therapeutic disruption of these heterotypical interactions as well as direct CTC targeting hold great promise, especially with the advent of new immunotherapies and personalised medicines. Understanding the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology will allow us to identify and characterise the most clinically relevant CTCs from patients. This will subsequently advance the clinical utility of CTCs in cancer diagnosis/prognosis.


Assuntos
Coagulação Sanguínea , Plaquetas/metabolismo , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Animais , Biomarcadores , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/etiologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Humanos , Neoplasias/sangue , Neoplasias/complicações , Neoplasias/etiologia , Neoplasias/patologia
4.
Acta Obstet Gynecol Scand ; 100(7): 1239-1247, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33590896

RESUMO

INTRODUCTION: CA 125, the biomarker in common clinical use for ovarian cancer, is limited by low sensitivity for early disease and high false positives. The aim of this study was to evaluate several candidate biomarkers, alone or in combination, compared with CA 125 in the prediction of malignant/borderline vs benign tumor status in premenopausal and postmenopausal women with pelvic masses. MATERIAL AND METHODS: This was a retrospective observational cohort study set in St James's Hospital, a tertiary referral center for gynecological malignancy in Dublin, Ireland. Women undergoing surgery for pelvic masses between 2012 and 2018 were included. Preoperative human epididymis protein 4 (HE4), the Risk of Ovarian Malignancy Algorithm, the Risk of Malignancy Index I and II, D-dimer, and fibrinogen were assessed. Logistic regression models were fitted for each biomarker alone and in combination. Receiver operating characteristics-area under the curve (ROC-AUC) and partial AUCs in the 90%-100% specificity range were determined. RESULTS: In all, 89 premenopausal and 185 postmenopausal women were included. In premenopausal women, no biomarker(s) outperformed CA 125 (AUC 0.73; 95% CI 0.63-0.84). In postmenopausal women, HE4 had a partial AUC (pAUC) of 0.71 (95% CI 0.64-0.79) compared with 0.57 (95% CI 0.51-0.69) for CA 125 (p = 0.009). HE4 + D-dimer had an improved pAUC of 0.74 (95% CI 0.68-0.81, p < 0.001) and HE4 + D-dimer + fibrinogen had a pAUC of 0.75 (95% CI 0.68-0.82). CONCLUSIONS: A novel biomarker panel of HE4 ± D-dimer ± fibrinogen outperformed CA 125 alone as a high-specificity biomarker in postmenopausal women and could aid in the preoperative triaging of pelvic masses. No biomarker(s) outperformed CA 125 in premenopausal women.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno Ca-125/sangue , Carcinoma Epitelial do Ovário/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/análise , Adulto , Algoritmos , Carcinoma Epitelial do Ovário/diagnóstico , Estudos de Coortes , Feminino , Humanos , Irlanda , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco
5.
Thromb Res ; 200: 91-98, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33571724

RESUMO

INTRODUCTION: Ovarian cancer patients are at high risk of thrombosis particularly during chemotherapy treatment however the mechanism is not understood. The aim of this study is to investigate the role of the activated protein C (aPC) pathway in the procoagulant activity observed in ovarian cancer patients undergoing neoadjuvant chemotherapy. PATIENTS AND METHODS: Thrombin generation was determined before and after addition of thrombomodulin (TM) in high grade serous ovarian cancer (HGSOC) patients treated with neoadjuvant chemotherapy (n = 29) compared with HGSOC patients who were chemo naïve (n = 23) and patients with benign tumours (n = 29). Plasma expression of proteins from the aPC pathway was analysed. mRNA expression was determined in endothelial (EA.hy926) and ovarian (OAW42) cell lines following addition of carboplatin and paclitaxel. RESULTS: Lower levels of ETP (p < 0.007; p < 0.003) and peak thrombin (p < 0.0008; p < 0.0018) were found in the neoadjuvant group compared with both chemo naïve and benign groups. Following addition of TM, ETP (p < 0.0005) and peak thrombin (p < 0.0049) were higher in the neoadjuvant group compared with the benign controls indicating an increase in aPC resistance. Increased TM and lower levels of protein S were found in the neoadjuvant group compared with benign controls (p < 0.05; p < 0.003). Factor V levels were increased in the neoadjuvant group compared with the chemo naïve group (p < 0.05). Carboplatin and paclitaxel altered the expression of EPCR and thrombomodulin in OAW42 cells with a modest effect on EA.hy926 cells. CONCLUSION: Chemotherapy induced procoagulant activity in HGSOC is associated with an alteration in expression of key members of the aPC pathway. This acquired aPC resistance may explain the procoagulant phenotype associated with ovarian cancer patients undergoing chemotherapy.


