Paget-Schroetter syndrome (PSS) is a rare form of thoracic outlet syndrome causedby axillosubclavian vein thrombosis which typically presents in healthy young adults. Prompt therapy, traditionally by means of catheter-directed thrombolysis (CDT) prior to definitive surgery, can prevent the subsequent onset of postthrombotic syndrome (PTS) and considerable disability. As CDT is associated with major haemorrhage and high overall treatment cost, pharmacomechanical thrombectomy (PMT) seems to be an attractive alternative which combines pharmacological thrombolysis with mechanical clot disruption. The Trellis-8 peripheral infusion catheter is an example of such a treatment which provides topical thrombolysis in an isolated zone. We describe the use of the Trellis-8 PMT system in the successful management of three patients with PSS. Paget-Schroetter syndrome (PSS) is the consequence of axillosubclavian vein thrombosis arising from thoracic outlet syndrome. Typically occurring in active young adults, it is the consequence of repetitive micro trauma to an abnormally stenotic subclavian vein and results in acute or acute-on-chronic thrombosis .Serious sequelae can result from untreated PSS, including pulmonary embolism (PE)  and postCatheter-directed thrombolysis (CDT) has become the standard of thrombolytic care in many institutions , 4, 5 buPMT devices include the AngioJet system and the Trellis-8 device  , 10, 11.We describe three cases of PSS managed in our institution with PMT via the Trellis-8 device prior to first rib resection.An 18-year-old male presented to the emergency department with a three-day history of pain, swelling, and discolouration in the left arm and clinical diagnosis of upper limb deep vein thrombosis was made.Catheter venography demonstrated occlusion of the left subclavian vein around the first rib with extensive thrombus and collateralised flow, typical of PSS. The brachiocephalic vein and superior vena cava were patent. ″ wire . 5000 units of unfractionated heparin were given via the sheath. An 8  French, 15 cm Trellis-8 device  was placed across the lesion and the balloons inflated. The distal balloon was positioned in the brachiocephalic vein and the proximal balloon in the axillary vein . An 8 French, 9 cm Brite-tip sheath  was placed in the brachial vein distal to the thrombus, and the occlusion was crossed with a hydrophilic 0.035ary vein , isolatiary vein  and intoVenoplasty was then performed on the tight, irregular stenosis of the subclavian vein as it crossed the first rib using an 8 × 40 mm fox plus balloon catheter . An intravenous unfractionated heparin infusion was commenced at 1000 u per hour, and the patient was listed for emergency first rib resection (within 2 hours). Our procedure was well tolerated by the patient with no requirements for sedoanalgesia.Repeating venography the following day showed a residual stenosis which responded to 10 mm balloon venoplasty. Subsequent duplex studies at 4 days and 6 weeks showed a patent vein with no residual stenosis. At discharge, anticoagulation using warfarin was commenced to achieve a target international normalised ratio (INR) of between 2.5 and 3.5. By six months, the patient was well with minimal swelling in the arm, anticoagulation was discontinued, and he has resumed his normal activities.A 26-year-old female presented to the emergency department with a history of sudden-onset left arm pain and swelling. Past medical history included recent commencement of the oral contraceptive pill and a first-degree relative with DVT.Venography revealed occlusive thrombus in the axillary and subclavian vein with extensive collateralisation . PMT wasThe arm swelling rapidly reduced, and the patient was discharged on full anticoagulation. She has been lost to followup.A 57-year-old male with positive antiphospholipid antibodies developed acute right arm swelling following strenuous exercise. Venous Doppler ultrasound demonstrated occlusive thrombus in the right subclavian and brachial veins. He underwent PMT with the Trellis-8 device using 10 mg rT-PA. Angiographic results were excellent  and the The patient was discharged following resolution of his symptoms and remain well at 6-month followup. Paget-Schroetter syndrome is a consequence of an anatomically deranged thoracic outlet, most commonly caused by congenital bands, cervical ribs, scalenus tendon hypertrophy, or variant insertion of the costoclavicular ligament. Consequently, normal upper-limb movements provide insult to the subclavian vein which responds with venous intimal hypertrophy, chronic inflammation, peri-venular fibrosis and acute or acute-on-chronic thrombosis.Presenting features include upper-limb pain, heaviness, swelling and cyanosis and are often preceded by a history of strenuous exercise or trauma. The influence of inherited thrombophilic disorders on this condition is unresolved .Postthrombotic syndrome (PTS) is a complication of venous thrombosis and has recently been recognised in upper-limb DVT. With an overall incidence of 7%–46% , it compAlthough jugulosubclavian vein bypass and patch venoplasty have been described in the management of PTS , supportCatheter-directed thrombolysis has become standard practice in many institutions prior to surgical management. However, this often requires Intensive Care Unit (ICU) admission, regular blood sampling and repeated angiography to assess treatment response. Median time to complete resolution in the upper-limb DVT averages 24–48 hours , and CDTPharmacomechanical thrombectomy obviates the need for ICU admission and eliminates the systemic effects of thrombolytic agents. In particular, the Trellis-8 system was shown to have a significantly greater rate of clot lysis (93%) in comparison with CDT 79%) in a recent meta-analysis of published trials [9% in a rAs Trellis-8 requires lower doses of a thrombolytic agent which is confined to the treatment zone, it is associated with lower rate of haemorrhagic complications, a shorter time in the angiography suite, and minimal (if any) time in the ICU. Consequently, Trellis-8 has been shown to confer an economic advantage to CDT [The Trellis-8 catheter has several advantages over other PMT devices. Firstly, there is no significant systemic thrombolysis evidenced by laboratory markers   which deHowever, certain issues require careful consideration when using the Trellis-8 infusion catheter. Firstly, although thrombolytic doses and the risk of haemorrhage are reduced, the overall safety of Trellis-8 in upper-limb PMT has not been formally evaluated in clinical trials. Additionally, concerns have been raised regarding the systemic effects of PMT, for example, the induction of bradyarrhythmias . FurtherPSS is a condition of young, healthy, and active patients with potentially serious long-term sequelae if untreated or undertreated. We have described three cases of successful treatment of PSS incorporating the Trellis-8 peripheral infusion catheter. PMT has several advantages over CDT in the management of PSS as a precursor to surgery, and the Trellis-8, which specifically provides isolated PMT, seems to be safe, effective and well tolerated in this patient population. This paper seeks to assist in raising the awareness of the clinical and venographic features of PSS and provide additional management options for the endovascular specialist.


Excess alcohol consumption adversely affects one-carbon metabolism and increases the risk of liver disease and liver cancer. Conversely, higher folate levels have been inversely associated with liver damage. The current study investigated the effects of alcohol and one-carbon metabolite intake on liver cancer incidence and liver disease mortality within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals (CIs) in a population of 27,086 Finnish males with 194 incident liver cancers and 213 liver disease deaths. In a nested case-control subset , logistic regression was used to calculate odds ratios and 95% CIs for serum one-carbon metabolites in relation to liver cancer risk.Daily alcohol consumption of more than 20.44 g was associated with an increased risk of both liver cancer incidence (Hazard Ratio (HR) 1.52, 95%CI 1.06–2.18) and liver disease mortality . These risks were unaffected by one-carbon metabolite intake. Similarly, in the case-control study, none of the serum one-carbon metabolites were associated with liver cancer.The current study provided no convincing evidence for a protective association of one-carbon metabolite intake or serum level on the risk of liver cancer or liver disease mortality. Excessive consumption of alcohol is a well-established risk factor for both liver disease and liver cancer The present study sought to assess the effect of alcohol consumption and one-carbon metabolite  intake on liver cancer incidence and liver disease mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. In addition, a nested case-control study examined the effects of serum levels of one-carbon metabolite levels and alcohol consumption on the development of liver cancer.Written informed consent was provided by all study participants. The study was approved by the institutional reviews boards of the National Cancer Institute, Bethesda, Maryland, U.S., and the National Public Health Institute, Helsinki, Finland.dl-α-tocopherol acetate (50 mg/day), all-trans-β-carotene (20 mg/day), or both, would reduce the incidence of lung or other cancers in male smokers. Men  between the ages of 50 and 69 years living in southwestern Finland were recruited between the years 1985 and 1988 and assigned to 1 of 4 groups in a 2×2 factorial design. The intervention ended on April 30, 1993, however cancer ascertainment via the Finnish Cancer Registry is still ongoing.As previously described, the ATBC Cancer Prevention Study was conducted in Finland as a joint project between the U.S. National Cancer Institute and the National Public Health Institute of Finland th revision of the International Classification of Diseases (ICD). Liver disease deaths (n = 239) through December 31, 2009 were identified via the Finnish Register of Causes of Death using code 571 for ICD-8 and ICD-9 and codes K70-K77 for ICD-10. Eight participants who developed incident liver cancer but died of liver disease were only included in the liver cancer analysis. After excluding individuals with missing questionnaire data and 28 men with self-reported history of cirrhosis at baseline, 194 incident liver cancer cases and 213 liver disease deaths were available for analysis in a cohort of 27,086 persons.Incident liver cancer cases (n = 208) diagnosed through December 31, 2009 were identified through the Finnish Cancer Registry using topography code 155 of the 9Within the nested case-control study, incident liver cancer cases were diagnosed through April 30, 2002. Cases were matched 1∶1 with controls who were alive and free of cancer at the time the case was identified. The matching factors