Maddalena Barba

Thromboprophylaxis for patients with cancer and central venous catheters: a systematic review and a meta-analysis.

Central venous catheter (CVC) placement increases the risk of thrombosis and subsequent death in patients with cancer. The objective of this systematic review was to determine the efficacy and safety of anticoagulation in reducing mortality and thromboembolic events in cancer patients with a CVC.

Extended perioperative thromboprophylaxis in patients with cancer. A systematic review.

We systematically reviewed the literature to compare the relative efficacy and safety of extended versus limited duration heparin for perioperative thromboprophylaxis in patients with cancer. We followed the Cochrane Collaboration systematic review methodology and searched MEDLINE, EMBASE, ISI the Web of Science, and CENTRAL. The outcomes of interest included mortality, symptomatic deep venous thrombosis (DVT), pulmonary embolism, and bleeding. We evaluated the quality of evidence by outcome using the GRADE approach. Of 3,986 identified citations, we included three randomized clinical trials using low-molecular-weight heparin (LMWH). The quality of evidence for mortality, DVT, and major bleeding was low. There was no significant difference between extended (4 weeks) and limited duration thromboprophylaxis in terms of death at three months (relative risk [RR] = 0.49; 95% confidence interval [CI] 0.12-1.94), or major bleeding at four weeks (RR = 2.94; 95% CI 0.12-71.85). An extended regimen was associated with a significantly lower risk of asymptomatic DVT (RR = 0.21; 95% CI 0.05-0.94). No data was available for symptomatic DVT. In conclusion, there is limited and low-quality evidence that extended duration LMWH for perioperative thromboprophylaxis reduces DVT in patients with cancer undergoing major abdominal or pelvic surgery. More and better quality evidence is needed to justify extended regimens.

Erythrocyte Membrane Phospholipid Composition as a Biomarker of Dietary Fat

Background/Aims: In a cross-sectional study, we investigated the relationship between erythrocyte membrane phospholipid fatty acid composition and dietary fat; we also investigated roles of menopausal status, age, body mass index (BMI) and waist-to-hip ratio (WHR) in interindividual variation of the biomarker. Methods: Study participants were 204 women, aged 39–65 years, drawn from the ORDET cohort and selected as controls in a study of breast cancer. Membrane composition was assessed using capillary gas chromatography. Dietary fat composition was evaluated using a food frequency questionnaire. Results: In pre- and postmenopausal women, erythrocyte membrane phospholipid levels of linoleic acid, oleic acid, and mono-unsaturated fatty acids were significantly associated with corresponding dietary measures (partial correlation coefficients: 0.23 and 0.39; 0.45 and 0.47; 0.40 and 0.48; respectively, in pre- and postmenopausal women). Among postmenopausal women, membrane poly-unsaturated fatty acids were correlated with the corresponding dietary measure (r = 0.39, p < 0.001). Membrane eicosapentanoic and docosahexanoic acid levels were significantly correlated with intake of fish/shell fish : r = 0.21 and r = 0.43 (premenopausal), and r = 0.41 and r = 0.44 (postmenopausal). Age, BMI and WHR had independent effects on membrane lipid composition. Age was associated with delta-6 desaturase activity in postmenopausal women (r = 0.25, p < 0.05). BMI was negatively associated with delta-9 desaturase activity in both pre- and postmenopausal women (r = –0.29, p = 0.01 and r = –0.22, p < 0.01, respectively). WHR was negatively associated with delta-5 desaturase activity in pre-menopausal women (r = –024, p < 0.05). Conclusions: Erythrocyte membrane levels of some specific fatty acids can be used as biomarkers of these fatty acids as proportions of dietary fat.

Low-molecular-weight heparins are superior to vitamin K antagonists for the long term treatment of venous thromboembolism in patients with cancer: a cochrane systematic review

BackgroundCancer and its therapies increase the risk of venous thromboembolism. Compared to patients without cancer, patients with cancer anticoagulated for venous thromboembolism are more likely to develop recurrent thrombotic events and major bleeding. Addressing all important outcomes including harm is of great importance to make evidence based health care decisions. The objective of this study was to compare low molecular weight heparin (LMWH) and oral anticoagulants (vitamin K antagonist (VKA) and ximelagatran) for the long term treatment of venous thromboembolism in patients with cancer.MethodsA systematic review of the medical literature. We followed the Cochrane Collaboration methodology for conducting systematic reviews. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.ResultsEight randomized controlled trials (RCTs) were eligible and reported data for patients with cancer. The quality of evidence was low for death and moderate for recurrent venous thromboembolism. LMWH, compared to VKA provided no statistically significant survival benefit (Hazard ratio (HR) = 0.96; 95% CI 0.81 to 1.14) but a statistically significant reduction in venous thromboembolism (HR = 0.47; 95% (Confidence Interval (CI) = 0.32 to 0.71). There was no statistically significant difference between LMWH and VKA in bleeding outcomes (RR = 0.91; 95% CI = 0.64 to 1.31) or thrombocytopenia (RR = 1.02; 95% CI = 0.60 to 1.74).ConclusionFor the long term treatment of venous thromboembolism in patients with cancer, LMWH compared to VKA reduces venous thromboembolism but not death.