Assuntos
Neoplasias Ovarianas , Proteína C , Carboplatina/uso terapêutico , Feminino , Humanos , Terapia Neoadjuvante , Neoplasias Ovarianas/tratamento farmacológico
6.
Gynecol Oncol ; 160(2): 514-519, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33213897

RESUMO

OBJECTIVES: To investigate whether HE4 and CA125 could identify endometrioid adenocarcinoma patients who might most benefit from full staging surgery with lymphadenectomy. METHODS: Sequential patients with a preoperative banked serum and histology of endometrioid adenocarcinoma of endometrium who had undergone surgical staging with lymph node dissection over a 5-year period between 2011 and 2016 were included from a tertiary Gynaecological Cancer Centre, Dublin, Ireland. Preoperative serum HE4 and CA125 were measured using ELISA, with the cut-offs HE4 81 pmol/L and CA125 35 U/ml. Predictive values were estimated using AUC, sensitivity, specificity and odds ratios. RESULTS: 9.5% of the cohort had lymph node metastases. A HE4 cut-off of 81 pmol/L yielded a sensitivity of 78.6% and specificity of 53.4% for predicting lymph node metastases. Sensitivity of CA125 at 35 U/ml was 57% and specificity 91.4%. The AUC was 0.66 (0.52-0.80) for HE4 and 0.74 (0.58-0.91) for CA125. Sensitivity was 92.8% and specificity 51.1% when an elevation of either HE4 or CA125 was included, AUC was 0.72 (0.61-0.83), this combination yielded the highest NPV of 98.6%. Sensitivity was 42.9% and specificity 93.8% if both markers were elevated simultaneously, AUC was 0.68 (0.51-0.86). Preoperative clinical predictors of high-grade preoperative histology and radiology had sensitivities of 21.4% and 41.7%, respectively. Patients with a HE4 above 81 pmol/L had an odds ratio of 4.2 (1.12-15.74), p < 0.05, of lymph node metastases and CA125 had an odds ratio of 14.2 (4.16-48.31), p < 0.001. CONCLUSIONS: Serum HE4 and CA125 improved on existing methods for risk stratification of endometrioid carcinomas and warrant further investigation.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno Ca-125/sangue , Carcinoma Endometrioide/diagnóstico , Neoplasias do Endométrio/diagnóstico , Metástase Linfática/diagnóstico , Proteínas de Membrana/sangue , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/sangue , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/cirurgia , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Endométrio/patologia , Endométrio/cirurgia , Feminino , Humanos , Histerectomia , Excisão de Linfonodo/estatística & dados numéricos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática/patologia , Pessoa de Meia-Idade , Gradação de Tumores/estatística & dados numéricos , Estadiamento de Neoplasias/estatística & dados numéricos , Valor Preditivo dos Testes , Período Pré-Operatório , Curva ROC , Valores de Referência , Estudos Retrospectivos , Medição de Risco/métodos , Salpingo-Ooforectomia
7.
Res Pract Thromb Haemost ; 4(5): 848-859, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32685894

