Disease In High-risk Patients Research Articles

Letermovir

Novel therapies are urgently needed for the management of cytomegalovirus (CMV) disease in high-risk patients. Currently licensed agents target the viral DNA polymerase, and although they are effective, they are fraught with toxicities to patients. Moreover, emergence of antiviral resistance is an increasing problem, particularly for patients on long-term suppressive therapy. A new agent, letermovir (AIC246), shows great promise for the management of CMV infection. Advantages include its good oral bioavailability, its lack of toxicity, and the apparent absence of drug-drug interactions. Letermovir has a novel mechanism of action, exerting its antiviral effect by interfering with the viral pUL56 gene product and in the process disrupting the viral terminase complex. This agent demonstrates substantial promise as an alternative to more toxic antivirals in patients at high risk for CMV disease, particularly in the transplantation setting.

Trans-population Analysis of Genetic Mechanisms of Ethnic Disparities in Neuroblastoma Survival

Black patients with neuroblastoma have a higher prevalence of high-risk disease and worse outcome than white patients. We sought to investigate the relationship between genetic variation and the disparities in survival observed in neuroblastoma. The analytic cohort was composed of 2709 patients. Principal components were used to assign patients to genomic ethnic clusters for survival analyses. Locus-specific ancestry was calculated for use in association analysis. The shorter spans of linkage disequilibrium in African populations may facilitate the fine mapping of causal variants in regions previously implicated by genome-wide association studies conducted primarily in patients of European descent. Thus, we evaluated 13 single nucleotide polymorphisms known to be associated with susceptibility to high-risk neuroblastoma from genome-wide association studies and all variants with highly divergent allele frequencies in reference African and European populations near the known susceptibility loci. All statistical tests were two-sided. African genomic ancestry was associated with high-risk neuroblastoma (P = .007) and lower event-free survival (P = .04, hazard ratio = 1.4, 95% confidence interval = 1.05 to 1.80). rs1033069 within SPAG16 (sperm associated antigen 16) was determined to have higher risk allele frequency in the African reference population and statistically significant association with high-risk disease in patients of European and African ancestry (P = 6.42 × 10(-5), false discovery rate < 0.0015) in the overall cohort. Multivariable analysis using an additive model demonstrated that the SPAG16 single nucleotide polymorphism contributes to the observed ethnic disparities in high-risk disease and survival. Our study demonstrates that common genetic variation influences neuroblastoma phenotype and contributes to the ethnic disparities in survival observed and illustrates the value of trans-population mapping.

Antihypertensive agents for preventing diabetic kidney disease.

Various blood pressure-lowering agents, and particularly inhibitors of the renin-angiotensin system (RAS), are widely used for people with diabetes to prevent the onset of diabetic kidney disease (DKD) and adverse cardiovascular outcomes. This is an update of a Cochrane review first published in 2003 and updated in 2005. This systematic review aimed to assess the benefits and harms of blood pressure lowering agents in people with diabetes mellitus and a normal amount of albumin in the urine (normoalbuminuria). In January 2011 we searched the Cochrane Renal Group's Specialised Register through contact with the Trials Search Co-ordinator. Randomised controlled trials (RCTs) comparing any antihypertensive agent with placebo or another agent in hypertensive or normotensive patients with diabetes and no kidney disease (albumin excretion rate < 30 mg/d) were included. Two investigators independently extracted data on kidney and other patient-relevant outcomes (all-cause mortality and serious cardiovascular events), and assessed study quality. Analysis was by a random effects model was applied to analyse results which were expressed as risk ratio (RR) and 95% confidence intervals (CI). We identified 26 studies that enrolling 61,264 participants. Angiotensin-converting enzyme inhibitors (ACEi) reduced the risk of new onset of microalbuminuria, macroalbuminuria or both when compared to placebo (8 studies, 11,906 patients: RR 0.71, 95% CI 0.56 to 0.89), with similar benefits in people with and without hypertension (P = 0.74), and when compared to calcium channel blockers (5 studies, 1253 participants: RR 0.60, 95% CI 0.42 to 0.85). ACEi reduced the risk of death when compared to placebo (6 studies, 11,350 participants: RR 0.84, 95% CI 0.73 to 0.97). No effect was observed for angiotensin receptor blockers (ARB) when compared to placebo for new microalbuminuria, macroalbuminuria or both (5 studies, 7653 participants: RR 0.90, 95% CI 0.68 to 1.19) or death (5 studies, 7653 participants: RR 1.12, 95% CI 0.88 to 1.41); however, meta-regression suggested possible benefits from ARB for preventing kidney disease in high risk patients. There was a trend towards benefit from use of combined ACEi and ARB for prevention of DKD compared with ACEi alone (2 studies, 4171 participants: RR 0.88, 95% CI 0.78 to 1.00).The risk of cough was significantly increased with ACEi when compared to placebo (6 studies, 11,791 patients: RR 1.84, 95% CI 1.24 to 2.72), however there was no significant difference in the risk of headache or hyperkalaemia. There was no significant difference in the risk of cough, headache or hyperkalaemia when ARB was to placebo. On average risk of bias was judged to be either low (27% to 69%) or unclear (i.e. no information available) (8% to 73%). Blinding of participants, incomplete outcome data and selective reporting were judged to be high in 23%, 31% and 31% of studies, respectively. ACEi were found to prevent new onset DKD and death in normoalbuminuric people with diabetes, and could therefore be used in this population. More data are needed to clarify the role of ARB and other drug classes in preventing DKD.

