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1.  Use of heparins in patients with cancer: individual participant data meta-analysis of randomised trials study protocol 
BMJ Open  2016;6(4):e010569.
Introduction
Parenteral anticoagulants may improve outcomes in patients with cancer by reducing risk of venous thromboembolic disease and through a direct antitumour effect. Study-level systematic reviews indicate a reduction in venous thromboembolism and provide moderate confidence that a small survival benefit exists. It remains unclear if any patient subgroups experience potential benefits.
Methods and analysis
First, we will perform a comprehensive systematic search of MEDLINE, EMBASE and The Cochrane Library, hand search scientific conference abstracts and check clinical trials registries for randomised control trials of participants with solid cancers who are administered parenteral anticoagulants. We anticipate identifying at least 15 trials, exceeding 9000 participants. Second, we will perform an individual participant data meta-analysis to explore the magnitude of survival benefit and address whether subgroups of patients are more likely to benefit from parenteral anticoagulants. All analyses will follow the intention-to-treat principle. For our primary outcome, mortality, we will use multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We will adjust analysis for important prognostic characteristics. To investigate whether intervention effects vary by predefined subgroups of patients, we will test interaction terms in the statistical model. Furthermore, we will develop a risk-prediction model for venous thromboembolism, with a focus on control patients of randomised trials.
Ethics and dissemination
Aside from maintaining participant anonymity, there are no major ethical concerns. This will be the first individual participant data meta-analysis addressing heparin use among patients with cancer and will directly influence recommendations in clinical practice guidelines. Major cancer guideline development organisations will use eventual results to inform their guideline recommendations. Several knowledge users will disseminate results through presentations at clinical rounds as well as national and international conferences. We will prepare an evidence brief and facilitate dialogue to engage policymakers and stakeholders in acting on findings.
Trial registration number
PROSPERO CRD42013003526.
doi:10.1136/bmjopen-2015-010569
PMCID: PMC4853971  PMID: 27130164
cancer; low molecular weight heparin; individual participant data meta-analysis; protocol; deep vein thrombosis; mortality
2.  Analysis of the potential of cancer cell lines to release tissue factor-containing microvesicles: correlation with tissue factor and PAR2 expression 
Thrombosis Journal  2016;14:2.
Background
Despite the association of cancer-derived circulating tissue factor (TF)-containing microvesicles and hypercoagulable state, correlations with the incidence of thrombosis remain unclear.
Methods
In this study the upregulation of TF release upon activation of various cancer cell lines, and the correlation with TF and PAR2 expression and/or activity was examined. Microvesicle release was induced by PAR2 activation in seventeen cell lines and released microvesicle density, microvesicle-associated TF activity, and phoshpatidylserine-mediated activity were measured. The time-course for TF release was monitored over 90 min in each cell line. In addition, TF mRNA expression, cellular TF protein and cell-surface TF activities were quantified. Moreover, the relative expression of PAR2 mRNA and cellular protein were analysed. Any correlations between the above parameters were examined by determining the Pearson’s correlation coefficients.
Results
TF release as microvesicles peaked between 30–60 min post-activation in the majority of cell lines tested. The magnitude of the maximal TF release positively correlated with TF mRNA (c = 0.717; p < 0.001) and PAR2 mRNA (c = 0.770; p < 0.001) expressions while the percentage increase correlated with PAR2 mRNA (c = 0.601; p = 0.011) and protein (c = 0.714; p < 0.001). There was only a weak correlation between resting TF release, and microvesicle release. However, TF release in resting cells did not significantly correlate with any of the parameters examined. Furthermore, TF mRNA expression correlated with PAR2 mRNA expression (c = 0.745; p < 0.001).
Discussion and Conclusions
In conclusion, our data suggest that TF and PAR2 mRNA, and PAR2 protein are better indicators of the ability of cancer cells to release TF and may constitute more accurate predictors of risk of thrombosis.
doi:10.1186/s12959-016-0075-3
PMCID: PMC4719208  PMID: 26793031
Tissue factor; Microvesicles; PAR 2; Blood coagulation; Cell line
3.  Palliative Radiotherapy in the Presence of Well-Controlled Metastatic Disease after Initial Chemotherapy May Prolong Survival in Patients with Metastatic Esophageal and Gastric Cancer 
Purpose
We report the outcomes of patients treated with palliative radiotherapy (pRT) to the primary tumour in the context of well-controlled metastatic disease after initial chemotherapy.