RESUMO

BACKGROUND: Gynecologic cancers are associated with high rates of venous thromboembolism (VTE), which is exacerbated by pelvic surgery and chemotherapy. OBJECTIVES: The aim of this study was to develop and validate a risk score for VTE in patients with gynecologic cancer and to test the predictive ability of the score following addition of procoagulant biomarker data. PATIENTS AND METHODS: Clinical and laboratory variables were used to develop a risk score for the prediction of VTE in patients with gynecological cancer (n = 616), which was validated in a separate cohort of patients (n = 406). Endogenous thrombin potential and D-dimer levels were determined in a subset (n = 290) of patients and used to produce an extended score in the validation cohort. RESULTS: Multivariable regression analysis identified BMI >30, hemoglobin <11.5 g/dL and chemotherapy as independent predictors of VTE, which formed the Thrombogyn score. Following competing risk regression analysis, subdistribution hazard ratios (SHRs), adjusted for cancer stage, were 8.16 (95% confidence interval [CI], 1.69-43.77) in the high-risk group (score = 2-3) and 4.12 (95% CI, 0.85-20.15) in the intermediate-risk group (score = 1) compared with the low-risk group (score = 0). SHRs for the validation cohort were 6.26 (95% CI, 1.24-31.39) and 3.00 (95% CI, 0.67-13.32), respectively. Cumulative incidence of VTE in the validation cohort high-risk group was 10.34% (95% CI, 6.51-16.41) per women-years compared with 1.06% (95% CI, 0.26-4.26) in the low-risk group. Using the extended Thrombogyn score, adjusted SHRs were 16.83 (95% CI, 4.20-67.37) in the high-risk group with a cumulative incidence of 21.15% (95% CI, 10.32-45.24). External validation of the score is required. CONCLUSIONS: The Thrombogyn score identifies patients with gynecologic cancer at high and low risk of VTE. Addition of biomarker data improves the predictive power of the score.

8.
Int J Gynecol Cancer ; 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992328

RESUMO

OBJECTIVE: Gynaecological cancer patients have a high risk of developing venous thromboembolism (VTE). There is limited information on patient experience and compliance with an extended low molecular weight heparin prophylaxis in this setting. The aim of this study was to assess patient compliance, satisfaction and experience with the extended low molecular weight heparin prophylaxis after major surgery for gynaecological cancer. METHODS: This was a prospective observational study conducted in a large tertiary center for gynaecological cancer between July 2017-March 2018. Consecutive patients undergoing surgery for gynaecological cancer who received low molecular weight heparin prophylaxis for four weeks following surgery were recruited. All participants received a log book to record all injections, side effects, and questionnaire to be completed at the end of the study. RESULTS: A total of 106 patients completed and returned the VTE prophylaxis logbook and questionnaire. Sixty-six (62%) patients received low molecular weight heparin for 28 days, twenty-five (24%) for 26-27 days, and 15 (14%) for less than 26 days. The median number of days of therapy was 28 days (range; 12-28 days). Reasons for missed or stopped injections included: forgetfulness(n=12), medical procedures (n=6), pain (n=5), incorrect prescription (n=4), patient choice (n=3), cost (n=2), physician request (n=2), non-availability of person administering the injections (n=1) or unknown (n=5). Sixty-one (58%) patients self-administered the injections. Patients who had the injection performed by a third person were twice as likely to experience pain compared to patients who self-administered (OR 2.81, p=0.003). Eighty-nine (84%) patients self-reported side effects during low molecular weight heparin prophylaxis including: bruising (75%), pain after injections (49%), itchiness (9%), swelling (9%) or other (8%). Although 83 (78%) patients were satisfied with injections, 91 (86%) admitted they would much prefer a tablet form. CONCLUSIONS: Compliance with standard recommended regimen of 28-days prophylaxis was completed by 62% of patients. Majority of patients (86%) reported a preference for a tablet form, if one was available.

9.
Int J Gynecol Cancer ; 28(6): 1066-1072, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29757874

RESUMO

OBJECTIVE: The aim of this study was to examine the clearance of serum human epididymis protein 4 (HE4) in the immediate postoperative period in patients undergoing maximal effort cytoreductive surgery for ovarian carcinoma. METHODS: The study was performed at a tertiary gynecologic oncology center. The surgery was performed by accredited gynecological oncologists. RESULTS: Preoperative and serial postoperative venous blood samples at 4, 8, 24, 48, 72, 96, and 120 hours were taken from 10 sequential patients. Pretreatment HE4 is considered elevated at greater than 70 pmol/L. Human epididymis protein 4 was greater than 70 pmol/L in 7 patients, including all patients with high-grade serous carcinoma. Patients with preoperative elevation of serum HE4 and complete cytoreduction cleared more than 80% of serum HE4 in the first 4 hours and more than 88% within 5 days of surgery. One patient with incomplete cytoreduction of high-grade serous carcinoma had 66% clearance at 4 hours and a plateau thereafter. CONCLUSIONS: Human epididymis protein 4 derived from ovarian carcinoma had a short half-life of less than 4 hours in the circulation when cytoreductive surgery was complete. Sustained low HE4 following surgery could be a useful indicator of the completeness of cytoreduction. Plateau or rise in serum HE4 could suggest persistent disease. Comparison of values on day 1 and day 4 or 5 might have value in assessing the completeness of cytoreduction.