were age (within 5 years) and date of serum draw (within 30 days). After excluding missing questionnaire data and serum data, 95 cases and 103 controls were available for analysis.At baseline, all participants completed a general risk factor questionnaire which included queries concerning vitamin supplement use. Participants also completed a food-frequency questionnaire (FFQ) to measure usual dietary consumption within the past 12 months. The FFQ was completed by 93% of study participants. The reproducibility and validity have been previously reported Study participants provided fasting blood samples prior to intervention-arm randomization. The serum samples were stored at −70°C prior to analysis in 2005–2006. Serum levels of folate and vitamin B12 were determined by radioimmunoassay  in the laboratory of Dr. Jacob Selhub at Tufts University, Boston, MA. The principal active form of vitamin B6, pyridoxal 5′-phosphate, was determined using the tyrosine decarboxylase apoenzyme method Hepatitis B virus (HBV) status was determined by testing for the presence of hepatitis B surface antigen (HBsAg) using an enzyme immunoassay . Hepatitis C virus (HCV) status was determined by testing for antibody to HCV (anti-HCV) using an enzyme-linked immunosorbent assay .2, 25–29 kg/m2, ≥30 kg/m2), diabetes  and study arm . In addition, HRs were calculated for the relationship between alcohol consumption and liver cancer and liver disease, stratified by tertiles of one-carbon metabolite intake. Likelihood ratio tests for interaction across tertiles of one-carbon metabolite consumption were computed based on cross-product terms with alcohol use. Tests for trend were calculated by assigning each participant the median value within each tertile and entering that value as a continuous variable in the adjusted multivariate model.Categorization of folate, cysteine, vitamin B6, riboflavin, vitamin B12, methionine, and alcohol was based on the total adjusted intake at baseline divided into tertiles within the entire cohort. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% Confidence Intervals (CIs). Models were adjusted for age (continuous age at randomization), education , smoking , body mass index (BMI)  and 95% CIs for the associations between alcohol and one-carbon metabolites and liver cancer incidence. The models were adjusted for study arm, age, HBV and HCV. In addition, ORs were calculated for median alcohol intake and serum one-carbon metabolite level in an interaction analysis adjusting for study arm, HBV and HCV. Pearson correlation coefficients between the serum levels and intake levels of the one-carbon metabolites were also calculated.The proportional hazard assumption was verified using a time interaction model. Statistical significance was set at P<0.05 based on two-sided tests. All statistical analyses were performed using SAS version 9.2 .The population characteristics of the study participants by tertile of each one-carbon metabolite and alcohol consumption are shown in Increasing levels of alcohol intake was also significantly associated with increased risk of liver disease mortality (p-trend<0.0001). In addition, the highest tertiles of folate , riboflavin  and vitamin B12  intake were all associated with an increased risk of liver disease mortality. In contrast, cysteine intake was inversely, but not significantly, associated with risk (p-trend = 0.07). Intakes of vitamin B6 and methionine had no association with liver disease mortality.In addition, interactions between alcohol and one-carbon metabolites were examined for effects on liver cancer incidence and liver disease mortality. None of the interactions were statistically significant (data not shown).In the nested case-control analysis, the relationships of alcohol consumption and serum one-carbon metabolite levels with liver cancer were examined. As shown in The Pearson correlation coefficients examining the correlation between intake and serum levels one-carbon metabolite levels were all statistically significant except for cysteine , with coefficients ranging from 0.31 for vitamin B6 to 0.64 for vitamin B12.In the current study, alcohol intake was positively associated with an increased risk of both liver cancer incidence and liver disease mortality, as anticipated. None of the one-carbon metabolites were significantly associated with liver cancer risk, however. Conversely, folate, riboflavin and vitamin B12 intakes were associated with an increased risk of liver disease mortality. The examination of serum levels of one-carbon metabolites in relation to liver cancer found no significant relationships.One-carbon metabolism, conducted by linked biochemical pathways that involve the interactions of B vitamins, homocysteine and methionine, is critical for the synthesis of both DNA and S-adenosylmethionine, a methyl donor for many reactions including DNA methylation While several experimental animal studies have shown that depleted one-carbon metabolites are associated with hepatocellular carcinoma (HCC) risk, only one human case-control study to date has found serum folate levels to be inversely associated with liver cancer In addition to differences in dietary patterns, smoking and drinking patterns also differed in the NIH-AARP and ATBC studies. All men in the ATBC study smoked 5 or more cigarettes per day at baseline, while in the NIH-AARP study 35% of participants were never smokers. Smokers are known to have lower serum levels of folate, vitamin B6, and vitamin B12, possibly due to a negative effect of components in tobacco smoke on one-carbon metabolism While intakes of one-carbon metabolites were not associated with the development of liver cancer, intakes of several metabolites were associated with increased risk of liver disease mortality. It is possible that these findings are due to men with existing liver disease at baseline being counseled to increase their intakes of B vitamins to prevent deficiencies associated with liver damage. Although men with cirrhosis were excluded from study participation, other forms of liver disease were not exclusionary criteria.Strengths of this study include using both a prospective design to examine one-carbon metabolite intake, and a nested case-control design to examine serum levels of one-carbon metabolites. The present study was also able to adjust for HBV and HCV which are known risk factors for liver disease and liver cancer. Study limitations include having a rather small case number, a population restricted to male cigarette smokers and the determination of dietary intake by a food-frequency questionnaire rather than a 24 hour dietary record. In addition, the inclusion of ex-drinkers in the non-drinking category may have biased the estimates toward the null. As a result, caution should be exercised when attempting to extrapolate the results to other populations.As a prior study in the NIH-AARP cohort found an inverse association between folate intake and risk of hepatocellular carcinoma among alcohol consumers, but the current study did not, further research on the topic is warranted.


Currently, no data on the optimal time point after acute ischemic stroke (IS) at which high-sensitivity C-reactive protein (hs-CRP) level is most predictive of unfavorable outcome. We tested the hypothesis that hs-CRP levels during both acute (48 h after IS) and convalescent (21 days after IS) phases are equally important in predicting 90-day clinical outcome after acute IS. We further evaluated the impact of erythropoietin (EPO), an anti-inflammatory agent, on level of hs-CRP after acute IS.Totally 160 patients were prospectively randomized to receive either EPO therapy   at 48 h and 72 h after acute IS, or placebo . Serum level of hs-CRP was determined using ELISA at 48 h and on day 21 after IS and once in 60 healthy volunteers.Serum level of hs-CRP was substantially higher in all patients with IS than in healthy controls at 48 h and day 21 after IS . Levels of hs-CRP did not differ between group 1 and 2 at 48 h and day 21 after IS . Multivariate analysis showed that hs-CRP levels (at 48 h and day 21) were independently predictive of 90-day major adverse neurological event (MANE)  , whereas EPO therapy was independently predictive of reduced 90-day MANE .EPO therapy which was independently predictive of freedom from 90-day MANE did not alter the crucial role of hs-CRP levels measured at 48 h and 21-day in predicting unfavorable clinical outcome after IS. Numerous studies have already shown that inflammation plays a crucial role in the initiation of endothelial dysfunction, atherosclerosis and plaque formation, propagation of plaque burden, and finally, rupture of the vulnerable plaque and acute arterial obstructive syndrome (AOS) -4. AlthoIndeed, not only is hs-CRP an inflammatory biomarker, but it has also been proved to directly participate in the inflammatory process contributing to acute AOS ,4,7. BesCRP, an acute-phase reactant, is synthesized and secreted in the liver 6 h after an acute inflammatory stimulus ,13 regarNot only has erythropoietin (EPO) been shown to enhance erythropoiesis under anemic condition, but it has also been reported to be anti-apoptotic ,18, antiThis study was a sub-study of our recently reported clinical trial  which waOur recently reported clinical trial  was prosStroke was defined as a sudden onset of loss of global or focal cerebral function persisting for more than 24 hours  includedAdditionally, patient who had history of allergy to EPO, hematological disorders including myeloproliferative disorder, leukemia, thrombocythemia, polycythemia, past history of deep vein thrombosis, abnormal elevation of hemoglobin , or received thrombolytic therapy upon presentation were also excluded from this trial.An estimated sample size of 157 patients was based on the effective size with an α = 0.05, a power of 80%, a difference in circulating level of EPCs between the patients with NIHSS < 12 and NIHSS ≥12 at 48 h after acute IS of 0.3%, and a standard deviation of 1.0% in patients with NIHSS < 12 and 0.9% in patients with NIHSS ≥ 12 at 48 h after acute IS. A 20% rate of protocol violations was assumed. The calculation of sample size for specific objective was based on our recent report .An overview of the study protocol has been shown in the clinical trial in details . From OcSixty age- and gender-matched healthy volunteers were also studied for circulating level of EPCs and serum level of hs-CRP. Informed consent was obtained from all study subjects.Evaluation of severity of neurological impairment in the patients with stroke was based on the National Institutes of Health Stroke Scale (NIHSS)  during tAfter admission, other imaging examinations included chest X-ray, routine brain computed tomography, duplex scanning of the carotid arteries, and routine cardiac analysis by 12-lead electrocardiogram and echocardiography.The criteria for radiological diagnosis of acute IS included brain