Low-Dose Valganciclovir for CMV Prophylaxis after Lung Transplantation

Purpose. Cytomegalovirus (CMV) remains an important pathogen following solid organ transplantation (SOT). Universal prophylaxis for CMV is adopted by most centers after lung transplantation. Various combinations studied for CMV prophylaxis include intravenous and oral ganciclovirs, oral valganciclovir, and CMV immunoglobulins. We present our experience with a low-dose of oral valganciclovir for CMV prophylaxis following lung transplantation. Methods and Materials. Our center started using 450 mg of daily oral valganciclovir for CMV prophylaxis in lung transplant recipients in Jan, 2001. A retrospective chart analysis of patients who underwent lung transplantation from January 2001 to December 2006 was done. Of 46 patients, 4 were excluded as they died within 30 days of transplant from postop complications. The mean age at transplant was 64 years, mostly single lung transplants (36/6) with a male-to-female ratio of 25/17. COPD was the most common reason for transplant (65%), and the serological CMV status of donors (D) and recipients (R) was as follows: D+/R+ 28, D+/R− 5, D−/R+ 5, and D−/R− 4. Valganciclovir was given for a total of 6 months posttransplant except for D−/R+ patients who received it for 12 months. Results. Five patients (12%) developed CMV disease with an average followup of 26 months. Only 2 (4.7%) developed CMV disease within six months of completing valganciclovir prophylaxis. This incidence is not significantly different from the best-reported results of CMV prophylaxis in lung transplant recipients. The remaining 3 patients developed the disease later in their course, one as late as 32 months posttransplant. The main side effects noted include leucopenia, neutropenia, and GI disturbances. However, the number of patients who had to temporarily stop or discontinue the medication (9.5%) was significantly lower than that reported in previous studies. Conclusions. Our experience suggests that low-dose valganciclovir is an effective method of prophylaxis for CMV disease in high-risk patients. It is a simple regimen that seems to have a better side effect profile and to improve patient compliance.

Reducing salt intake for prevention of cardiovascular diseases in high-risk patients by advanced health education intervention (RESIP-CVD study), Northern Thailand: study protocol for a cluster randomized trial.