Assuntos
Carcinoma Epitelial do Ovário/sangue , Carcinoma Epitelial do Ovário/cirurgia , Proteínas/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/sangue , Procedimentos Cirúrgicos de Citorredução , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Pessoa de Meia-Idade , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos , Adulto Jovem
10.
Ir J Med Sci ; 187(3): 789-794, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29299762

RESUMO

BACKGROUND: High-grade serous carcinoma (HGSC) is the most common tubo-ovarian cancer. The fallopian tube harbours the precursor lesion: serous tubal intraepithelial carcinoma (STIC). Bilateral salpingo-oophorectomy is an effective risk-reducing surgical (RRS) strategy for breast cancer susceptibility gene mutation carriers (BRCAm). The value of RRS in those without defined genetic risk is unknown but these women represent a substantial cohort in prophylactic surgical practice. METHODS: This is a retrospective review of RRS at an Irish university teaching hospital. RESULTS: One hundred and thirty women underwent RRS; group 1 = 46 BRCAm; group 2 = 19 BRCAm negative/65 genetic status unknown. Group 1 had one occult HGSC. Group 2 had no STIC or cancers and were older and more likely to have hysterectomy and benign pathology. Other pathologies included serous tubal intraepithelial lesions (STIL) (2), p53 signatures (2), endometriosis (6), fibroids/adenomyosis (4) and atypical endometrial hyperplasia (1). CONCLUSION: More than 60% of women undergoing RRS were BRCAm negative or untested. Counselling of high-risk women without defined germline mutations remains a challenge for gynaecologists because the likelihood of removing STIC lesions or occult invasive cancer is low. Removal of coincidental pathology may give added value to RRS in these women.


Assuntos
Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Feminino , Humanos , Irlanda , Pessoa de Meia-Idade , Neoplasias Ovarianas/etnologia , Estudos Retrospectivos , Comportamento de Redução do Risco
12.
Afr J Disabil ; 6: 350, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28936419

RESUMO

BACKGROUND: Only 2% of people with disabilities in developing countries have access to basic services and rehabilitation. OBJECTIVES: To bridge this gap, Motivation has been running Peer Training activities since 1993 and has identified that there is a growing need for Peer Training. The overall aim of Peer Training is for wheelchair users (Peer Trainers) to provide others (with similar disabilities) with the relevant knowledge on health issues, rights and skills to achieve a basic level of independence and greater quality of life. METHOD: To test the impact of Peer Training, Motivation created a knowledge, skills and well-being questionnaire, which has been trialled in two locations: Kenya and Malawi. RESULTS: Overall, Motivation found that most participants reported an increase in knowledge, skills and well-being, supporting their experience that this training provides vital information and support mechanisms for wheelchair users in low- and middle-income countries. Further work is needed to ensure this tool measures the impact of Peer Training and lessons learnt have been identified to strengthen the methodology. CONCLUSION: Although Peer Training is not a replacement for rehabilitation services, Motivation believes it is an effective way to not only increase knowledge and skills of persons with disabilities but also reduce the sense of social isolation that can often be a result of disability.

16.
Cancer Lett ; 356(2 Pt B): 628-36, 2015 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-25451316

RESUMO

Ovarian cancer is the seventh most common cancer in women and the most frequent cause of gynaecological malignancy-related mortality in women. Currently, no standardized reliable screening test exists. MicroRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis and response to treatment of human tumours. The aim of this study was to determine if a microRNA signature could distinguish between malignant and benign ovarian disease. A training set of 5 serous ovarian carcinomas and 5 benign serous cystadenomas were selected for the initial experiments. The validation set included 20 serous ovarian carcinomas and 20 benign serous cystadenomas. The serum/plasma focus microRNA Exiqon panel was used for the training set. For the validation set a pick and mix Exiqon panel, which focuses on microRNAs of interest was used. A panel of 4 microRNAs (let-7i-5p, miR-122, miR-152-5p and miR-25-3p) was significantly down regulated in cancer patients. These microRNAs target WNT signalling, AKT/mTOR and TLR-4/MyD88, which have previously been found to play a role in ovarian carcinogenesis and chemoresistance. let-7i-5p, miR-122, miR-152-5p and miR-25-3p could act as diagnostic biomarkers in ovarian cancer.


