Cancer associated thrombosis in pediatric patients

The etiology of pediatric cancer associated thrombosis (CAT) is multifactorial and may reflect pro-coagulant alterations of the hemostatic system induced by presence of cancer itself or by therapeutic chemotherapy, tumor mass effects, tumor thrombi, and inherited thrombophilia. Age, diagnosis of hematological malignancy and presence of a central venous line significantly increase the risk of thrombosis. With over 80% cure rates of childhood cancer, strategies for prevention as well as for early diagnosis and optimal treatment of (thromboembolism) TE in children with malignancies are of major importance. Currently use of therapeutic low molecular heparin (LMWH) still prevails, as prospective studies and real world data regarding Direct oral anticoagulant (DOAC) use for treatment or prevention of pediatric CAT are scarce. The following review will address the epidemiology, etiology and risk factors for CAT in children, and describe the presently available evidence associated with anticoagulant therapy and prevention strategies.     

Insulin-pump use in everyday practice: data from an exhaustive regional registry in France

AIM: The aim of this study is to evaluate the effectiveness and safety of continuous subcutaneous insulin infusion (CSII) under real-life conditions among all patients treated with CSII in the south of Paris. METHODS: The 42 diabetologists practising in the region enrolled all patients treated with CSII or admitted for CSII initiation. During the study visit, the data for pump use and clinical results were recorded. RESULTS: Data were obtained for 424 patients, mean age 44.2+/-15.6 years, disease duration 18.7+/-10.6 years, including 339 treated with CSII for longer than three months (mean duration: 3.5+/-3.5 years; range: 3-258 months). Most of the patients (N=285, 84.8%) had type 1 diabetes; 44 (13.1%) had type 2 diabetes. In patients treated for more than three months, HbA1c decreased significantly between CSII initiation (9.1+/-1.9%) and the study visit (7.8+/-1.4%; P<0.0001). Patients with HbA1c >9%, using the pump, experienced a significant 0.9% improvement in their HbA1c levels with CSII versus multiple daily injections (P=0.001). The number of episodes of moderate hypoglycaemia was 2.7+/-2.5 per patient per week; of severe hypoglycaemia, 0.34 per patient per year and of ketoacidosis, 0.11 per patient per year. Factors significantly associated with HbA1c levels included amount of physical activity, pregnancy, HbA1c at CSII initiation and number of glucose self-determinations. Those associated with the number of moderate hypoglycaemia episodes were basal rate number, female gender and HbA1c level. HbA1c was negatively correlated with moderate hypoglycaemia (P<0.001), but not with severe hypoglycaemia. CONCLUSION: This 'pump' registry establishes the effectiveness of CSII in everyday practice, yet underscores the risks of severe hypoglycaemia and ketosis episodes. It could help diabetologists to improve patient training programmes and follow-up.     

Routine pressure-derived fractional flow reserve guidance: from diagnostic to everyday practice

The pressure-derived fractional flow reserve (FFR) is a valuable and well validated index for assessing the ischemic significance of coronary lesions. The 0.75 cutoff value of FFR discriminates between lesions with and without ischemic potential, helps decision making as to whether to revascularize a coronary stenosis and assists in evaluating the results of catheter-based treatment. Recent data show that the FFR index is also useful in managing patients with complex coronary disease. The aim of this paper is to provide an overview of the theoretical background of this index and its clinical applicability in the catheterization laboratory.     

High-sensitivity cardiac troponins in everyday clinical practice

High-sensitivity cardiac troponin(hs-cTn) assays are increasingly being used in many countries worldwide,however,a generally accepted definition of high-sen-sitivity is still pending.These assays enable cTn mea-surement with a high degree of analytical sensitivity with a low analytical imprecision at the low measuring range of cTn assays(coefficient of variation of 10% at the 99th percentile upper reference limit).One of the most important advantages of these new assays is that they allow novel,more rapid approaches to rule in or rule out acute coronary syndromes(ACSs) than with previous cTn assay generations which are still more commonly used in practice worldwide.hs-cTn is also more sensitive for the detection of myocardial damage unrelated to acute myocardial ischemia.Therefore,the increase in early diagnostic sensitivity of hs-cTn assays for ACS comes at the cost of a reduced ACS specificity,because more patients with other causes of acute or chronic myocardial injury without overt myocardial isch-emia are detected than with previous cTn assays.As hs-cTn assays are increasingly being adopted in clinical practice and more hs-cTn assays are being developed,this review attempts to synthesize the available clinical data to make recommendations for their everyday clini-cal routine use.     