BackgroundDecreasing salt consumption can prevent cardiovascular diseases (CVD). Practically, it is difficult to promote people’s awareness of daily salt intake and to change their eating habits in terms of reducing salt intake for better cardiovascular health. Health education programs visualizing daily dietary salt content and intake may promote lifestyle changes in patients at high risk of cardiovascular diseases.Methods/DesignThis is a cluster randomized trial. A total of 800 high-CVD-risk patients attending diabetes and hypertension clinics at health centers in Muang District, Chiang Rai province, Thailand, will be studied with informed consent. A health center recruiting 100 participants is a cluster, the unit of randomization. Eight clusters will be randomized into intervention and control arms and followed up for 1 year. Within the intervention clusters the following will be undertaken: (1) salt content in the daily diet will be measured and shown to study participants; (2) 24-hour salt intake will be estimated in overnight-collected urine and the results shown to the participants; (3) a dietician will assist small group health education classes in cooking meals with less salt. The primary outcome is blood pressure change at the 1-year follow-up. Secondary outcomes at the 1-year follow-up are estimated 24-hoursalt intake, incidence of CVD events and CVD death. The intention-to-treat analysis will be followed.Blood pressure and estimated 24-hour salt intake will be compared between intervention and control groups at the cluster and individual level at the 1-year follow-up. Clinical CVD events and deaths will be analyzed by time-event analysis. Retinal blood vessel calibers of CVD-risk patients will be assessed cross-sectionally. Behavioral change to reduce salt intake and the influencing factors will be determined by structured equation model (SEM). Multilevel regression analyses will be applied. Finally, the cost effectiveness of the intervention will be analyzed.DiscussionThis study is unique as it will recruit the individuals most vulnerable to CVD morbidity and mortality by applying the general Framingham CVD risk scoring system. Dietary salt reduction will be applied as a prioritized, community level intervention for the prevention of CVD in a developing country.Trial registrationISRCTN39416277

Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe −/− mice

Inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as sitagliptin, increase glucagon-like peptide-1 (GLP-1) concentrations and are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes exhibit a high risk of developing severe atherosclerosis, we investigated the effect of sitagliptin on atherogenesis in Apoe (-/-) mice. Apoe (-/-) mice were fed a high-fat diet and treated with either sitagliptin or placebo for 12 weeks. Plaque size and plaque composition were analysed using Oil Red O staining and immunohistochemistry. Furthermore, in vitro experiments with the modified Boyden chamber and with gelatine zymography were performed to analyse the effects of GLP-1 on isolated human monocyte migration and metalloproteinase-9 (MMP-9) release. Treatment of Apoe (-/-) mice with sitagliptin significantly reduced plaque macrophage infiltration (the aortic root and aortic arch both showing a 67% decrease; p < 0.05) and plaque MMP-9 levels (aortic root showing a 69% and aortic arch a 58% reduction; both p < 0.01) compared with controls. Moreover, sitagliptin significantly increased plaque collagen content more than twofold (aortic root showing an increase of 58% and aortic arch an increase of 73%; both p < 0.05) compared with controls but did not change overall lesion size (8.1 ± 3.5% vs 5.1 ± 2.5% for sitagliptin vs controls; p=NS). In vitro, pretreatment of isolated human monocytes with GLP-1 significantly decreased cell migration induced by both monocyte chemotactic protein-1 and by the protein known as regulated on activation, normal T cell expressed and secreted (RANTES) in a concentration-dependent manner. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages. Sitagliptin reduces plaque inflammation and increases plaque stability, potentially by GLP-1-mediated inhibition of chemokine-induced monocyte migration and macrophage MMP-9 release. The effects observed may provide potential mechanisms for how DPP-IV inhibitors could modulate vascular disease in high-risk patients with type 2 diabetes mellitus.

Sa2029 Impact of Adalimumab in the Prevention of Postoperative Recurrences of Crohn's Disease in High-Risk Patients

Sa2029 Impact of Adalimumab in the Prevention of Postoperative Recurrences of Crohn's Disease in High-Risk Patients

Radial artery pulse wave analysis for non-invasive assessment of coronary artery disease

BackgroundAngiographically-normal coronary arteries are reported in 10–20% of patients undergoing diagnostic coronary angiography despite screening with risk factors and functional tests. We sought to validate and determine the clinical value of radial artery pulse wave analysis (PWA), a simple, quick and non-invasive marker of central artery stiffness and define its ability to predict coronary artery disease in high-risk patients. Materials and methods531 consecutive patients referred for elective coronary angiography, irrespective of previous co-morbidity, were assessed in a prospective, multicenter observational study [the Alternative Risk Markers in Coronary Artery Disease (ARM-CAD) study]. ResultsMean age was 65±11years, 33% were women, 18% had impaired left-ventricular function and 22% a prior myocardial infarction. Angiography demonstrated normal coronary arteries in 20% of participants. The only independent associations with this outcome were younger age, female gender, absence of diabetes and PWA-derived central augmentation pressure <24mm Hg. The odds ratio for the latter after adjustment for medications and baseline risk factors (including blood pressure, high-sensitivity C-reactive protein and B-type natriuretic peptide) was 3.4 (95% CI 1.2 to 9.5; p=0.021). The specificity for the multivariate model that included PWA was 95.7% with a receiver operator curve area of 0.876. Validation studies suggested that systolic variables from PWA were robust regardless of waveform quality and similar to measured aortic pressures (mean difference 2.7mm Hg). ConclusionsAssessment of radial artery waveforms is a useful non-invasive clinical test that can stratify the likelihood of coronary disease and assist in identifying patients who require diagnostic angiography.