computed tomography showing a new finding of low attenuation density in focal or diffuse brain area, or MRI examination showing area(s) of high intensity (bright spots) on diffusion weighted image (DWI) MRI as described in details in our recent report .Blood samples were obtained at 48 h (acute phase) and on day 21  after IS at 9.00 a.m. for assessment of the serum level of hs-CRP in IS patients. Blood samples were also obtained once in control subjects who participated in a health screening program in our Health Clinic at 9.00 a.m.0 C before hs-CRP assay.Venous blood was obtained from the antecubital vein into tubes with EDTA. White blood cell (WBC) count, red blood cell (RBC) count, hemoglobulin level, and biochemical data were acquired at 48 h and on day 21 after acute IS using standard laboratory methods. After centrifugation, aliquots of the serum samples were stored at -80Serum hs-CRP level was measured by duplicated determination with a commercially available ELISA kit . The analytical range extended from 5 to 5000 pg/mL. The intra-individual variability of hs-CRP levels was assessed in both study patients and control subjects. The mean intra-assay coefficients of variance were all less than 4.0%.Aspirin was the first choice for patients with acute stroke in the absence of allergy, intolerance, or a history of peptic ulcer or upper gastrointestinal tract bleeding during aspirin therapy. Clopidogrel was used in patients intolerant to aspirin therapy. Other commonly used drugs included statins, angiotensin converting enzyme inhibitors (ACEIs)/angiotensin II type I receptor blockers (ARB), diuretics, calcium channel blocking agents, and beta blockers.t test. Continuous variables among the three groups were analyzed by one-way ANOVA followed by multiple comparison procedure by Bonferroni correction. The Spearman's Rank test was used to assess the correlations between quantitative variables without normal distribution. The receiver operating characteristics (ROC) curve analysis was utilized to determine which serum hs-CRP level at 48 h after acute IS was the most powerful predictive of 90-day MANE. Multivariate logistic regression analysis was utilized for identifying the independent predictors of prognostic outcomes. Statistical analysis was performed using SPSS statistical software for Windows version 13 . A value of p < 0.05 was considered statistically significant.Categorical data were analyzed by Chi-square test or Fischer's exact test between two groups. Continuous variables between two groups were performed using Student 1C level, incidence of extra-cranial carotid artery stenosis, and medication use did not differ between group 1 and group 2.Table By day 21, the serum level of hs-CRP also did not differ between EPO group and placebo group. However, the hs-CRP level remained significantly higher in both EPO group and placebo group compared with that in the healthy control group .There were no significant differences in terms of NIHSS, Barthel Index, and modified Rankin Scale score at 48 h after acute IS between patients in group 1 and group 2. Besides, the 90-day NIHSS was also similar between the two groups. Similarly, the 90-day mortality did not differ between the two groups. However, the incidence of recurrent stroke and 90-day NIHSSS ≥ 8 were remarkably higher in group 2 than in group 1. Moreover, the combined major adverse neurological event (MANE)  was notably higher in group 2 than in group 1.All the variables in Table The statistically significant predictors which were shown in Table The ROC curve analysis Figure  revealedAssessment of the correlation between hs-CRP level and degree of neurological impairment demonstrated good correlations between serum level of hs-CRP and NIHSS, Barthel Index, as well as modified Rankin Scale score at 48 h after acute IS Figure , 3 &4. BThis study, which compared the role of serum hs-CRP level during acute phase (at 48 hour) with that during convalescent phase (day 21) in predicting 90-day clinical outcome of patients after acute IS with or without EPO therapy, yielded several striking implications. First, hs-CRP levels during both acute and convalescent phases were remarkably higher in IS patients than in healthy control subjects. Second, EPO therapy did not significantly alter the serum level of hs-CRP. Third, hs-CRP levels during both acute phase and convalescent phase of IS were significantly and independently predictive of 90-day MANE. In contrast, EPO therapy was significantly and independently predictive of freedom from 90-day MANE.Consistent with the results of other recent studies ,14, our The association between increased circulating level of hs-CRP and unfavorable short-term ,15 and lInterestingly, although the level of hs-CRP during acute phase of IS has been shown to be significantly predictive of the severity of stoke and prognostic outcome ,15,31,32The importance of the current study is that hs-CRP levels were obtained from the same group of study patients during both acute and convalescent phases for determining the association of this biomarker with clinical outcome. In addition, another important finding is that hs-CRP level at 48 h after IS was significantly and strongly correlated with NIHSS, Barthel Index, and modified Rankin Scale score. Above all, the most important finding is that hs-CRP levels during both acute and convalescent phases were significantly and independently predictive of 90-day MANE. Our findings, therefore, support the validity of using serum hs-CRP level in predicting clinical outcome in patients with and without IS regardless of the timing for blood sampling ,15,31-33Some clinical observational studies ,37 have The baseline variables Table  were ideThe association between blood pressure and clinical outcome after acute IS has been extensively investigated in previous studies -41. ContFirst, this study only chose two time points rather than constant blood samplings during the whole time course to determine the changes in serum level of hs-CRP in patients after acute IS. Therefore, we did not provide information on the serial changes in circulating hs-CRP level after IS. Second, although this study did not show significant reduction in serum hs-CRP level following a standard EPO dosage, whether a higher dose of EPO would actually reduce the serum level of hs-CRP in the setting of acute IS remains unclear.Serum level of hs-CRP during both acute and convalescent phases was significantly and independently predictive of 90-day MANE, whereas EPO therapy was significantly and independently predictive of freedom from 90-day MANE. However, EPO treatment did not diminish the predictive value of hs-CRP for unfavorable clinical outcome after acute IS.The authors declare that they have no competing interests.All authors have read and approved the final manuscript.YKH, TTH, CHT, and SL designed the experiment, drafted and performed animal experiments. CSY, SS, CYL, LHS and YCM were responsible for the laboratory assay and troubleshooting. YKH, THT and HKY participated in refinement of experiment protocol and coordination and helped in drafting the manuscript.All authors report no disclosures and have any commercial associations or interests, including consultancies, stock ownership or other competing equity interest.Tzu-Hsien Tsai contributed equally as the first author to this work. Chun-Man Yuen contributed equally compared with the corresponding author to this work.


A better understanding of multimolecular interactions involved in tumor dissemination is required to identify new effective therapies for advanced prostate cancer (PCa). Several groups investigated protein-glycan interactions as critical factors for crosstalk between prostate tumors and their microenvironment. This review both discusses whether the “galectin-signature” might serve as a reliable biomarker for the identification of patients with high risk of metastasis and assesses the galectin-glycan lattices as potential novel targets for anticancer therapies. The ultimate goal of this review is to convey how basic findings related to galectins could be in turn translated into clinical settings for patients with advanced PCa. Prostate cancer (PCa) is the second most common cancer in men and represents a significant cause of mortality worldwide . About 1Effective cancer therapies for PCa typically capitalize on molecular differences between healthy and neoplastic tissues that can be targeted with drugs . In the Galectins  are a family of evolutionarily conserved glycan-binding proteins characterized by their affinity for N-acetyllactosamine sequences which can be displayed on cell surface glycoconjugates , 10. ThrInterestingly, alterations in Gal expression are observed in pathologic processes such as inflammation, cancer, and autoimmunity , 15–17. http://www.functionalglycomics.org/CFGparadigms/index.php/Main_Page). Members of the Gal family are found in vertebrates, invertebrates, and protists; Gal-related sequences have also been found in plants and viruses. The high degree of conservation of Gal sequences suggests that they have an important role in basic cellular mechanisms [Galectins are a family of fifteen described lectins that bind to the carbohydrate portion of cell surface glycoproteins or glycolipids and are defined by at least one carbohydrate recognition domain (CRD) with affinity for beta-galactosides through a conserved sequence motif . Howeverchanisms , 20. Howchanisms ).Galectins have been subdivided into three groups  based onGalectins are synthesized in the cytoplasm and secreted using a nonclassical pathway ; thus, tGalectins could be affected by posttranscriptional modifications such as cleavage or phosphorylation. In fact, phosphorylation or proteolysis affects Gal-3 structure and localization altering important biologic functions of this lectin in human carcinomas –48. Gal-The expression pattern of different Gals changes during tissue development and is altered at sites of inflammation and tumor. Different reports in colon, breast, prostate, thyroid, and laryngeal cancers have demonstrated an important role of Gals in tumor emergence and progression (see for review ). At thiin vitro by Vaarala and colleagues [Few studies investigated the expression of Gals in normal prostate , 53 and lleagues ) is ablelleagues .Studying the role of Gals in PCa cell lines is certainly not enough to validate relevance in the human pathology. For clinical relevance, Lotan's group has studied by immunohistochemistry (IHC) the expression of Gals in normal human prostate tissue and prostate adenocarcinoma, containing formalin-fixed, paraffin-embedded sections of 7 normal human prostates, 8 cases of prostatic intraepithelial neoplasia (PIN), 20 primary adenocarcinomas of the prostate, and 12 PCa metastases. Gal-1 was expressed in most cases, irrespective of the histology stages. In contrast, Gal-3 expression significantly decreased in primary carcinoma and