Materials and Methods
Clinical records of 132 patients with metastatic esophago-gastric (OG) cancer treated with palliative chemotherapy (pCT) between January 2009 and June 2013 were reviewed. Ninetyseven patients had responding or stable disease after 3 months of chemotherapy, of whom 53 patients received pRT to the primary tumour after initial chemotherapy in the presence of well-controlled metastatic disease (group A, pCT-RT). The remaining 44 patients were treated with pCT alone (group B, pCT). Treatment-related outcomes were assessed in above groups including time to local progression (TTLP), progression-free and overall survival.
Results
The median overall survival for patients treated with pRT after initial chemotherapy (group A) was 23.3 months (95% confidence interval [CI], 17.70 to 28.89 months) and significantly higher than the 14 months (95% CI, 10.91 to 17.08 months) in patients treated with pCT alone (group B) (p < 0.001). The use of pCT-RT was an independent predictor of OS in multivariate analysis. Local recurrence was observed in 12/53 of patients (23%) in group A compared to 16/44 (36%) in group B. The median TTLP was significantly higher in patients after pCT-RT at 17.3 months (5.23 months to 44.50 months) compared to 8.3 months (range, 4.10 to 25.23 months) in patients treated with pCT alone (p=0.006).
Conclusion
The possibility of pRT influencing systemic disease in advanced OG cancer has not been reported, and results from the present study present strong arguments for investigation of this therapeutic strategy in a randomized trial.
doi:10.4143/crt.2014.174
PMCID: PMC4614191  PMID: 25687854
Esophageal neoplasms; Stomach neoplasms; Palliative treatment; Radiotherapy; Chemotherapy
4.  Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients 
Melanoma Research  2015;25(5):432-442.
Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0–1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.
doi:10.1097/CMR.0000000000000185
PMCID: PMC4560270  PMID: 26225580
expanded access programme; ipilimumab; metastatic melanoma; treatment outcomes
5.  Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial 
The Lancet. Oncology  2015;16(8):967-978.
Summary
Background
Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival.
Methods
In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0–1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine [on days 1 and 8 every 21 days, for up to eight cycles]) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00939848, and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented.
Findings
Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 12·2 months (IQR 7·3–18·5), median progression-free survival was 8·0 months (95% CI 6·5–9·3) in the cediranib group and 7·4 months (5·7–8·5) in the placebo group (HR 0·93, 80% CI 0·74–1·19, 95% CI 0·65–1·35; p=0·72). Patients who received cediranib had more grade 3–4 toxic effects than did patients who received placebo: hypertension (23 [37%] vs 13 [21%]; p=0·05), diarrhoea (eight [13%] vs two [3%]; p=0·05); platelet count decreased (ten [16%] vs four [6%]; p=0·09), white blood cell decreased (15 [24%] vs seven [11%]; p=0·06) and fatigue (16 [24%] vs seven [11%]; p=0·04).
Interpretation
Cediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational.
Funding
Cancer Research UK and AstraZeneca Pharmaceuticals.
doi:10.1016/S1470-2045(15)00139-4
PMCID: PMC4648082  PMID: 26179201
6.  Characterization of physical properties of tissue factor–containing microvesicles and a comparison of ultracentrifuge-based recovery procedures 
Journal of Extracellular Vesicles  2014;3:10.3402/jev.v3.23592.