Hybrid Coronary Revascularization for the Treatment of Left Main Coronary Artery Disease in High-Risk Patients

Hybrid coronary revascularization is an alternative for treatment for high-risk patients with coronary artery disease. We evaluated the efficacy of staged hybrid coronary revascularization for the treatment of unprotected left main coronary artery disease in high-risk patients. Patients with left main or proximal left anterior descending coronary artery stenosis who are not good candidates for percutaneous coronary intervention and who had suitable lesions in the right coronary and circumflex arteries were considered for staged hybrid therapy if they had poor left ventricular functions (ejection fraction <0.40) and comorbid illnesses. From January 2008 through December 2010, 11 patients (8 men, 3 women; mean age: 66.1 ± 9.1 years) were treated with off-pump coronary artery bypass grafting combined with staged percutaneous coronary intervention. Nine patients had left main coronary artery stenosis together with circumflex or right coronary artery stenosis, and 2 patients had proximal left anterior descending artery stenosis and right coronary artery stenosis. After off-pump coronary artery bypass grafting, procedure-related complications did not occur, and there was no in-hospital death. Coronary re-angiography after a median of 16 days revealed patent and functioning left internal mammarian artery grafts in all patients. Applying subsequent percutaneous transluminal coronary angioplasty and occasional stenting (n = 14), a total of 14 lesions were treated successfully. Procedure related complications did not occur. All patients remained angina-free, and no stress electrocardiographic changes were recorded. Our preliminary results indicate that a "staged hybrid" approach to the treatment of left main coronary artery disease in high-risk patients is safe and effective. Hybrid coronary revascularization enables complete revascularization and may be an alternative method of treating left main coronary artery disease in selected high-risk patients.

Cardiovascular protection of magnolol: cell-type specificity and dose-related effects

Magnolia officinalis has been widely used in traditional Chinese medicine. Magnolol, an active component isolated from Magnolia officinalis, is known to be a cardiovascular protector since 1994. The multiplex mechanisms of magnolol on cardiovascular protection depends on cell types and dosages, and will be reviewed and discussed in this article. Magnolol under low and moderate dosage possesses the ability to protect heart from ischemic/reperfusion injury, reduces atherosclerotic change, protects endothelial cell against apoptosis and inhibits neutrophil-endothelial adhesion. The moderate to high concentration of magnolol mainly acts on smooth muscle cells and platelets. Magnolol induces apoptosis in vascular smooth muscle cells at moderate concentration and inhibits proliferation at moderate and high concentration. High concentration of magnolol also abrogates platelet activation, aggregation and thrombus formation. Magnolol also serves as an smooth muscle relaxant only upon the high concentration. Oral intake of magnolol to reach the therapeutic level for cardiovascular protection is applicable, thus makes magnolol an agent of great potential for preventing cardiovascular diseases in high-risk patients.

Adalimumab in prevention of postoperative recurrence of Crohn's disease in high-risk patients