metastatic disease compared with normal and premalignant tissue, suggesting that loss of Gal-3 expression may be associated with the evolution of the disease . Additio Furthermore, alteration in the nuclear/cytoplasmic expression ratio of Gal-3 correlates with PCa progression , and decAn evaluation of Gal-3 expression in tissue microarrays prepared from 83 tumor, 78 adjacent-benign, and 75 benign tissues obtained from 83 patients who had undergone prostatectomy for clinically localized PCa suggests that the expression of this lectin could be used as predictor of biochemical recurrence . In thisin vivo [in vivo. Gal-8 mRNA, which has been postulated as a PCa marker [As Gal-1 and Gal-3 are the two best studied Gal members in cancer and particularly in PCa, we wondered if other Gals could show a particular profile of expression. As Gals play fundamental, although divergent, roles in diverse tumor microenvironments , identifin vivo –60. Totaa marker , 61, wasa marker .The differential expression of Gals in PCa cell lines prompted us to investigate the profile of these lectins in biopsies obtained from 60 patients naive of any therapeutic treatment. Samples were classified according to TNM classification . A large spectrum of PCa phases, T1, T2, T3, and T4 in addition to a benign stage (BHP), were represented. Gal expression was analyzed by IHC in paraffin embedded tissue samples. These results are summarized in Galectins have contrasting effects on apoptosis. While Gal-1 is an apoptosis promoter, Gal-3 shows both pro- or antiapoptotic effects depending on its subcellular localization in PCa. For instance, induction of differentiation and apoptosis by butyrate was investigated in four human PCa cell lines including LNCaP . Treatmeper se is not the final determinant of cell apoptosis; instead, regulation of lectin expression and the glycan repertoire determines the final phenotype, sensitivity, or resistance to apoptosis induction. It is well demonstrated that Gal-1 could act extracellularly to induce apoptosis in glycopermissive cells . In PCa,In an opposite way, Gal-3 has a dual role in controlling cell apoptosis depending on the PCa cell model. To study whether Gal-3 regulates drug-induced apoptosis, Raz's group either transfected LNCaP cells with Gal-3 or silenced Gal-3 expression in PC-3 cells. They tested sensitivity to cis-diammine-dichloroplatinum and showed apoptosis induction in Gal-3 expressing LNCaP, more precisely through inhibition of cytochrome c release and caspase-3 activation . On the More interestingly, Gal-3 also shows a dual role upon its subcellular localization promoting or alternatively inhibiting apoptosis in Gal-3 transfected LNCaP cells. While nuclear Gal-3 targeting allowed by fusion with nuclear localization sequences was found to have proapoptotic properties, the cytoplasmic form is antiapoptotic and promotes tumor progression . These rDuring tumor progression, malignant cells acquire the ability to overcome cell-cell adhesion and invade surrounding tissues, a state known as metastatic disease. It is important to understand this process and identify inducers of tumor metastasis in order to develop treatments that target metastatic cells for long-term tumor regression.Galectin-1 is involved in numerous biological functions including capillaries formation. Gal-1 is expressed by endothelial cells (EC) from capillaries infiltrating the tumor tissue in 64% of the cases of 100 human prostate carcinoma samples, but in only few cases (7%) in endothelial cells in the adjacent nontumoral stroma. These results strongly suggest that tumor cells induce Gal-1-expressing EC allowing tumor adhesion to vessel endothelium. To verify this hypothesis, Clausse and colleagues incubated HUVECs cells with conditioned media from PC-3 or DU145 prostate carcinoma cells and they observed a significant increase of Gal-1 protein expression. Additionally, both PC-3 conditioned medium and recombinant Gal-1 induced increased PC-3 cells adhesion to EC, while conditioned media complemented by an anti-Gal-1 antiserum abolished this modulation . It is iβ1,3GalNAc) on the surface of endothelial cells could be efficiently recognized by Gal-3, thus priming them for harboring metastatic cancer cells [Capillary formation is essential for tumors to obtain nutriments as well as for migration and the metastasis process. Interactions of metastatic cancer cells with blood vessels are critical during early stages of cancer metastasis but also in the lodge of tumor cells in specific organs and tissues. In 2005, Glinskii and colleagues demonstrated that mechanical entrapment alone, in the absence of tumor cell adhesion to blood vessel walls, is not sufficient for metastatic cell arrest in the microvasculature of the target organ. The analysis of the frequency and location of fluorescent tumor cells in different organs and tissues following intravenous inoculation revealed that PCa cells go into a wide variety of tissues and organs but not to the lung capillary bed. Results showed that arrest of metastatic cells in target organ microvessels is not a consequence of mechanical trapping, but is supported predominantly by intercellular adhesive interactions mediated by cancer-associated Thomsen-Friedenreich (TF) antigen and Gal-3 . Additioer cells .In vitro, PCa cells adhered preferentially to HBME-1 when compared with endothelium derived from other sources, and this adhesion was inhibited by anti-Gal-3 and anti-LFA-1 sera [In mCRPC, bones are a privilege site for the metastatic disease that causes osteoblastic growth. However, the mechanisms that contribute to bone metastasis are poorly understood. It was suggested that the bone provides a favorable environment for PCa cells growth and that tumor cells preferentially bind to bone marrow EC. To verify this hypothesis, cancer cell adhesion to a human bone marrow endothelial (HBME-1) cell and EC lines from other organs was assessed. A-1 sera . These dA-1 sera . As in nA-1 sera . This suBeing currently incurable, PCa metastasis has a remarkable ability to spread to the skeleton. Advanced PCa cells are essentially characterized by bone metastasis that predominantly causes an osteolytic phenotype. In a PC-3 cellular model, it has been shown that both the conditioned media from these PCa cells containing Gal-1 and recombinant Gal-1 inhibited the osteoblastic proliferation and differentiation of human bone marrow stromal (hBMS) cells. Thus, the authors hypothesized that Gal-1 could be involved in the osteoblastic response caused by PCa cells metastasizing to the bone, by affecting the matrix mineralization . To datein vivo: Gal-3 expression drives spontaneous metastasis using rat PCa models such as Dunning or Copenhagen rat [in vitro. As Gal-3 is not expressed in advanced stages of the disease, other factors act to promote spreading of tumor cells and have to be identified to attempt to cure mCRPC patients.Gal-3 is the only member of this family of lectins that was studied agen rat . The oraagen rat , 35, andagen rat . Indirecagen rat . These ragen rat ), or usiagen rat . AltogetGalectin-8 was initially called Prostate Cancer Tumor Antigen-1 (PCTA-1) because of its exclusive expression in neoplastic prostate cells and its absence in normal prostate tissue. In fact, Gal-8 levels of expression positively correlate with certain human neoplasms . Gal-8, Interestingly, glycosyltransferase-mediated regulation of carbohydrate expression on cell membrane-glycoconjugates has been recently shown to be involved in migration and invasion properties of the PC-3 cell line. It is well known that Gals link to tri- and tetrabranched N-glycans forming multivalent lattices that enhance cell surface residency of growth factor receptors and focal adhesion turnover. Silencing N-acetylglucosaminyltransferase I  by RNA interference in PC-3 was enough to inhibit cell invasion by affection of focal adhesion and microfilament organization, thus generating a less motile phenotype. More importantly, orthotopic injection of MGAT1-silenced PC-3 in nude mice revealed a decrease in primary tumor growth and poor incidence of lung metastases as well . Not onlCancer metastasis involves a series of steps including angiogenesis, detachment of tumor cells from the primary tumor, intravasation, evasion of host defense, arrest and attachment at a distant site, extravasation, dormant survival, and establishment of new growth. During extravasation, tumor cells bind to endothelial cells through protein, carbohydrate interactions and penetrate through the endothelium and basement membrane. Besides providing tumors with nutrients, newly formed capillaries constitute a potential escape route for tumor cells, thus favoring metastatic dissemination, and also provide an access to host immune cells.in vitro culture of HUVEC cells in normal medium complemented by conditional media from PC-3 or DU145 led to enhanced Gal-1 expression in EC [Analysis of Gal-1 expression in EC from 100 PCa patients who had undergone a radical prostatectomy for localized prostate cancer (Gleason score from 2 to 10) revealed increased frequency of Gal-1 expression in capillaries infiltrating the tumor compared to those present in the non tumoral adjacent tissue . Althougon in EC . These ron in EC . HoweverBecause Gal-1 expression is associated with PCa aggressiveness and has emerged as a novel proangiogenic factor in other tumor types , 66, we  in vitro tubulogenesis. PCa CM induced the formation of tubular-like structures when added to EC. The involvement of Gal-1 in this process was assessed by using an anti-Gal-1 neutralizing mAb, which considerably reduced the formation of these structures [in vitro effects of Gal-1-expressing PCa cells on endothelial cell morphogenesis prompted us to investigate the role of this lectin in angiogenesis in vivo. Our experimental approach consisted in the s.c. injection of 22Rv1 PCa cells in Matrigel plugs. Importantly, we were able to differentiate the source of Gal-1 : firstly, a blocking anti-Gal-1 mAb was added to the mix ; alternatively, we used 22Rv1 tumor cells transduced with a human specific Gal-1 shRNA-coding lentivirus . A marked reduction of microvessel density was observed using both experimental approaches, indicating that tumor cells are the main source of Gal-1, at least at early time points of tumor implantation and neovascularization. Confirming this reasoning, intermediate effects were observed when Gal-1 was partially downregulated in PCa cells. Altogether, these in vitro and in vivo results reveal a key role of Gal-1 in PCa-induced angiogenesis. More importantly, we showed that in vivo silencing of Gal-1 expression by tumor cells does not interfere with other pro- or anti-angiogenic factors such as VEGF or thrombospondin and bFGF, revealing the preponderant role of Gal-1 in promoting PCa neovascularization and suggesting Gal-1 as a new potent target for clinic therapeutic approaches in advanced PCa patients [Given the promising therapeutic value of anti-angiogenic strategies in advanced androgen-refractory PCa , we wereructures . These ipatients .in vitro tubulogenesis and VEGF-induced blood vessels formation in Matrigel plug assays [Gal-3 could also act as an angiogenic inducer by recognizing the TF disaccharide antigen present on the surface of most cancer cells. Using a purified glycopeptide TFD100 that binds Gal-3 with picomolar affinity, the authors blocked Gal-3-mediated interactions and inhibited angiogenesis of PC-3 tumors in mice . In thisg assays . AltogetAn efficient immune response against pathogens or tumors needs effective egress of lymphocytes from the blood into the target tissue. This process is allowed in part by specific EC proteins promoting lymphocyte adhesion to and migration across endothelium. Other molecules negatively regulate transendothelial migration of lymphocytes. Gal-1 is one of the best studied members that acts as inducer of immune tolerance in cancer . As it wex-vivo loading of autologous dendritic cells with the recombinant antigen which is PAP-GM-CSF: chimera of PAP and the granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune adjuvant. This new treatment is only intended for men with asymptomatic or minimally symptomatic and metastasized PCa that are resistant to standard hormone treatment. In controlled and multicenter clinical trials, several adverse events have been reported in the PROVENGE group, which include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. The most common adverse events (incidence ≥ 15%) reported were chills, fatigue, fever, back pain, nausea, joint ache, and headache [PCa is curable only when detected in its early stages as a result of both prostate-specific antigen (PSA) blood test screening and digital rectal exam. When patients suffer from metastatic disease and undergo mCRPC, docetaxel-based combination chemotherapy is the only available therapy that has demonstrated a survival benefit in 50% of these advanced stages of PCa. Moreover, FDA approved new therapies, most are being evaluated on clinical trials and are based on targeting the angiogenesis, the tumor microenvironment, or immunotherapy . All theheadache .Xtandi , an androgen receptor antagonist, is a new PCa treatment approved by FDA in August 2012 to treat mCRPC patients, with spreading or recurred cancer even with medical or surgical therapy and resistant to docetaxel-based chemotherapy.Finally, Xofigo was approved by FDA in mid-2013 for patients with CRPC, symptomatic metastases that spread to bones but not to other organs as in visceral metastatic disease. Xofigo binds with minerals in the bone to deliver radiation directly to bone tumors, limiting the damage to the surrounding normal tissues. Xofigo is an alpha particle-emitting radioactive therapeutic agent (radium-223 dichloride). The most common side effects were nausea, diarrhea, vomiting, swelling of the leg, ankle, or foot, and blood cells abnormalities with less than 5 months of improved OS. in vivo is still unclear. Under this scenario, a more deeply comprehension of the influence of Gals in evolution of PCa could help to define new drugs that treat advanced and mCRPC patients. For instance, the ratio of phosphorylated/dephosphorylated Gal-3 might be used as a complementary value to that of PSA for prognosis of PCa [Therefore, it is critical to identify new molecular targets to efficiently cure advanced cancers. A limited number of studies consider potential implications of individual Gals in the modulation of the metastatic process, yet the role of these essential proteins s of PCa . in vitro inhibition of PC-3 cell migration after wounding and displayed a potent antitumor activity against PC-3 tumor xenografts in nude mice [From a therapeutic point of view, Gal-3 has been conjugated to the chemotherapy drug 5-Fluoracil and delivered to PC-3 tumors by using a copolymer system named Gal-3-targeted HPMA copolymer-(G3-C12-)5-Fluorouracil conjugates. This drug showed ude mice . Drug resistance is a major obstacle for PCa therapy, but its underlying mechanisms are not clear, especially in patients with advanced stages of the disease. A comparative proteomic profiling of camptothecin- (CPT-) resistant PC-3 and CPT-sensitive LNCaP human PCa cell lines identified a signature of 144 proteins with different expression levels between the two cell lines that are suggested to contribute to the development of drug resistance . In thisRecently, we confirmed pioneer studies of Gal-1 as a tumoral marker of poor prognosis for PCa patients , and we Galectins are not only shown to be involved in antiapoptotic functions and edition of immune tolerance; several studies clearly revealed their proangiogenic functions in cancers , 76–78. L, or Bax proteins [While localized PCa can be cured, metastatic and advanced prostate cancers pose a significant therapeutic challenge. We and others identified a “galectin-regulated signature” as new prognostic markers and molecular targets of novel therapeutic avenues for preventing metastasis. Tumor metastasis is a multistep process involving several cellular and molecular interactions. Recognition of glycoconjugates by galectins regulates tumor behavior through both intrinsic as well as extrinsic signals involving modulation of homotypic cell aggregation, tumor cell apoptosis, angiogenesis, and tumor immune escape . In factproteins . Thus, bproteins . Gals reproteins . In addiproteins , 63, 81.in vivo studies addressing the source and function of Gals and exploring these phenotypes in PCa [in vivo experimental models. A key role of this glycan-binding protein in the formation of spontaneous metastasis was demonstrated using peptide inhibitors in experimental animal models of PCa [Despite these observations, there are relatively few s in PCa , 82, 83.s in PCa , 82, 84.s of PCa , 39. Mors of PCa . Silencis of PCa . Taking s of PCa , 87. Thes of PCa , 89. TheGalectin profile in cancer may be intrinsically determined and consequently considered as biomarkers of cell transformation. In this respect, we can assume that each type of tumor can be associated with characteristic profiles of Gals. Our study on PCa cell lines and patient samples proposes a particular profile of Gals through disease progression , 76. HowIn spite of considerable progress in dissecting the functions of individual Gals, an integrated portrait of the “galectin signature” of the human PCa microenvironment is still missing. In addition, it is not clear which cellular compartment expresses a given Gal and when this expression is required for cancer progression. While only Gals-1 and -3 were extensively studied in PCa, these Gals have been already shown to be potential new factors that participate directly in PCa progression and cancer drug resistance. In fact, Raz's group showed that phosphorylated Gal-3 is responsible for drug resistance in PCa and should be considered as new target to improve efficiency of chemotherapeutic agents such as cisplatin and etoposide . We demoFinally, Gal-8 is another tandem-repeat Gal of importance in PCa. This Gal has been defined first in 1996  and 2000


Multivessel coronary artery disease is more often treated either with coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) with stenting. The advent of drug-eluting stent (DES) has changed the revascularization strategy, and caused an increase in the use of DES in multivessel disease (MVD), with reduced rate of repeat revascularization compared to conventional bare metal stent. The comparative studies of DES-PCI over CABG have shown comparable safety; however, the rate of major adverse cerebrovascular and cardiac events and repeat revascularization was significantly higher with DES-PCI at long term. In diabetic patients with MVD, concern of repeat revascularization with DES-PCI is persistent. More recent, one-year economic outcomes have reported that the CABG is favored among patients with high angiographic complexity. The higher rate of repeat revascularization with DES-PCI in MVD would lead to increased economic burden on patient at long term besides bearing high cost of DES. In diabetic MVD patients, CABG is associated with having better clinical outcomes and being more cost-effective approach when compared to DES-PCI at long term. Coronary Artery Disease (CAD) is a major public health and medical concern in both developed and developing countries . CAD, chEarlier treatment of multivessel disease (MVD) was limited to balloon angioplasty or CABG, which then was managed with coronary stenting using Bare Metal Stent (BMS) with favorable clinical outcomes , 5. DespA number of studies have established the benefits associated with BMS over balloon angioplasty, prompting its use worldwide and by 1999, 84.2% of all interventions involved use of BMS –12. ThesSeveral studies  comparinP < 0.69), but repeat revascularization were reported significantly more frequent after BMS-PCI than CABG  in a pooled analysis of 4 randomized trials  [Long-term safety profile, expressed by death, stroke, and myocardial infarction, was similar to that of CABG at 5 years  . Long-term mortality at 5 years was similar after CABG and PCI (8.4% versus 10.0%) from collaborative analysis of individual patients with MVD, from six balloon angioplasty and four BMS trials. However, in subsets of patients older than 65 year and diabetic patients, reduced rate of mortality was reported following CABG as compared to PCI . Many studies have compared the cost effectiveness of both treatments in patients with MVD . The incThus, in MVD patients BMS-PCI reduces rate of repeat revascularization as compared to balloon angioplasty but has higher repeat revascularization as compared to CABG accounting for increased follow-up cost with similar long-term safety profile.Substantial change in the revascularization practice of MVD was noted after the introduction of DES . StructuEarly studies like ARTS II and ERACI III have reported that DES-PCI was comparable to CABG with lower rate of repeat revascularization when compared with BMS cohort; however, the rate of repeat revascularization was reported higher as compared to CABG cohort , 35. In a meta-analysis of 24,268 patients with multivessel CAD treated with CABG or DES-PCI, overall Major Adverse Cerebrovascular and Cardiac Events (MACCE) were higher after DES-PCI due to excess of redo-revascularization compared with CABG at mean follow-up time of 20 months . More recent, results from multivessel revascularization registry of 5 years outcome of DES-PCI reported significantly higher rates of revascularization in DES-PCI group as compared to CABG, with similar rates of mortality and of the composite safety outcomes. This was also observed for diabetic subgroup .P < 0.001), with significant difference in rate of revascularization  at 3 years. The study also reported that in patients with less complex multivessel disease (low SYNTAX score), DES-PCI