Microvesicles were isolated from the conditioned media of 3 cell lines (MDA-MB-231, AsPC-1 and A375) by ultracentrifugation at a range of relative centrifugal forces, and the tissue factor (TF) protein and activity, microvesicle number, size distribution and relative density compared. Also, by expressing TF-tGFP in cells and isolating the microvesicles, the relative density of TF-containing microvesicles was established. Nanoparticle tracking analysis (NTA) indicated that the larger-diameter microvesicles (>200 nm) were primarily sedimented at 100,000g and possessed TF-dependent thrombin and factor Xa generation potential, while in the absence of factor VII, all microvesicles possessed some thrombin generation capacity. Immuno-precipitation of TF-containing microvesicles followed by NTA also indicated the range of these microvesicles to be 200–400 nm. Analysis of the microvesicles by gradient density centrifugation showed that lower-density (<1.1 g/ml) microvesicles were mainly present in the samples recovered at 100,000g and were associated with TF antigen and activity. Analysis of these fractions by NTA confirmed that these fractions were principally composed of the larger-diameter microvesicles. Similar analysis of microvesicles from healthy or patient plasma supported those obtained from conditioned media indicating that TF activity was mainly associated with lower-density microvesicles. Furthermore, centrifugation of healthy plasma, supplemented with TF-tGFP-containing microvesicles, resulted in 67% retrieval of the fluorescent microvesicles at 100,000g, but only 26% could be recovered at 20,000g. Pre-centrifugation of conditioned media or plasma at 10,000g improved the speed and yield of recovered TF-containing microvesicles by subsequent centrifugation at either 20,000g or 100,000g. In conclusion, TF appears to be associated with low-density (1.03–1.08 g/ml), larger-diameter (200–350 nm) microvesicles.
doi:10.3402/jev.v3.23592
PMCID: PMC4134674  PMID: 25206957
tissue factor; microvesicles; ultracentrifugation; size distribution; relative density; thrombin generation activity
7.  A feasibility study to inform the design of a randomized controlled trial to identify the most clinically and cost effective Anticoagulation Length with low molecular weight heparin In the treatment of Cancer Associated Thrombosis (ALICAT): study protocol for a mixed-methods study 
Trials  2014;15:122.
Background
Venous thromboembolism is common in patients with cancer and requires anticoagulation with low molecular weight heparin. Current data informs anticoagulation as far as six months, yet guidelines recommend anticoagulation beyond six months in patients who have locally advanced or metastatic cancer. This recommendation, based on expert consensus, has not been evaluated in a clinical study. ALICAT (Anticoagulation Length in Cancer Associated Thrombosis) is a feasibility study to identify the most clinically and cost effective length of anticoagulation with low molecular weight heparin in the treatment of cancer associated thrombosis.
Methods/Design
ALICAT is a randomized multi-centre phase two mixed-methods study with three components: a randomized controlled trial, embedded qualitative study and a survey investigating pathways of care. The randomized controlled trial will compare ongoing low molecular weight heparin treatment for cancer-associated thrombosis versus cessation of low molecular weight heparin at six months treatment (current licensed practice) in patients with locally advanced or metastatic cancer. The embedded qualitative study will include focus groups with clinicians to investigate attitudes to recruiting to the study, identify the challenges of progressing to a full randomized controlled trial, and also semi-structured interviews with patients and relatives/carers to explore their attitudes towards participating in the study and potential barriers and concerns to participation. Finally, a UK wide survey exercise will be undertaken to develop a classification and enumeration system for the cancer associated thrombosis models and pathways of care.
Discussion
There is a lack of evidence determining the length of anticoagulation for patients with cancer associated thrombosis and subsequently treatment length varies. The ALICAT study will consider the feasibility of recruiting patients to a phase three trial.
Trial registration
Current Controlled Trials ISRCTN37913976.
doi:10.1186/1745-6215-15-122
PMCID: PMC4003288  PMID: 24726032
Venous thromboembolism; Pulmonary embolus; Deep vein thrombosis; Cancer associated thrombosis; Low molecular weight heparin; Randomized controlled trial; Mixed methods; Palliative care; Qualitative research; Framework analysis
8.  Isolated pancreatic heamorrhage in association with anticoagulation 
Thrombosis Journal  2013;11:20.