To evaluate the effectiveness of adalimumab in preventing recurrence after intestinal resection for Crohn's disease in high-risk patients. A multicenter, prospective, observational study was conducted from June 2009 until June 2010. We consecutively included high-risk Crohn's disease patients who had undergone an ileal/ileocolonic resection. High-risk patients were defined as two or more criteria: smokers, penetrating pattern, one or more previous surgical resections or prior extensive resection. Subcutaneous adalimumab was administered 2 wk (± 5 d) after surgery at a dose of 40 mg eow, with an initial induction dose of 160/80 mg at weeks 0 and 2. Demographic data, previous and concomitant treatments (antibiotics, 5-aminosalicylates, corticosteroids, immunomodulators or biologic therapies), smoking status at the time of diagnosis and after the index operation and number of previous resections (type and reason for surgery) were all recorded. Biological status was assessed with C-reactive protein, erythrocyte sedimentation rate and fecal calprotectin. One year (± 3 mo) after surgery, an ileocolonoscopy and/or magnetic resonance enterography was performed. Endoscopic recurrence was defined as Rutgeerts score ≥ i2. Morphological recurrence was based on magnetic resonance (MR) score ≥ MR1. Twenty-nine patients (55.2% males, 48.3% smokers at diagnosis and 13.8% after the index operation), mean age 42.3 years and mean duration of the disease 13.8 years were included in the study. A mean of 1.76 (range: 1-4) resections previous to adalimumab administration and in 37.9% was considered extensive resection. 51.7% had previously received infliximab. Immunomodulators were given concomitantly to 17.2% of patients. Four of the 29 (13.7%) developed clinical recurrence, 6/29 (20.7%) endoscopic recurrence and 7/19 (36.8%) morphological recurrence after 1-year. All patients with clinical recurrence showed endoscopic and morphological recurrence. A high degree of concordance was found between clinical-endoscopic recurrence (κ = 0.76, P < 0.001) and clinical-morphological recurrence (κ = 0.63, P = 0.003). Correlation between endoscopic and radiological findings was good (comparing the 5-point Rutgeerts score with the 4-point MR score, a score of i4 was classified as MR3, i3 as MR2, and i2-i1 as MR1) (P < 0.001, r(s) = 0.825). During follow-up, five (17.2%) patients needed adalimumab dose intensification (40 mg/wk); Mean time to intensification after the introduction of adalimumab treatment was 8 mo (range: 5 to 11 mo). In three cases (10.3%), a biological change was needed due to a worsening of the disease after the dose intensification to 40 mg/wk. One patient suffered an adverse event. Adalimumab seems to be effective and safe in preventing postoperative recurrence in a selected group of patients who had undergone an intestinal resection for their CD.

Abstract 9436: Sitagliptin Reduces Plaque Macrophage Content and Stabilizes Arteriosclerotic Lesions in Apoe-Deficient Mice

Objective: Glucagon-like peptide-1(7-36) (GLP-1) based therapies are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes are at a high risk to develop a severe atherosclerosis, we investigated the effect of GLP-1 on chemokine-induced migration of human monocytes and macrophage MMP-9 expression, both crucial steps in atherogenesis and plaque destabilisation. Furthermore, we explored the translation of these effects to plaque inflammation and plaque stability in ApoE -/- mice treated with the DPP-IV inhibitor sitagliptin, which increases plasma levels of active GLP-1. Methods and Results: In the modified Boyden-chamber, pretreatment with GLP-1 reduced the MCP-1 induced migration of isolated human monocytes in a concentration dependent manner from a 3.3±0.8 to a 1.4±0.5 fold induction at 10 nM GLP-1 (n = 8, p &lt; 0.05), which was associated with a decreased MLC-phosphorylation in these cells. Similar effects were seen when RANTES was used as a chemokine to induce cell migration. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages as determined by zymography. In vivo , treatment of ApoE -/- mice with the DPP-IV inhibitor sitagliptin, which increases plasma levels of active GLP-1, resulted in a 75% reduction of macrophage infiltration, a 75% reduction in plaque MMP-9 expression and a more than 3-fold increase in plaque collagen content compared to controls as shown by MAC3, Picrosirus Red and immunohistologic staining, respectively (n=6-8, p &lt; 0.05). Conclusion: Thus, GLP-1 reduces plaque inflammation and increases plaque stability potentially by inhibiting chemokine-induced migration of monocytes and by inhibition of macrophage MMP-9 expression. The effects observed may provide a potential mechanism of how GLP-1 based therapies may modulate vascular disease in high-risk patients with type 2 diabetes mellitus.