is an acceptable revascularization procedure  [P < 0.001) in the overall cohort [Comparision between PCI using Paclitaxel coated eluting stent and CABG  was the largest randomized trial in 1800 patients, which assessed the optimal revascularization strategy in patients with three-vessel or left main coronary artery disease and enrolled more than 70% of multivessel CAD patients with or without left main disease. In MVD subset, the trial concluded that rate of MACCE was significantly higher in DES-PCI compared with CABG  , 39. Extl cohort . Although historically CABG has been the treatment of choice in MVD, DES-PCI has been increasingly used in MVD as an off-label indication. The clinical safety and efficacy of DES-PCI over CABG have been examined in several studies in MVD patients mentioned below.P = 0.001) and MACCE  with comparable safety endpoints  was observed with DES-PCI in diabetic subgroup analysis of SYNTAX trial at 3 years [Diabetic subgroup trials reported that mortality and safety composite were comparable between the treatments, whereas revascularization was significantly higher in the DES-PCI as compared to CABG , 42. Sim 3 years . P < 0.001) [In 5-year followup of ARTS trial, results reported that CABG has comparable safety and superior efficacy compared to BMS and SES in diabetic patients with MVD, with significantly lower rate of repeat revascularization  . Meta-analysis of studies comparing CABG with DES-PCI in diabetic patients with MVD have concluded that DES-PCI is safe, which may represent a viable alternative to CABG for selected diabetic MVD patients . FREEDOM trial was designed to determine the optimal revascularization strategy most recent to contemporary practice for the diabetic MVD patients and have addressed the clinical and cost effectiveness of DES-PCI over CABG at long term . The resThere has been continuous debate about which revascularization strategy amongst CABG and DES-PCI is more promising, as measured by overall cost effectiveness. The cost of a DES  is at least three times higher than the price of a conventional BMS ($600 to $700) and most authors reported implantation of 3-4 DES per patient treated for MVD, leading to a significant increase in the initial total procedural cost , 38. NumA prospectively designed health economic evaluation embedded within the SYNTAX trial revealed that PCI using DES is an economically attractive strategy over the first year for patients with low and moderate angiographic complexity, while CABG is favored among patients with high angiographic complexity. The detailed cost analysis demonstrated that the procedural cost in PCI using DES were significantly higher , owing to number of DES used (average 4.5 Stent), guide wires, balloon catheter, and medication cost, while overall initial hospitalization cost was $5,693/patient higher with CABG. At 1 year, follow-up cost was $2,282/patient higher with DES-PCI, mainly due to more frequent revascularization procedures. Finally, the total 1 year costs remained $3,590/patient higher with CABG, while quality-adjusted life expectancy was slightly higher with PCI. In a subset of patients with triple vessel disease, cost analysis revealed that the cost difference was 1,768/patient higher in CABG, with mean difference of repeat revascularization of 12.01 events/100 patients, and the incremental cost effectiveness ratio for CABG was reported $14,664 per repeat revascularization avoided. In addition, the complexity of MVD measured by SYNTAX score demonstrated that in patients with high angiographic complexity, total 1-year costs were similar for CABG and DES-PCI (difference of $466/patient), and the incremental cost-effectiveness ratio for CABG was $43,486 per quality-adjusted life-year gained .P = 0.05) [Besides, clinical outcomes and cost effectiveness, relief from angina and quality of life, may play a critical role in selecting a revascularization strategy. A sub-study of SYNTAX trial demonstrated that among patients with three-vessel or left main CAD, there was greater relief from angina after CABG than after DES-PCI at 6 and 12 months, although the extent of the benefit was small. The proportion of patients who were free from angina was similar in the two groups at 1 month and 6 months and was higher in CABG group than in the PCI group at 12 months  .At 4-year followup it has been reported that, CABG is a more cost-effective strategy than DES-PCI in terms of preventing repeat revascularization, myocardial infarction and death, hence saving costs . A cost According to very recent data, CABG was associated with higher initial cost  than PCI which subsequently reduced to $3,600 at 5 years due to higher follow-up cost with PCI in diabetic MVD patients . Economic benefits of DES-PCI over CABG have been examined in very few studies that have enrolled MVD patients. According to most studies, the incidence of death/stroke/myocardial infarction in patients with MVD at long term was similar in CABG and DES-PCI. At long term, rates of repeat revascularization and MACCE are higher with DES-PCI than CABG. In diabetic MVD patients, similar outcomes were observed. However, the critical determining factor in MVD patients is the angiographic complexity. Based on current evidences, DES-PCI is an economically dominant strategy for patients with low and intermediate complexities while CABG is favored among patients with high angiographic complexities over first year in consideration of the clinical and cost effective outcomes.


Background. Pleomorphic sarcoma is an aggressive soft tissue sarcoma. In patients with high-risk extremity sarcomas, the significant survival benefits conferred by an intense regimen of neoadjuvant chemoradiotherapy and surgery were reported. To our knowledge, this is the first report in the literature of the neoadjuvant use of trabectedin in a patient with high-grade pleomorphic sarcoma, ineligible for standard neoadjuvant combination therapy with an anthracycline-based regimen. Case Presentation. Here we present a 58-year-old White male with a large tumor in the left thigh, but with no signs of metastases. Owing to the history of severe heart attack, three cycles of neoadjuvant trabectedin were administrated to achieve surgically wide margins. After two cycles, an 18F-FDG-PET showed a large proportion of the central tumor area was without metabolic activity. According to RECIST and Choi criteria, the tumor was stable. After the third cycle of trabectedin, the patient underwent a complete resection, which revealed completely necrotic high-grade pleomorphic sarcoma (stage pT2b), with only a small vital area. Conclusion. The present paper on a promising treatment with neoadjuvant trabectedin of patients with high-grade pleomorphic sarcoma might suggest that such treatment approach may provide a greater chance of cure and survival of such patients. The high-risk stage III soft tissue sarcomas (STS) are a heterogeneous group of relatively rare mesenchymal neoplasms with important differences in chemosensitivity. The use of chemotherapy in the neoadjuvant and adjuvant settings in STS is controversial. When preoperative chemotherapy is used, tumor responses can result in clinically meaningful tumor shrinkage prior to surgery and, thus, may facilitate subsequent surgical resection. Nowadays there are some pieces of evidence for the use of perioperative chemotherapy in this highly malignant disease. Mullen and colleagues have reported the significant survival benefits in patients with high-risk, extremity STS who received an intense regimen of neoadjuvant chemoradiotherapy with concomitant radiotherapy . AnotherTreatment guidelines of sarcoma research and treatment organizations so far recommend a shared decision-making process considering among others patients age, tumor-subtype, grading, and size . AccordiTo date, the standard for perioperative chemotherapy is combining anthracycline with high-dose ifosfamide , 7. ThisEcteinascidia turbinata and currently produced synthetically [in vitro production of proinflammatory mediators, such as interleukin-6 (IL-6) and CCL2, was markedly downregulated by trabectedin in circulating monocytes, macrophages, and tumor-associated macrophages (TAM) from human tumors [Trabectedin (Yondelis) is a marine-derived antineoplastic compound isolated from the Caribbean tunicate etically . Trabectetically . Moreoven tumors –11. TherTrabectedin shows nearly similar response rates in leiomyosarcoma and liposarcomas (L-sarcomas) as those in combination-therapies and by far is less toxic . In addiHerein we present the results of the neoadjuvant use of trabectedin in a patient with high-grade pleomorphic sarcoma, ineligible for standard neoadjuvant combination therapy with an anthracycline-based regimen.A 58-year-old White male presented with a large tumor in the left thigh. The patient had a history of severe cardiac problems with myocardial infarction two years before diagnosis and consecutively underwent prophylactic defibrillator implantation, having an ejection fraction of 45% after surgery. A cross-sectional imaging showed an approximately 30 × 14 × 11 cm lobulated tumor. Staging was completed with a computerized tomography (CT) scan of the chest and abdomen and a fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan. This scan confirmed the presence of the mass and revealed an increased FDG uptake with a maximal standardized uptake value of 10.5 in the proximal region. No metastases were detected. Incision biopsy finally confirmed a high-grade sarcoma without distinct classification. Microscopic findings discovered up to 10 mitoses in 10 high-power fields (HPF) and a 30% necrosis.2 body surface area, administered as an intravenous infusion over 24 hours. After two cycles, an 18F-FDG-PET was performed, showing no significant decrease in standardized uptake value (SUV) in the hyper-metabolic regions of the tumor: maximal SUV was 9.5 versus 10.5 in the proximal and 4.4 versus 5.2 in the distal tumor  and another 12 of 23 had at least a good regression rate (>50% regression) as assessed by central pathological review .2 given intravenously over 24 hours every 21 days) the tumor showed a very good pathological response with 85% of necrotic area. Given that histopathological response can translate into a better overall response, this represents a promising and meaningful finding [ After only three cycles of the recommended dose of trabectedin (1.5 mg/m finding . Since p finding .The duration of therapy was chosen in concordance to the publication of Gronchi et al., showing that three cycles of neoadjuvant chemotherapy are equal to five cycles administered perioperatively . Today iIn conclusion, this is the first report on a promising treatment with neoadjuvant trabectedin of high-grade pleomorphic sarcoma. More research is needed, particularly regarding the selection of patients who would benefit the most from appropriate neoadjuvant perioperative chemotherapy.