Haemorrhage is the primary complication of anticoagulation therapy with the gastrointestinal, urinary and nasal tracts the most common sites of bleeding. Haematoma within solid organs is uncommon especially in the absence of blunt trauma. We describe two patients on long term Warfarin therapy who developed focal haematomas within the pancreas. To the best of our knowledge these are the first isolated unprovoked focal pancreatic hematoma cases reported in the literature. The non-specific clinical symptoms and confusing radiological features mimicked pancreatic malignancy and this led to misdiagnosis in the one patient who underwent unnecessary surgical exploration. The haematoma was correctly identified in the second patient who was managed conservatively and had an uneventful recovery.
doi:10.1186/1477-9560-11-20
PMCID: PMC3849517  PMID: 24228740
9.  Developing a complex intervention for the outpatient management of incidentally diagnosed pulmonary embolism in cancer patients 
Background
Most patients with pulmonary embolism (PE) spend 5–7 days in hospital even though only 4.5% will develop serious complications during this time. In particular, the group of patients with incidentally diagnosed PE (i-PE) includes many patients with low risk features potentially ideal for outpatient management; however the evidence for their optimal management is lacking hence relative practices may vary considerably. We describe the development process, components, links and function of a nurse-led service for the management of patients with i-PE, developed in accordance to the UK Medical Research Council complex intervention guidance.
Methods
Phase 0 (Theoretical underpinning): The Pulmonary Embolism Severity Index (PESI) was selected for patient risk assessment and the American Society of Clinical Oncology (ASCO) guideline for the management of PE in cancer patients (2007) was selected as quality measure. Historical registry and audit data from our centre regarding i-PE incidence and management for the period between 2006 and 2009 illustrating the then current practices were reviewed. Phase 1 (Modelling): Modelling of the pathway included the following: a) Identification of training needs, planning and implementation of training schemes and development of transferable competencies and training materials. b) Mapping patient pathways and flow and c) Production of key documentation and Standard Operating Procedures for the delivery of the service.
Results
Phase 2 (Implementation and testing of the intervention): During the initial 12 months of implementation, remedial action was taken to address identified deficiencies regarding patient referral to the pathway, compliance with treatment protocol, patient follow up, selection challenges from the use of PESI in cancer patients and challenges regarding the “first-pass” identification of i-PE.
Conclusion
We have developed and piloted a complex intervention to manage cancer patients with incidental PE in an outpatient setting. Adherence to evidence- based care, improvement of communication between professionals and patients, and improved quality of data is demonstrated.
doi:10.1186/1472-6963-13-235
PMCID: PMC3718646  PMID: 23806053
Incidental pulmonary embolism; Outpatient management; Nurse-lead; Complex intervention
10.  The ethical decisions UK doctors make regarding advanced cancer patients at the end of life - the perceived (in) appropriateness of anticoagulation for venous thromboembolism: A qualitative study 
BMC Medical Ethics  2012;13:22.
Background
Cancer patients are at risk of developing blood clots in their veins - venous thromboembolism (VTE) - which often takes the form of a pulmonary embolism or deep vein thrombosis. The risk increases with advanced disease. Evidence based treatment is low molecular weight heparin (LMWH) by daily subcutaneous injection. The aim of this research is to explore the barriers for doctors in the UK when diagnosing and treating advanced cancer patients with VTE.
Method
Qualitative, in-depth interview study with 45 doctors (30 across Yorkshire, England and 15 across South Wales). Doctors were from three specialties: oncology, palliative medicine and general practice, with a mixture of senior and junior staff. Framework analysis was used.
Results
Doctors opinions as to whether LMWH treatment was ethically appropriate for patients who were symptomatic from VTE but at end of life existed on a shifting continuum, largely influenced by patient prognosis. A lack of immediate benefit coupled with the discomfort of a daily injection had influenced some doctors not to prescribe LMWH. The point at which LMWH injections should be stopped in patients at the end of life was ambiguous. Some perceived ‘overcaution’ in their own and other clinicians’ treatment of patients. Viewpoints were divergent on whether dying of a PE was considered a “good way to go”. The interventionalism and ethos of palliative medicine was discussed.