Parenteral anticoagulation may prolong the survival of patients with limited small cell lung cancer: a Cochrane systematic review.

BackgroundTo determine the efficacy and safety of heparin (unfractionated heparin (UFH) or low-molecular-weight-heparin (LMWH)) and fondaparinux in improving the survival of patients with cancer.MethodsWe conducted in January 2007 a comprehensive search for relevant randomized clinical trials (RCTs). We used a standardized form to extract in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, thromboembolic events, and bleeding events. We assessed the methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodologyResultsOf 3986 identified citations, we included 5 RCTs, none of which evaluated fondaparinux. The quality of evidence was moderate for survival, low for major and minor bleeding, and very low for DVT. Heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95%CI = 0.65–0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95%CI = 0.38–0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95%CI = 0.60–1.06) or patients with advanced cancer (HR = 0.84; 95%CI = 0.68–1.03). The increased risk of bleeding with heparin was not statistically significant (relative risk (RR) = 1.78; 95%CI = 0.73–4.38).ConclusionThis review suggests a survival benefit of heparin in cancer patients in general, and in patients with limited small cell lung cancer in particular.

Emerging biological treatments for uterine cervical carcinoma.

Cervical cancer is the third most common cancer worldwide, and the development of new diagnosis, prognostic, and treatment strategies is a major interest for public health. Cisplatin, in combination with external beam irradiation for locally advanced disease, or as monotherapy for recurrent/metastatic disease, has been the cornerstone of treatment for more than two decades. Other investigated cytotoxic therapies include paclitaxel, ifosfamide and topotecan, as single agents or in combination, revealing unsatisfactory results. In recent years, much effort has been made towards evaluating new drugs and developing innovative therapies to treat cervical cancer. Among the most investigated molecular targets are epidermal growth factor receptor and vascular endothelial growth factor (VEGF) signaling pathways, both playing a critical role in cervical cancer development. Studies with bevacizumab or VEGF receptor tyrosine kinase have given encouraging results in terms of clinical efficacy, without adding significant toxicity. A great number of other molecular agents targeting critical pathways in cervical malignant transformation are being evaluated in preclinical and clinical trials, reporting preliminary promising data. In the current review, we discuss novel therapeutic strategies which are being investigated for the treatment of advanced cervical cancer.

Molecular profiles of screen detected vs. symptomatic breast cancer and their impact on survival: results from a clinical series.

BackgroundStage shift is widely considered a major determinant of the survival benefit conferred by breast cancer screening. However, factors and mechanisms underlying such a prognostic advantage need further clarification. We sought to compare the molecular characteristics of screen detected vs. symptomatic breast cancers and assess whether differences in tumour biology might translate into survival benefit.MethodsIn a clinical series of 448 women with operable breast cancer, the Kaplan-Meier method and the log-rank test were used to estimate the likelihood of cancer recurrence and death. The Cox proportional hazard model was used for the multivariate analyses including mode of detection, age at diagnosis, tumour size, and lymph node status. These same models were applied to subgroups defined by molecular subtypes.ResultsScreen detected breast cancers tended to show more favourable clinicopathological features and survival outcomes compared to symptomatic cancers. The luminal A subtype was more common in women with mammography detected tumours than in symptomatic patients (68.5 vs. 59.0%, p=0.04). Data analysis across categories of molecular subtypes revealed significantly longer disease free and overall survival for screen detected cancers with a luminal A subtype only (p=0.01 and 0.02, respectively). For women with a luminal A subtype, the independent prognostic role of mode of detection on recurrence was confirmed in Cox proportional hazard models (p=0.03). An independent role of modality of detection on survival was also suggested (p=0.05).ConclusionsMolecular subtypes did not substantially explain the differences in survival outcomes between screened and symptomatic patients. However, our results suggest that molecular profiles might play a role in interpreting such differences at least partially.Further studies are warranted to reinterpret the efficacy of screening programmes in the light of tumour biology.

Metformin, diet and breast cancer: an avenue for chemoprevention.