Generation of An Automated Tool for the Identification of Genetics Markers and Signatures in Multiple Myeloma Risk-Stratification

Abstract 2881Multiple myeloma (MM) is characterized by a remarkable heterogeneity in outcome following standard and high-dose therapies. Significant efforts have been made to identify genetic changes and signatures that can predict clinical outcome and include them in the routine clinical care. Gene expression profiling (GEP) studies have achieved a central role in the study of multiple myeloma (MM), as they become a critical component in the risk-based stratification of the disease. To molecularly stratify disease-risk groups, we performed GEP on purified plasma cells (obtained from the immunobead selection of CD138+ cells) from 489 MM samples in different stages of the disease using the Affymetrix U133Plus2.0 array. A total of 162 probes were analyzed using an in house automated script to generate a GEP report with the most used risk stratification indices and signatures, including the UAMS 70-gene, UAMS class, TC classification, proliferation and centrosome signature, and NFKB activation indices. In a subset of 57 samples, IgH translocations were analyzed using FISH and results were correlated with GEP data. A macrophage index was calculated and used as a surrogate measurement of non-plasma cell contamination. A total of 49 samples (10%) were excluded from subsequent analysis as the macrophage index indicated a significant contamination with no plasma cells, hence potentially compromising the results. The percent of high-risk disease patients identified from different signatures ranged from 26.4% by using high proliferation index to 28.8% with high centrosome signature and 31.3% with high 70-gene index. This percent of high-risk cases based on the 70-gene index is similar to what was found in Total therapy 2 (TT2) and TT3 cohorts. A third of patients (33.2%) were classified as D1 in the TC class, followed by 11q13 (19.3%), D2 (16.4%), 4p16 (13.8%), MAF (6.1%), None (4.7%), D1+D2 (4.5%) and 6p21 (1.8%). The NF-kB pathway was likely activated in 45.5% to 59.5% of cases, depending on the index used for its calculation. High proliferation index and high centrosome signature significantly correlates with 70-gene high-risk group (p<0.0001). Conversely, the activation of NF-kB pathway was not significantly different between high- and low- risk subgroups. TC subgroups D1 (p<0.0001) and 11q13 (p=0.01) were significantly more common in the 70-gene low-risk group. Similarly, TC subgroups 4p16 (p=0.0004), Maf (p=0.02) and D2 (p=0.05) were enriched in the high-risk group. Translocations t(4;14)(p16;q32), t(11;14)(q13;q32) and t(14;16)(q32;q23) were precisely predicted by the TC classification (100% correspondence). Cases with IgH translocations with unknown partner were classified in subgroups D1 (33%), D2 (25%), 6p21 (25%) and Maf (16%). Here we summarized the associations between the most significant gene expression indices and signatures relevant to MM risk-stratification. The multiple variables simultaneously analyzed in an automated way, provide a powerful and fast tool for risk-stratification, helping in the therapeutic decision-making. Disclosures:Stewart:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding. Fonseca:Consulting :Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.

Correlation of serum HE4 with tumor size and myometrial invasion in endometrial cancer

ObjectiveTo evaluate the utility of serum (HE4) as a marker for high risk disease in patients with endometrial cancer (EC). MethodsPreoperative serum HE4 levels were measured from a cohort of 75 patients surgically treated for EC. Cases were compared to matched controls without a history of cancer. HE4 levels were analyzed as a function of primary tumor diameter, grade, stage and histological subtype. Wilcoxon rank-sum test, ROC curve, Spearman rank correlation coefficient and contingency tables were used for statistical analyses. ResultsStage distribution was as follows: 49 stage I, 2 stage II, 20 stage III, 4 stage IV. Type I EC was present in 54 patients, type II in 21. Median HE4 was significantly elevated in both types I and II EC compared to controls (P<0.001 and P=0.019, respectively). There was significant correlation between type I EC, median HE4, deep myometrial invasion (MI) (>50%, P<0.001) and primary tumor diameter (PTD) (>2cm, P=0.002). Low risk patients (type I, MI≤50% and PTD≤2cm) had significantly lower median HE4 compared to all other type I EC patients (P<0.01). In comparison to prior investigations, HE4 (cutoff of 8mfi) was more sensitive than CA125 in detecting advanced stage disease. ConclusionOur data suggest that HE4 is elevated in a high proportion of EC patients, is correlated with PTD and MI, and is more sensitive than CA125 in EC. These observations suggest potential utility of HE4 in the preoperative prediction of high risk disease and the necessity for definitive surgical staging.