Conclusions
Decisions are difficult for doctors to make regarding LMWH treatment for advanced cancer patients with VTE. Treatment for this patient group is bounded to the doctors own moral and ethical frameworks.
doi:10.1186/1472-6939-13-22
PMCID: PMC3459796  PMID: 22947200
Venous thromboembolism; Heparin; Low-molecular-weight; Palliative care; Qualitative research; Ethics; Medical
11.  Diagnosis and management of people with venous thromboembolism and advanced cancer: how do doctors decide? a qualitative study 
Background
The treatment of cancer associated thrombosis (CAT) is well established, with level 1A evidence to support the recommendation of a low molecular weight heparin (LMWH) by daily injection for 3–6 months. However, registry data suggest compliance to clinical guidelines is poor. Clinicians face particular challenges in treating CAT in advanced cancer patients due to shorter life expectancy, increased bleeding risk and concerns that self injection may be too burdensome. For these reasons decision making around the diagnosis and management of CAT in people with advanced cancer, can be complex, and should focus on its likely net benefit for the patient. We explored factors that influence doctors’ decision making in this situation and sought to gain an understanding of the barriers and facilitators to the application of best practice.
Methods
Think aloud exercises using standardised case scenarios, and individual in depth interviews were conducted. All were transcribed. The think aloud exercises were analysed using Protocol Analysis and the interviews using Framework Analysis.
Participants: 46 participants took part in the think aloud exercises and 45 participants were interviewed in depth. Each group included oncologists, palliative physicians and general practitioners and included both senior doctors and those in training.
Setting: Two Strategic Health Authority regions, one in the north of England and one in Wales.
Results
The following key issues arose from the data synthesis: the importance of patient prognosis; the concept of “appropriateness”; “benefits and burdens” of diagnosis and treatment; LMWH or warfarin for treatment and sources of information which changed practice. Although interlinked, they do describe distinct aspects of the factors that influence doctors in their decisions in this area.
Conclusions
The above factors are issues doctors take into account when deciding whether to send a patient to hospital for investigation or to anticoagulate a patient with confirmed or suspected VTE. Many factors interweave and are themselves influenced by and dependent on each other. It is only after all are taken into account that the doctor arrives at the point of referring the patient for investigation. Some factors including logistic and organisational issues appeared to influence whether a patient would be investigated or treated with LMWH for a confirmed VTE. It is important that services are optimised to ensure that these do not hinder the appropriate investigation and management of individual patients.
doi:10.1186/1472-6947-12-75
PMCID: PMC3445826  PMID: 22818215
Venous thromboembolism; Cancer; Palliative; Clinical decision making
12.  Chemotherapy plus percutaneous radiofrequency ablation in patients with inoperable colorectal liver metastases 
AIM: To access the efficacy of chemotherapy plus radiofrequency ablation (RFA) as one line of treatment in inoperable colorectal liver metastases.
METHODS: Eligible patients were included in three Phase II studies. In the first study percutaneous RFA was used first followed by 6 cycles of 5-fluorouracil, leucovorin and irinotecan combination (FOLFIRI) (adjunctive chemotherapy trial). In the other two, chemotherapy (FOLFIRI or 5-fluorouracil, leucovorin and oxaliplatin combination) up to 12 cycles was used first with percutaneous RFA offered to responding patients (primary chemotherapy trials).
RESULTS: Thirteen patients were included in the adjunctive chemotherapy trial and 17 in the other two. At inclusion they had 1-4 liver metastases (up to 6.5 cm in size). Two patients died during chemotherapy. All patients in the adjunctive chemotherapy trial and 44% in the primary chemotherapy studies had their metastases ablated. Median PFS and overall survival in the adjunctive study were 13 and 24 mo respectively while in the primary chemotherapy studies they were 10 and 21 mo respectively. Eighty one percent of the patients had tumour relapse in at least one previously ablated lesion.
CONCLUSION: Chemotherapy plus RFA in patients with low volume inoperable colorectal liver metastases seems safe and relatively effective. The high local recurrence rate is of concern.
doi:10.4251/wjgo.v3.i4.60
PMCID: PMC3083497  PMID: 21528091
Chemotherapy; Colorectal cancer; Liver metastases; Radiofrequency ablation
13.  Chemoradiation in Pancreatic Adenocarcinoma: A Literature Review 
The Oncologist  2010;15(3):259-269.
This article reviews the published literature on the use of chemoradiation as a modality in various stages of pancreatic adenocarcinoma and highlights areas that future trials in this field should target for a way forward in this malignancy.