Healthy body weight is an important factor for prevention of breast cancerrecurrence. Yet, weight loss and weight gain are not currently included inclinical-practice guidelines for posttreatment of breast cancer. The work reportedaddresses one of the questions that must be considered in recommending weight lossto patients: does it matter what diet plan is used, a question of particularimportance because breast cancer treatment can increase risk for cardiovasculardisease.Women who completed treatment for breast cancer were enrolled in a nonrandomized,controlled study investigating effects of weight loss achieved by using twodietary patterns at the extremes of macronutrient composition, although both dietarms were equivalent in protein: high fat, low carbohydrate versus low fat, highcarbohydrate. A nonintervention group served as the control arm; women wereassigned to intervention arms based on dietary preferences. During the 6-monthweight-loss program, which was menu and recipe defined, participants had monthlyclinical visits at which anthropometric data were collected and fasting blood wasobtained for safety monitoring for plasma lipid profiles and fasting glucose.Results from 142 participants are reported.P = 0.21). Beneficial effects of weight loss on cholesterol , triglycerides , and low-densitylipoprotein (LDL) cholesterol  were observed in bothgroups. For cholesterol (P = 0.07) and LDL cholesterol (P =0.13), greater reduction trends were seen on the low-fat diet pattern; whereas,for triglycerides (P = 0.01) and high-density lipoprotein (HDL)cholesterol (P = 0.08), a decrease or increase, respectively, was greateron the low-carbohydrate diet pattern.Adverse effects on fasting blood lipids or glucose were not observed in eitherdietary arm. A decrease in fasting glucose was observed with progressive weightloss and was greater in participants who lost more weight, but the effect was notstatistically significant, even though it was observed across both diet groups(Because an individual's dietary preferences can affect dietary adherence andweight-loss success, the lack of evidence of a negative effect of dietary patternon biomarkers associated with cardiovascular risk is an important consideration inthe development of breast cancer practice guidelines for physicians who recommendthat their patients lose weight. Whether dietary pattern affects biomarkers thatpredict long-term survival is a primary question in this ongoing clinicaltrial. A lifestyle change can halve the risk of breast cancer recurrence and reduce the risk ofbreast cancer-associated mortality by one third. However, many clinicians do notrecommend this strategy to their patients. The simple course of action, which generallyis not discussed, is promoting a healthy weight, and for many individuals, this meansweight loss. In this article, we begin to address this dormant opportunity in theclinical management of breast cancer with the goal of stimulating interest in generatingthe scientific evidence base required for considering weight management in clinicalpractice guidelines for the long-term survival of breast cancer patients.2), that is considered to be inthe normal range  versus women who are overweight or obese  [A number of reports indicate that the prognosis for long-term survival after treatmentfor breast cancer is better in women who have a body weight for height, assessed by bodymass index /(height (m)) ≥ 30.0) . Consist ≥ 30.0) ,13. If oOverweight and obesity are common problems in the United States, and little evidenceindicates that prevalence is less in breast cancer survivors than in the population atlarge, which is estimated to be more than 60% -16. ThusAlthough many studies have been reported about differences in effectiveness amongvarious approaches to weight loss -25, relaFor the analyses reported, magnitude of weight loss was dichotomized as being greater orless than the mean weight loss of the study population. This was done to address whetherall participants are affected similarly or if the blood-biomarker outcomes are dependenton the magnitude of weight loss.2).Women recruited for participation were from the same oncology practice and were atleast 4 months after chemotherapy, radiation, and surgical treatment for breastcancer and considered clinically free of cancer. Accrual occurred from 2008 to 2010.Participants were referred by their medical oncologist and had a BMI in theoverweight or obese class I range ; maintain orincrease physical activity as prescribed to achieve negative energy balance requiredfor 0.5 to 1.0 kg weight loss per week; wear a pedometer and record daily activity;wear an accelerometer/heart-rate monitor for 2 weeks during the study; wear a body orswim suit and cap for body-composition testing; record food intake daily; attend upto 10 one-on-one clinic visits and five group visits over a 27-week period, andprovide seven fasting blood samples and 3-day pooled urine samples.This study, referred to as CHOICE, compares the effects of opposing dietary patterns(carbohydrate and fat content at opposite extremes of popular weight-loss dietcomposition) on weight loss and body composition changes, as well as effects onbiomarkers of metabolic and hormonal processes known to affect breast carcinogenesisand that are predictive of long-term survival. The details of the CHOICE researchprotocol have been published. The datDemographic data and usual food intake via food-frequency questionnaire  were collected at baseline. At the initiation of the studyand at 4-week intervals thereafter, up to 6 months, anthropometry including weight,waist-to-hip ratio, BMI, body composition , and bioelectrical impedance  were obtained. Blood samples were obtained to assess cardiovascular-risk markers.These measures were assessed and compared at baseline and at 6 months in the controlgroup. The clinical protocol was approved by the Institutional Committee for theProtection of Human Subjects. Written consent was obtained before enrollingparticipants.Individuals not interested in joining the weight-loss arms of the study but whowished to participate were assigned to the nonintervention control group and weregiven the same information currently provided to all breast-cancer patients aboutthe importance of avoiding posttreatment weight gain, and the health benefits ofhaving a BMI in the normal range.Intervention participants follow a structured diet/physical activity programdesigned to create a weekly negative energy balance equivalent to 3, 500 kcal,after adjustments for metabolic adaptations that occur during extended periods ofweight loss. The intervention groups received the same physical-activity protocolpromoting the physical-activity guidelines and translated into steprecommendations, but one of two diets that reflect commonly used weight-lossapproaches that were identified in women attending a private oncology practice forlong-term breast-cancer follow-up.The diet plan for each group comprised a 28-day cycle of menus and recipes. Theingredients for each day's diet plan were entered into ProNutra Diet Analysissoftware. The macronutrient composition of the 28-day menu plan is shown in TableLaboratory analyses were performed by Quest Diagnostics Inc. Fasting glucose wasmeasured by using the hexokinase/glucose-6-phosphate dehydrogenase method withspectrophotometry . Total cF test in a one-wayanalysis of variance. Maximum likelihood (ML) estimates of a repeated-measures model [P values from largest to smallest [(k) , Pk-1) Cohort characteristics at baseline were described as mean ± SD, and differencesacross diet groups were evaluated by using the global es model  by usinges model . The algsmallest : (k) , PThe adjustments are valid whether test statistics are independent or positivelycorrelated.P < 0.05).The effect of dietary pattern on blood-lipid and -glucose profiles was evaluated in 142study participants. Data at baseline for the participants are shown in Table The research protocol involved monthly clinical visits during which fasting blood wasdrawn, and anthropometric data were collected. Blood was sent to the clinical laboratoryroutinely used by the office practice in which the weight management facility is locatedto base analysis and interpretation of results on the same source of data routinely usedby the attending physicians. The detailed data from each clinic visit throughout thecourse of the study for each subgroup are shown in Table P = 0.21). Similarly, the magnitude of the decrease in fastingglucose over time was somewhat greater in the low-fat arm than in the low-carbohydratearm when data were collapsed across weight-loss groups: the difference in slopes was-0.31 ± 0.24 (P = 0.21). These findings are notable for several reasons.First, widespread debate is ongoing about the potential for high-fat diets to promoteatherogenesis through the induction of insulin resistance, which can lead to elevatedfasting glucose [P = 0.06) than the differences between weight-loss groups averaged overdiet (P = 0.21). This finding is consistent with the importance of weight lossto attain a body weight in the target range for height, which is generally stated as abody mass index  between 18.5 and24.9, although the target range can vary based on race [Fasting blood glucose was assessed because elevations in this parameter can be an earlyindicator of developing insulin resistance, which is a risk factor for cardiovasculardisease ,39; data glucose . Second, glucose -44. Henc glucose ,46. In t on race .P = 0.001), triglycerides (P= 0.01), and LDL cholesterol (P = 0.06) in individuals who lost more than10 kg versus those individuals who were less successful. A more-detailed inspection ofthe regression coefficients reveals that overall (irrespective of whether weight losswas below or above the mean), differential effects on the lipid analytes were found,depending on dietary assignment. For cholesterol (P = 0.07) and LDL cholesterol(P = 0.13), greater reductions appeared on the high-carbohydrate dietpattern; whereas, for triglycerides (P = 0.01) and HDL cholesterol (P= 0.08), changes in the beneficial direction were greater on the high-fat dietarypattern. Similar effects have been reported in a non-cancer survivor population [Table pulation .Breast-cancer patients have elevated cardiovascular disease risk depending on theirtreatment; in patients who receive anthrocyclins, a well-known potential exists toinduce cardiomyopathies with associated problems . BecauseThe findings on lipid metabolites also have implications related to mechanisms of tumorprogression -54. AlthParticipants in this study were breast-cancer survivors from one clinical practice,which may limit the generalizability of the findings. We caution about theoverinterpretation of these findings because the data were not the primary measuresfor the trial; we elected to control the type I error rate for the four comparisonsdone within each marker but not across markers. Another potential limitation of thestudy was that assignment to dietary arm was not randomized; however, this is likelyto have translational value because individuals generally self-select dietaryapproaches that they prefer by which to lose weight.The work reported herein is a component of a systematic effort to increase awarenessabout the important contribution that weight loss and weight maintenance in the healthyrange can offer to promote the long-term survival of breast-cancer patients. Given theprevalence of overweight and obesity, not only in the U.S. population as a whole, butalso globally, and that a majority of women who have undergone treatment for breastcancer are overweight or obese, the importance of this issue is emphasized. The resultsof this investigation address a safety aspect of a question commonly asked of physiciansby their patients: does it matter what dietary plan I choose to lose weight? Because anindividual's dietary preferences can affect dietary adherence and weight-loss success,the lack of evidence of a negative effect of dietary pattern on cardiovascular risk isan important consideration in the development of clinical practice guidelines forphysicians who recommend that their patients lose weight. Once weight is lost, questionssimilar to those being asked in this study must be addressed in the context of long-termweight maintenance.BMI: Body mass index; HDL: high-density lipoprotein; HOMA-IR: homeostasis modelassessment of insulin resistance; ML: maximal likelihood.The authors declare that they have no competing interests.HJT, SMS, PW, JNM, and MRW participated in the design and implementation of the study.DP, MCP, EAD, and SNB participated in the implementation of the study. All authorsparticipated in the preparation of the manuscript.