Results and Challenges for the Endovascular Repair of Aortic Arch Aneurysms

Endovascular aortic arch reconstruction provides an attractive alternative to treat aortic arch disease in high-risk patients who would otherwise be unsuitable for open repair. Success with multibranched stent grafts in the thoracoabdominal aorta along with recent advances in design such as the precurved inner nitinol cannula have simplified the endovascular reconstruction of aortic arch aneurysms with multibranched stent grafts. These devices allow for greater flexibility in conforming to difficult anatomy and preserving important side branches. During the first surgical stage, a left carotid -subclavian bypass or left subclavian artery transposition is performed. The second stage is the endovascular procedure. The device is inserted through a transfemoral approach, and crossing of the aortic valve with the device is necessary. The stent graft is deployed during brief periods of rapid pacing. Bridging from the branches to the innominate and left common carotid arteries requires a suitable covered stent. In the case of a large-diameter innominate artery, a custom-made bridging limb has to be used to ensure that adequate length and size are available. Direct flow to the innominate and left common carotid arteries do not cease for any significant time during the procedure. Initial experience with mean follow up more than 6 months is encouraging. The method is not suitable for patients with extensive atheromatous involvement of the aortic arch. Careful preoperative planning (preoperative imaging, device construction, and access issues), high endovascular skills, and appropriate imaging equipment are imperative for a successful result. Long-term follow-up is necessary to evaluate the efficacy and safety of these new devices.

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Multimodality treatment of locally advanced soft-tissue sarcomas of the extremities

Background Adjuvant radiotherapy (RTE) still has a fundamental role as a post-operative treatment of locally advanced soft tissues sarcomas of the extremities. Moreover the employment of combined modalities in locally advanced soft tissues sarcomas of the extremities allow to maximize the chance of local cure even in difficult presentation cases, and possibly improve survival, especially in high-risk disease patients. In patients with sarcomas of the extremities in which definitive surgery has not been radical (with positive or “close” margins) radiotherapy can improve the results in terms of Disease Free Survival (DFS) and, together with chemotherapy, of Overall Survival (OS). We recommend radiotherapy in case of deep tumor location, inadequate surgical margins and grade 3 tumour; for positive or “marginal (or close)” excision (that means inadequate surgery) or in selected patients with a bad prognosis, we believe that a multidisciplinary approach can be preferable. Introduction Adjuvant radiotherapy (RTE) still has a fundamental role as a post-operative treatment. In patients with sarcomas of the extremities in whom definitive surgery has been or not radical (positive or “close” margins), radiotherapy with chemotherapy can improve the results in terms of Disease Free Survival (DFS) and Overall Survival (OS), while RTE alone seems to improve local control. Materials and methods From 1/2000 to 12/2005 we treated 34 patients affected by locally advanced sarcomas of the upper or lower extremities with radiotherapy (doses ranging from 54 to 66 Gy) and chemotherapy in 18/34 with an adjuvant scheme that consisted in Epirubicine (120 mg/m 2) plus Ifosfamide (7000–9000 mg/m 2). Results Disease Free Survival (DFS) and the Overall Survival (OS) rates were 76% and 82%, respectively. Eighteen patients developed one or more long-term side effects. Most of these complications were mild: all patients experienced only erithema, edema, local sclerosis or moderate pain. Conclusion Radiotherapy has an important role as a post-operative treatment also when surgery was non-radical. It improves local control more in patients with high-grade sarcomas of the extremity with positive or close margins. It is still difficult to assess the role of adjuvant chemotherapy.