Adenocarcinoma of the exocrine pancreas has an annual incidence of 7,400 cases in the U.K. In comparison with other common cancers of solid organs, namely, breast, colorectal, and prostate cancer, pancreatic cancer has a high morbidity and mortality. Radical resection is possible in only 15%–20% of patients, and only 3%–4% of all patients presenting with this condition achieve long-term control and cure. Various strategies in the form of neoadjuvant and adjuvant treatment have been employed over the years to improve outcome, with limited success. Systemic chemotherapy remains the gold standard in the metastatic setting in good performance status patients, and adjuvant chemotherapy after resection of localized and locally advanced cancer has been found to improve outcome. The role of radiotherapy, however, remains controversial and is an area that merits further investigation in well-conducted multicenter trials at various stages of the disease in combination with systemic agents and exploiting recent advances in the delivery of radiotherapy. In this article, we review the published literature on the use of chemoradiation as a modality in various stages of pancreatic adenocarcinoma and highlight areas that future trials in this field should target for a way forward in this malignancy.
doi:10.1634/theoncologist.2009-0272
PMCID: PMC3227952  PMID: 20203172
Pancreatic cancer; Chemoradiation; Chemoradiotherapy; IMRT
14.  Low molecular weight heparin suppresses tissue factor-mediated cancer cell invasion and migration in vitro 
Elevated expression of tissue factor (TF) has been associated with an increased risk of thrombosis in the majority of cancers. Moreover, treatment of cancer patients with low molecular weight heparin (LMWH) appears to have beneficial effects that reach beyond controlling the immediate hypercoagulable state. In this study, we investigated the influence of the treatment of cancer cells with LMWH (0–2,000 μg/ml) on cell invasiveness and migration in cancer cell lines from five separate tissues; pancreatic, breast, colocarcinoma, ovarian and melanoma. The rate of cell invasion across collagen IV-coated membranes was suppressed in all cell lines tested on incubation with 2,000 μg/ml LMWH, but BxPC-3 and MDA-MB-231 cells also responded to the lowest concentration of 20 μg/ml LMWH. Furthermore, the rate of cell migration was reduced to varying extents in all of the cell lines tested on incubation with 20 μg/ml or higher concentrations of LMWH. The decrease in the rates of invasion and migration also strongly correlated with the reduction in TF protein expression and TF activity in these cells following incubation with LMWH. Moreover, the LMWH-mediated decreases in cellular invasion in the most affected cell lines (BxPC-3 and MDA-MB-231) were restored by transfection of the cells with the mammalian pCMV-XL5-TF expression vector allowing independent overexpression of TF. In conclusion, LMWH appears to suppress the rate of cancer cell invasion and migration in vitro, through a mechanism that is at least in part dependent on the TF protein expression and activity in cancer cells.
doi:10.3892/etm.2011.211
PMCID: PMC3440644  PMID: 22977511
tissue factor; low molecular weight heparin; cell invasion; cell migration
15.  The Hemostasis Apparatus in Pancreatic Cancer and Its Importance beyond Thrombosis 
Cancers  2011;3(1):267-284.
Laboratory evidence of aberrant coagulation is found in the majority of patients with advanced pancreatic cancer and a clinical consequence of this is the high incidence and prevalence of vascular thromboembolic events. Other sequelae are hypothesized to be the facilitation and acceleration of mechanisms that define the malignant phenotype, such as invasion, trafficking and anchoring, establishing the metastatic niche and inducing angiogenesis. We review the in vitro and preclinical evidence that supports the role of the coagulation apparatus in the metastatic process of pancreatic cancer, with a particular emphasis on interaction of this pathway with clinically-targeted growth factor receptor pathways. Links between hemostasis, angiogenesis and epidermal growth factor pathways and their significance as therapeutic targets are considered.
doi:10.3390/cancers3010267
PMCID: PMC3756361  PMID: 24212618
pancreatic cancer; thrombosis; hemostasis; tissue factor; microparticles
16.  Malignant melanoma as a target malignancy for the study of the anti-metastatic properties of the heparins 
Cancer Metastasis Reviews  2010;29(4):777-784.