Lifestyle factors have been implicated in ischaemic heart disease (IHD) development however a limited number of longitudinal studies report results stratified by cardio-protective medication use.This study investigated the influence of self-reported lifestyle factors on hospitalisation for IHD, stratified by blood pressure and/or lipid-lowering therapy.A population-based cohort of 14,890 participants aged 45+ years and IHD-free was identified from the Western Australian Health and wellbeing Surveillance System (2004 to 2010 inclusive), and linked with hospital administrative data. Adjusted hazard ratios for future IHD-hospitalisation were estimated using Cox regression.2; adjusted HR=1.28; 95% CI: 1.04-1.57) or obese . Weekly leisure-time physical activity (LTPA) of 150 minutes or more and daily intake of 3 or more fruit/vegetable servings reduced risk by 21% (95% CI: 0.64-0.97) and 26% (95% CI: 0.58-0.96) respectively. Benefits of LTPA appeared greatest in those on blood pressure lowering medication . IHD risk in smokers was most pronounced in those taking neither medication .Current smokers remained at higher risk for IHD-hospitalisation  after adjustment for medication use, as did those considered overweight (BMI=25-29 kg/mThis study confirms the contribution of previously reported lifestyle factors towards IHD hospitalisation, even after adjustment for antihypertensive and lipid-lowering medication use. Medication stratified results suggest that IHD risks related to LTPA and smoking may differ according to medication use. A number of biomedical and behavioural risk factors have been identified for the development of CVD. These risk factors include smoking, diabetes mellitus (DM), insufficient physical activity, hypertension, high cholesterol, overweight and obesity, and an unhealthy diet ,5. CurreThe study was approved by the Human Research Ethics Committees of Edith Cowan University and the Western Australian Department of Health, and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. ® telephone directory using a stratified random process with over-sampling representative to the population in rural and remote areas. Each year since its inception, more than 75% of those contacted completed the survey [This population-based cohort study utilised self-reported lifestyle survey information  individually linked with hospital admission data . The HWSS is a comprehensive monthly survey commissioned by the Health Department to provide information on a wide range of issues pertaining to the Western Australian population’s physical and mental well-being. It utilises computer-assisted telephone interviewing to assess approximately 6,000 Western Australians each year who are selected from the WA White Pagese survey  and a mae survey . This liBetween 1 January 2004 and 31 December 2010, some 40,445 surveys for which consent was provided for data linkage, were completed as part of the HWSS. Where participants had been surveyed more than once  during the study period, their first survey was included for analysis. Upon further restriction to those eligible for a subsidised health check-up with their doctor, i.e. aged 45+ years and without prior IHD-hospitalisation, a final study cohort of 14,890 remained.2). These exposures were also stratified by self-reported current use (at time of survey) of medications for high blood pressure or elevated total cholesterol. Participants were grouped into 4 categories; no current use of antihypertensive or lipid-lowering medications, antihypertensive medications only, lipid-lowering medications only, both antihypertensive and lipid-lowering medications. The primary outcome was hospitalisation for IHD according to the principal diagnosis  post survey date. The study population was restricted to those having no previous IHD-related hospitalisation (in any of the 22 administrative diagnostic categories) within 5 years of the survey date.Exposures of interest included smoking status , leisure-time physical activity (LTPA) in past week , fruit and/or vegetable intake daily , and body mass index , moderate and vigorous activity, where minutes of vigorous activity were multiplied by two . For th2), overweight (25-29 kg/m2) or obese (30+ kg/m2) [Categorisation of self-reported daily fruit and vegetable intake was based on evidence suggestive of a protective effect of 3 or more fruit/vegetables daily on fatal-IHD risk . BMI cat+ kg/m2) . SedentaIn order to determine participants’ medication usage at time of survey, participants were asked if they took any medication for blood pressure, and separately asked if they took medication for high cholesterol. Disaggregation to class of anti-hypertensive or lipid-lowering agent was not possible, nor was ascertainment of dosage or adherence.Additional confounding factors adjusted for in the analyses were age at survey , year of survey, gender, diagnosis of DM in any hospitalisation diagnostic category within 5 years prior to the survey date, and Charlson comorbidity index score  within Person-time was calculated from the date of survey until the admission date for a principal IHD-hospitalisation, death, or until end of follow-up (31 Dec 2010), whichever occurred first. Cox proportional hazards regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CIs) for future IHD-hospitalisation. The final adjusted model included age, sex, smoking status, Charlson comorbidity index, LTPA, sedentary behaviour, BMI, daily fruit and vegetable intake, survey year, and known DM. Socioeconomic index for areas (SEIFA) and region  were not included in the adjusted model as they were not significantly associated with the outcome in crude Cox models.2 respectively) was observed in the 1st year of follow-up, compared to the 2nd follow-up period (2 years), however overlapping confidence intervals suggest the differences were not significant. Subsequent HR estimates for longer follow-up periods differed by about 3% to their previous year’s HR estimate and similarly had overlapping confidence interval compared with the 1st year confidence intervals. We therefore presented the HR estimates for the entire period rather than stratified by year. To test whether or not the HR estimates for other risk factors might differ as a result of any possible violation in propotional hazards by BMI, an adjusted Cox regression model stratified by BMI (BMI was placed in a strata statement) was performed. Estimates did not vary by more than 0.05 following stratification of BMI. The proportional hazards assumption that the ratio of mortality rates according to the exposure variable remained constant for the adjusted models was tested by inclusion of an interaction term with ln in the model. This identified one violation of the proportional hazards, namely BMI. We further tested this by estimating HRs and their confidence intervals separately by number of years of follow-up. A 24-27% higher HR estimate  of the final study cohort  which raThe mean number of person-years of follow-up ranged from 2.8 to 3.2 years between exposure groups, with a maximum of almost seven years for each of the four exposure categories. The crude IHD-hospitalisation rate ranged from 932 per 100,000 person-years in the ‘no medication’ category, to 2,102 IHD-hospitalisations per 100,000 person-years in the combined medication group.a priori selected risk factors aside from sedentary behaviour demonstrated significant increased or decreased risk for future IHD-hospitalisation (2) or obesity (BMI of ≥30kg/m2) afforded an increased risk of 28%  and 31%  respectively, and current smoking provided a corresponding 57%  increased risk for future IHD-hospitalisation. Addition of interaction terms to the Cox regression model revealed no significant interaction effects between the aforementioned risk factors and medication use in future IHD-hospitalisation.After adjustment for current medication use, all lisation , regardl2 was associated with a 39%  increased risk, compared to those with a BMI of less than 25kg/m2. Neither smoking nor BMI demonstrated any significant increased risks within other sub-groups of medication use, although in some cases this is likely due a lack of sufficient power within the medication sub-groups.When adjusted hazard ratios were estimated for risk factors within sub-groups of medication users  the beneficial effects of LTPA were only observed in those on antihypertensive medications only. However within this antihypertensive medication sub-group, significant protective effects of 50%  and 36%  were observed for <150 minutes and ≥150 minutes respectively. Within the ‘no medication’ sub-group, current smoking doubled the risk for IHD-hospitalisation  and a BMI of 25-29kg/mIn this population-based cohort study of 14,890 Western Australians, a significant increased risk (adjusted for commonly reported risk factors) of future IHD-hospitalisation was observed for those who currently smoked (57% higher), or were overweight (28% higher) or obese (31% higher). In contrast, meeting public health guidelines of 150 minutes of physical activity and daily intake of 3 or more servings of fruit or vegetables appeared to decrease risk by 21% and 26%, respectively.Medication sub-group analyses suggested that benefits or risks associated with certain lifestyle factors might be more or less pronounced, depending upon medication use. The benefits from not being a current smoker were greatest in individuals who were not taking antihypertensive and/or lipid-lowering medications, and benefits of higher levels of physical activity appeared most pronounced in the antihypertensive medication group. Estimates of gain from pharmacological therapies in terms of CVD risk have ranged from 20% to 30% ,16. This2 increase in BMI. This suggests our observed risks for overweight and obese participants are comparably low, however the Danish study did not adjust for insufficient physical activity or fruit/vegetable intake which may have contributed toward the relatively high observed risk.Obesity has consistently been shown to contribute to risk for IHD in large, well designed studies –25. In tThe impact of physical activity on IHD incidence and mortality has been reported previously ,19,27,28Sufficient fruit and vegetable intake has been implicated as a risk factor of both fatal and non-fatal IHD ,12,30–32The population-based nature of this study means that results can be generalised to the broader community who have access to a listed telephone line. Whilst there are areas (particularly remote to very-remote areas) in Western Australia with limited or no access to telephones, the proportion of the overall population is very low. However it should be noted that this inaccessible population is likely to contain a higher proportion of indigenous people than is represented by the study cohort. Importantly, since data were available for all hospitals within Western Australia, we are likely to have included the vast majority of those who develop IHD as very few are treated in the community  and migrAlthough primary exposures (medication use) and secondary lifestyle exposures were self-reported, this is unlikely to lead to a differential misclassification of the exposures due to the prospective nature of the study. It is therefore most likely that any misclassification of exposure would underestimate the actual risk estimates. Our inability to identify which antihypertensive or lipid-lowering medication(s) participants are taking, the dosage, and adherence are limitations of this study. General Practitioner prescription estimates from the BEACH report  suggest In conclusion, our study highlights the contribution of smoking, overweight and obesity, insufficient physical activity, and low daily fruit and vegetable intake towards IHD hospitalisation, even after adjustment for antihypertensive and lipid-lowering medication use, in the Western Australian population. It confirms the importance of prevention and management of such modifiable risk factors at a population level to bring about reductions in IHD incidence and mortality in the community. Furthermore, given the potential medication-stratified differences in risk attributable to lifestyle factors identified in this study, further investigation of possible interactive effects may be warranted.