Neoadjuvant targeted therapy in renal cell carcinoma

we read with interest the article published by vincenzo Ficarra and Giacomo novara (Kidney cancer: neoadjuvant targeted therapies in renal cell carcinoma. Nat. Rev. Urol. 7, 63–64; 2010).1 in the past few years, randomized trials have shown the efficacy of targeted therapies in renal cell carcinoma (rCC); these results have dramatically changed the therapeutic approach. it is important to draw attention to the following issues. First, the appropriateness of using tnM staging to determine eligibility of patients for neoadjuvant treatment. it has been shown that the tnM system is not sufficient for risk stratification of patients with resected or advanced rCC. a combination of clinical and histological factors, such as tnM staging, Fuhrman’s tumor grade and eastern Cooperative Oncology Group (eCOG) performance status, have more relevant prognostic value in terms of survival, according to the uCLa integrated staging system (uiss).2 Patients with nonmetastatic highrisk disease have a high rate of systemic failure, suggesting the presence of occult metastases at diagnosis that are not detectable using current imaging methods. Moreover, similar survival curves have been published for nonmetastatic high-risk patients and metastatic low-risk patients.3 neoadjuvant therapy is commonly used in an effort to downstage locally advanced tumors, as well as to improve survival. Parameters in current use—including large tumor size, involvement of vital structures, and bulky lymphadenopathy—may not be sufficient to identify patients who are eligible for medical treatment. Precisely defining the uiss risk class could be more useful in the presurgical decisionmaking phase. Considering the lack of data supporting adjuvant treatments in patients with rCC, neoadjuvant medical therapy that has the effect of delaying nephrectomy could facilitate earlier onset of systemic disease control. Considerable doubt remains regarding the poor response rate of primary tumors treated with targeted agents, relative to the higher overall response rate reported in a number of phase iii trials of bevacizumab plus interferon, or sunitinib, in metastatic rCC. 91% of patients treated with sunitinib in phase iii trials had previously undergone nephrectomy; as such, comparable data on primary tumor shrinkage are not available.4 it is possible that the poor response of primary tumors, as published in preliminary reports, is not a function of limited efficacy of anti-angiogenic treatment. rather, it might be ascribed to a reduced ratio of neoplastic tissue to tumor necrosis, which is usually present at the center of the primary disease site.5 the superior response rate observed in the metastatic setting could be a function of the higher burden of non-necrotic tumor. in the neoadjuvant setting, a 15% reduction in tumor size is not considered an exciting result, even though a mean size decrease of 10% has been reported to be an optimal criterion for identification of patients with metastatic rCC who will derive benefit from sunitinib treatment in terms of progression-free and overall survival.6,7 whether the achieved degree of tumor downsizing is sufficient to facilitate surgery is an unresolved issue, as is the optimal timing of neoadjuvant treatment. in conclusion, the rapidity of recent advances in rCC management make it difficult to establish a therapeutic algorithm that accounts for the numerous and evolving prognostic/predictive factors. the use of targeted therapies in a neoadjuvant setting, with the aims of significantly reducing tumor volume before surgery and gaining better control of disease in high-risk patients, is a fascinating future option. these theoretical advantages could balance the published possible risk of perioperative complications associated with neoadjuvant anti-angiogenic therapies.

Review: Hydroxyoctadecadienoic acids: novel regulators of macrophage differentiation and atherogenesis

Hydroxyoctadecadienoic acids (HODEs) are stable oxidation products of linoleic acid, the generation of which is increased where oxidative stress is increased, such as in diabetes. In early atherosclerosis, 13-HODE is generated in macrophages by 15-lipoxygenase-1. This enhances protective mechanisms through peroxisome proliferator-activated receptor (PPAR)-g activation leading to increased clearance of lipid and lipid-laden cells from the arterial wall. In later atherosclerosis, both 9-HODE and 13-HODE are generated nonenzymatically. At this stage, early protective mechanisms are overwhelmed and pro-inflammatory effects of 9-HODE, acting through the receptor GPR132, and increased apoptosis predominate leading to a fragile, acellular plaque. Increased HODE levels thus contribute to atherosclerosis progression and the risk of clinical events such as myocardial infarction or stroke. Better understanding of the role of HODEs may lead to new pharmacologic approaches to modulate their production or action, and therefore lessen the burden of atherosclerotic disease in high-risk patients.

Controversias en el tratamiento quirúrgico de los tumores del estroma gastrointestinal (GIST) primarios

It is estimated that 50% of GIST are located at the time of their diagnosis. A complete surgical resection can be performed in up to 95% of these cases, making this the most important prognostic factor. This surgery must fulfil a series of technical requirements so as to be really effective, as it has to be R0, with no tumour rupture, with preservation of the pseudo-capsule, etc. Although the majority of GIST are gastric, their location in other anatomical areas, such as the oesophagus, duodenum or rectum, require the surgeon to use more complex techniques. Laparoscopy is increasingly used; however, we must avoid its use, due to there being few experienced groups or if there are large tumours. The use of neoadjuvant therapy has revived great interest by allowing to resection tumours that were once non-resectable or in very compromised anatomical locations, with less aggressive surgery. The use of pre-surgical biopsy is not exempt from serious risks, thus it should only be used for establishing a neoadjuvant treatment or if there are diagnostic doubts with other diseases in high risk patients.