Assuntos
Biomarcadores Tumorais/sangue , Cistadenocarcinoma Seroso/diagnóstico , MicroRNAs/sangue , MicroRNAs/genética , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/genética , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Hemólise , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/genética , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Thromb Res ; 134(2): 234-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24984985

RESUMO

INTRODUCTION: Low molecular weight heparin (LMWH) prophylaxis has been recommended for morbidly obese pregnant women (>40kg/m(2)). There is very little data on the anticoagulant effects of LMWH in this group. We investigated two different dosing regimens; fixed dose and weight-adjusted dose on the anticoagulant effects of the LMWH tinzaparin used for thromboprophylaxis in obese pregnant women. MATERIALS AND METHODS: Twenty morbidly obese pregnant women were started on a fixed dose of tinzaparin (4,500 iu/day) at 32weeks gestation and then changed to a weight-adjusted dose (75iu/kg/day) for the remainder of their pregnancy. Four-hour post LMWH, venous bloods were taken after each initial dose and repeated every two weeks until delivery. Twenty normal weight women who did not receive LMWH at the same gestation were used as controls. RESULTS: Prior to LMWH prophylaxis, tissue factor pathway inhibitor (TFPI) levels in the obese group at 32weeks were significantly lower (p<0.001) and endogenous thrombin potential (ETP) and peak thrombin levels in obese group were significantly higher, compared with controls (p<0.0001; p<0.001). There was no significant difference between ETP levels before and after fixed LMWH. However, ETP levels were significantly lower post weight-adjusted dose compared with post fixed dose. There was a significant effect of LMWH on TFPI levels, (p<0.0001). ETP correlated positively with total body weight prior to LMWH (r=0.631) (p<0.05) and at fixed dose (r=0.578) (p<0.05). CONCLUSION: Morbidly obese pregnant women have increased thrombin generation and reduced natural anticoagulant in third trimester. This prothrombotic state was more effectively attenuated by weight-adjusted than fixed LMWH doses.


Assuntos
Fibrinolíticos/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Obesidade Mórbida/complicações , Complicações Cardiovasculares na Gravidez/prevenção & controle , Trombina/antagonistas & inibidores , Tromboembolia Venosa/prevenção & controle , Adulto , Peso Corporal , Estudos de Coortes , Feminino , Fibrinolíticos/administração & dosagem , Heparina de Baixo Peso Molecular/administração & dosagem , Humanos , Obesidade Mórbida/sangue , Obesidade Mórbida/patologia , Gravidez , Complicações Cardiovasculares na Gravidez/sangue , Complicações Cardiovasculares na Gravidez/etiologia , Tinzaparina , Tromboembolia Venosa/sangue , Tromboembolia Venosa/etiologia
18.
Phytomedicine ; 21(2): 155-8, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23972791

RESUMO

Phytoestrogens are popular alternatives to estrogen therapy however their effects on hemostasis in post-menopausal women are unknown. The aim of this study was to determine the effect of the phytoestrogens, genistein, daidzein and equol on the expression of key genes from the hemostatic system in human hepatocyte cell models and to determine the role of estrogen receptors in mediating any response seen. HepG2 cells and Hep89 cells (expressing estrogen receptor alpha (ERα)) were incubated for 24 h with 50 nM 17ß-estradiol, genistein, daidzein or equol. Tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), Factor VII, fibrinogen γ, protein C and protein S mRNA expression were determined using TaqMan PCR. Genistein and equol increased tPA and PAI-1 expression in Hep89 cells with fold changes greater than those observed for estradiol. In HepG2 cells (which do not express ERα), PAI-1 and tPA expression were unchanged. Increased expression of Factor VII was observed in phytoestrogen treated Hep89 cells but not in similarly treated HepG2s. Prothrombin gene expression was increased in equol and daidzein treated HepG2 cells in the absence of the classical estrogen receptors. These data suggest that phytoestrogens can regulate the expression of coagulation and fibrinolytic genes in a human hepatocyte cell line; an effect which is augmented by ERα.