In the report by Oliveros-Ferraras et al. (Cell Cycle 2009; 8:1633–6), the authors accurately reported that confirmation of the efficacy of metformin on cancer cell proliferation has opened up an avenue for large chemoprevention clinical trials.2-5 Our Letter-to-the-Editor wishes to communicate that, in Italy, there are two further on-going randomized controlled clinical trials (RCTs), highly intertwined, in addition to the two mentioned in the cited paper. The two trials are characterized by the same study design (Metformin versus Placebo for both, plus a diet-intervention focus for a study in Milan), the same population as well as the same inclusion and exclusion criteria. • The first of these is the Plotina study, a RCT on primary prevention of breast cancer, conducted at the Italian National Cancer Institute in Rome, Italy. The aim of the on-going study is to evaluate the effect of Metformin on breast cancer primary prevention and on primary prevention of cardiovascular diseases. Participants are randomly assigned to the treatment arm (metformin 850 mg twice a day) or placebo. The study is being conducted on postmenopausal women, 45–74 years of age. As well as being in the relevant age group, women included in the study are required to have large waist circumference (>88 cm) and at least one other component of metabolic syndrome reported below: ◦ high plasma levels of glucose (>110 mg/100 mL) ◦ high levels of triglycerides (>150 mg/100 mL) ◦ low levels of HDL cholesterol (<50 mg/100 mL) ◦ hypertension (Systolic Blood Pressure >130 mm Hg or Diastolic Blood Pressure >85 mm Hg). • A second randomized controlled clinical trial is currently being conducted at the Italian National Cancer Institute in Milan, Italy. As mentioned above, this trial is similar to the one described in terms of inclusion and exclusion criteria, number of recruited participants, outcome and other methodological aspects. However, this trial has a further element characterized by diet intervention. The diet intervention is based on the reduction of high caloric food and food at a high glycemic index as well as an increase in vegetable intake. The diet intervention is also combined with 30’ of physical activity per day. Participants will be randomized to lifestyle and/or metformin according to a factorial design. Breast Cancer Outcome Both studies include histologically confirmed invasive breast cancer diagnosed after recruitment to the trial (date at interview) and before the end of the last follow-up period. With an overall sample size of 16,000 postmenopausal women, we have estimated 325 incidents of breast cancer cases among the trial participants over a five year follow-up period. As well as breast cancer cases, major cardiovascular events, in particular myocardial infarction, stroke, revascularization treatment (bypass or angioplasty) and sudden death will be identified, by means of a linkage between mortality records and hospital discharge registers recorded in the files of the Italian National Health System. We have estimated 260 incidents of cases of cardiovascular events among the trial participants over the study period. A third research area related to the trial is a molecular analysis of metformin efficacy. This component supports a series of in-vitro and in-vivo studies as well as clinical predictive studies on metformin efficacy.6-13 We believe that the results of the two trials outlined above will enrich efforts already implemented by the scientific community in order to clarify the role of metformin as a chemopreventive agent.

Equol Status Modifies the Association of Soy Intake and Mammographic Density in a Sample of Postmenopausal Women

Only 30% to 50% of people produce the daidzein-metabolite equol after eating soy. We conducted a cross-sectional study of the associations between equol status, intake of soy foods, and mammographic density in a sample of postmenopausal women recruited at a radiology clinic near Buffalo, New York. Participants were 48 to 82 years old, had no history of cancer or breast reduction/augmentation, and no recent use of antibiotics or hormones. Percent density was measured by computer-assisted analysis of digitized images of craniocaudal films. Equol status was assessed using a soy-challenge protocol and usual soy intake by questionnaire. General linear models were used to assess independent and joint effects of equol status and intake of soy on multivariate adjusted percent density (covariates included age, body mass index, parity, age at first birth, and ever use of combined hormone therapy). Of 325 enrolled, 232 (71%) participants completed study assessments and are included in the present analysis. Mean percent density was 34% (±18%). Seventy-five (30%) participants were producers of equol. Forty-three (19%) participants reported regularly eating >1 soy food or supplement/wk. There were no significant independent associations of equol status or soy intake with percent density, but the interaction between these factors was significant (P < 0.01). Among equol producers, those with weekly soy intake had lower percent density (30.7% in weekly consumers of soy versus 38.9% in others; P = 0.08); among nonproducers, weekly soy intake was associated with higher percent density (37.5% in weekly soy consumers versus 30.7% in others; P = 0.03). Results suggest that equol producers and nonproducers may experience different effects of dietary soy on breast tissue. (Cancer Epidemiol Biomarkers Prev 2008;17(1):33–42)

Vitamin D supplementation and breast cancer prevention : a systematic review and meta-analysis of randomized clinical trials

In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L.