The outlook for metastatic melanoma to the brain is dismal. New therapeutic avenues are therefore needed. The anti-metastatic mechanisms that may underpin the effects of low molecular weight heparins (LMWHs) in in vitro and preclinical melanoma models warrant translating to a clinical setting. This review outlines a rationale that supports our proposal that metastatic melanoma to the brain is a clinical setting in which to study the anti-metastatic potential of LMWHs. Prevention or delay of brain metastases in melanoma is a clinically relevant and measurable target. Studies to explore the effect of anticoagulants on cancer survival are underway in other malignancies such as lung, pancreas, ovary, breast, and stomach cancer. However, no study to our knowledge has a methodology that could produce clinical evidence in support of a mechanism for whatever benefit may be seen. The setting we propose would allow translation of the molecular knowledge of the metastatic pathways mediated by platelets and the selectins—all potential targets of heparin—in a “time to appearance” of brain metastases endpoint. Since brain metastases are so common and they have a singularly adverse impact on survival, the “biological neuroprotection” model we propose in metastatic melanoma could provide the translational evidence to support the benefit of LMWHs in melanoma. More significantly, this would open the door to a wider “anti-metastatic” approach that could have much greater impact in patients with minimal disease being treated in adjuvant settings for the more common malignancies such as breast and colon cancer.
doi:10.1007/s10555-010-9263-y
PMCID: PMC2962791  PMID: 20936327
Low molecular weight heparins; Metastatic melanoma; Selectin; Anti-metastatic
17.  Mesenteric desmoid tumor developing on the site of an excised gastrointestinal stromal tumor 
Rare Tumors  2010;2(2):e33.
We present a case of a rare and unusual occurrence of a desmoid tumor at the site of a resected gastrointestinal stromal tumor and mimicking a recurrence, with a brief discussion of the management of desmoid tumors.
doi:10.4081/rt.2010.e33
PMCID: PMC2994513  PMID: 21139835
mesenteric desmoid tumor; gastrointestinal stromal tumor.
18.  Pancreatic cancer: A model cancer for the study of the therapeutic effects of anticoagulants 
Cancer-related thromboembolic disease is a well recognized syndrome since first described by Armand Trousseau in 1865. Preventing the morbidity and mortality related to thromboembolism in these patients is becoming a priority research area with the advent of new anti-coagulants. It is only recently that randomized trials of improved quality are been undertaken to study this question. Many of these trials however are still not accounting for the heterogeneity of “cancer” in terms of anatomical site, histology, stage and treatment. This editorial review highlights why pancreatic cancer may serve as a model malignancy to study this question.
doi:10.4251/wjgo.v1.i1.38
PMCID: PMC2999087  PMID: 21160772
Pancreatic Cancer; Vascular; Thromboembolism; Vascular thromboembolic disease; Heparin; Anticoagulants
19.  Sinusoidal obstruction syndrome (veno-occlusive disease) in a patient receiving bevacizumab for metastatic colorectal cancer: a case report 
Introduction
We present the case of a patient with colon cancer who, while receiving bevacizumab, developed sinusoidal obstruction syndrome (veno-occlusive disease) (SOSVOD). Certain antitumour agents such as 6-mercaptopurine and 6-thioguanine have also been reported to initiate hepatic SOSVOD in isolated cases. There have been no reports so far correlating bevacizumab with SOSVOD.
Case presentation
A 77-year-old man was being treated with oxaliplatin and a modified de Gramont regimen of 5-fluorouracil for metastatic colon cancer. Bevacizumab (7.5 mg/kg) was added from the seventh cycle onwards. Protracted neutropenia and thrombocytopenia led to discontinuation of oxaliplatin after the ninth cycle. A computed tomography scan showed complete response and bevacizumab was continued for another 3 months, after which time the patient developed right hypochondrial pain, transudative ascites, splenomegaly and abnormal liver function tests. Upper gastrointestinal endoscopy showed oesophageal varices. Liver biopsy showed features considered to be consistent with SOSVOD. Bevacizumab was stopped and a policy of watchful waiting was adopted. He tolerated the acute damage to his liver and subsequently the ascites resolved and liver function tests normalised.
Conclusion
We need to be aware that bevacizumab can cause sinusoidal obstruction syndrome (veno-occlusive disease) and that the occurrence of ascites should not be attributed to progressive disease without appropriate evaluation.
doi:10.1186/1752-1947-2-227
PMCID: PMC2481264  PMID: 18620573

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