Assuntos
Coagulação Sanguínea/genética , Equol/farmacologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Hemostáticos/farmacologia , Isoflavonas/farmacologia , Fitoestrógenos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fator VII/genética , Fator VII/metabolismo , Fibrina/metabolismo , Expressão Gênica/efeitos dos fármacos , Genisteína/farmacologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Extratos Vegetais/farmacologia , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Protrombina/genética , Protrombina/metabolismo , RNA Mensageiro/metabolismo , Ativador de Plasminogênio Tecidual/genética , Ativador de Plasminogênio Tecidual/metabolismo
19.
Thromb Res ; 132(5): 627-34, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24094893

RESUMO

INTRODUCTION: Ovarian cancer is known to display a particular association with venous thromboembolism (VTE) with reports up to 42% of patients developing thromboembolic complications. Tissue Factor (TF) and its inhibitor Tissue Factor Pathway Inhibitor (TFPI) have been implicated in VTE risk in cancer. The aim of this study was to measure tumour derived TF and TFPI and to investigate their potential role in VTE in ovarian cancer patients. METHODS: TF and TFPI mRNA expression was measured using TaqMan real time PCR in 99 ovarian tumour samples. Nineteen cases complicated by VTE were matched to 19 cases without VTE. TF and TFPI protein levels were measured using ELISA and immunohistochemistry was used to localize TF expression. The role of TF expression on overall survival was also determined. RESULTS: TF mRNA and protein expression was increased in tumours from patients with clear cell carcinoma (p<0.001). TF protein expression was also increased in endometroid carcinoma (P<0.01) compared with benign tumours. TFPI mRNA expression was increased in clear cell carcinoma (P<0.01). TF mRNA and antigen level was increased in malignant tumours of patients who developed VTE compared with matched malignant õtumours of patients who remained thrombosis free (P<0.01). There was no difference in TFPI expression between the two groups. CONCLUSION: TF expression in ovarian cancer is significantly higher in patients who develop VTE. TF expression was increased in clear cell ovarian cancer and endometroid cancer and this may explain the higher risk of VTE in these subgroups. TF derived from these tumours may be the trigger for VTE in ovarian cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Lipoproteínas/genética , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/genética , Tromboplastina/genética , Trombose Venosa/etiologia , Idoso , Feminino , Humanos , Imuno-Histoquímica , Lipoproteínas/análise , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Ovário/patologia , RNA Mensageiro/genética , Tromboplastina/análise , Regulação para Cima , Trombose Venosa/genética
20.
Eur J Obstet Gynecol Reprod Biol ; 170(1): 214-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23830352

RESUMO

OBJECTIVES: Ovarian cancer has a higher incidence of venous thromboembolism (VTE) than other cancers. Clear cell cancers carry the highest risk at 11-27%. The aim of this study was to identify the predisposing factors for VTE in a population of ovarian cancer patients and to determine the influence of VTE on overall survival. STUDY DESIGN: VTE events were identified from hospital and general practice/community care records for all patients with ovarian cancer who were diagnosed and treated in a tertiary cancer center between 2006 and 2010. RESULTS: The overall incidence of VTE was 9.7% (33) in 344 patients. Sixteen (48%) had pulmonary embolism. Six (18%) presented with VTE. Five (15%) had VTE diagnosed during pre-treatment routine CT scanning. Eleven (33%) developed VTE following surgery and eleven (33%) developed VTE during chemotherapy. Risk factors associated with the occurrence of VTE were BMI≥30 (p<0.01), clear cell carcinoma (p<0.05), advanced stage (p<0.01), high grade (p<0.01) and CA125>500 IU/ml (p<0.001). The occurrence of VTE was associated with decreased overall survival time (p<0.001). CONCLUSION: The incidence of VTE is high in ovarian cancer especially in the clear cell subtype. VTE adversely affects survival in ovarian cancer. Obesity, high grade and stage of cancer, clear cell subtype and high CA 125 level should be incorporated into protocols of VTE prophylaxis in women with ovarian cancer.


Assuntos
Carcinoma/complicações , Carcinoma/mortalidade , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/mortalidade , Tromboembolia Venosa/epidemiologia , Idoso , Feminino , Humanos , Incidência , Irlanda/epidemiologia , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/etiologia
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