Changing perspectives in portal vein thrombosis

The aetiology of portal vein thrombosis (PVT) is heterogeneous. Important primary risk factors for PVT are cirrhosis, hepatobiliary malignancies and pancreatitis. Newly discovered thrombotic risk factors, such as latent myeloproliferative disorders and prothrombotic genetic defects, have also been identified as major risk factors for PVT. At least one-third of PVT patients demonstrate a combination of thrombotic risk factors. PVT, which does not have a detrimental effect on liver function, usually becomes manifest as a variceal haemorrhage in the oesophagus months to years after the development of thrombosis. Owing to intact coagulation variceal bleeding has a better prognosis among patients with PVT than cirrhotics. Endoscopic sclerotherapy or band ligation is the primary therapeutic option for variceal bleeding in patients with PVT. It is questionable whether anticoagulant therapy should be started, since it has not proven beneficial for most PVT patients. Therapy with anticoagulants is only recommended for those with acute PVT (especially in association with mesenteric vein thrombosis), those who recently underwent a portosystemic shunt procedure, and those with other thrombotic manifestations, particularly in case of proven hypercoagulability. Mortality of patients with PVT may be associated with concomitant medical conditions which lead to the PVT or with manifestations of portal hypertension, such as variceal haemorrhage. Multivariate analysis of a large Dutch PVT population has shown that age, malignancy, ascites and the presence of mesenteric vein thrombosis are independently related to survival. Death due to a variceal haemorrhage is rare. Poor outcome of PVT thus appears to be associated primarily with concomitant diseases which lead to PVT, and not the complications of portal hypertension. It is therefore uncertain whether surgical portosystemic shunting affects survival favourably.     

Angiographically confirmed stent thrombosis in contemporary practice: Insights from intravascular ultrasound

Objective : We hypothesized that patients presenting with stent thrombosis (ST) have a high prevalence of stent underexpansion and malapposition when assessed by intravascular ultrasound (IVUS). Background : IVUS can provide mechanistic insight into mechanical factors, including stent underexpansion, malapposition, and fracture that may predispose to ST. Methods : All consecutive cases of angiographically confirmed ST from a multicenter registry (from 2005 to 2010) were reviewed. All IVUS images were reviewed off‐line for the presence of stent underexpansion, malapposition, and fracture. Kaplan–Meier analysis was used to determine whether use of IVUS at the time of ST was associated with long‐term mortality and major adverse cardiovascular events. Results : IVUS was performed in 32 of 173 subjects with ST (18%). Stent underexpansion was present in 82% of cases and in all cases of early ST, with a mean stent expansion of 0.7 ± 0.23 by MUSIC criteria. Stent malapposition was most frequently observed in very late ST (40%). In‐hospital mortality was similar between subjects who had IVUS performed at the time of ST when compared with the non‐IVUS group (3.2% vs. 4.3%, P = 0.8). Subjects who had IVUS performed at the time of ST had lower rates of mortality (HR 0.4, 95% CI 0.1‐1.6, P =0.2) and major adverse cardiovascular events (HR 0.5, 95% CI 0.2–1.4, P =0.2) at follow‐up, but these values were not statistically significant. Conclusions : There is a high prevalence of stent underexpansion in early ST, while the prevalence of malapposition is higher in very late ST. Use of IVUS during treatment for ST may identify mechanisms underlying the development of ST. © 2012 Wiley Periodicals, Inc.     

Low molecular weight heparins in everyday practice]

Standard nonfractioned heparin has been used for fifty years in the treatment of thromboembolic accidents, and for fifteen years, since Kakkar's works, in the prevention of thromboembolic complications in a surgical and medical context [5]. The antithrombotic efficacy of nonfractioned heparin (NFH) is accompanied by hemorrhagic complications occurring in about 10% of the patients receiving a "curative" treatment at hypocoagulating doses and in about 5% of the patients receiving the low-dose "preventive" treatment. The interest raised by low molecular weight heparins (LMWH), prepared as early as 1970, was based on a concept that is currently called into question: their anti-Xa activity, accounting for the antithrombotic activity, is high, while the anti-IIa (antithrombin) activity, producing the hemorrhagic risks, is lower. The pharmacokinetic properties, including longer-lasting action and better bioavailability with subcutaneous delivery relative to standard heparin, have greatly facilitated their use in the clinical field by allowing the reduction of the daily number of injections. Extensive clinical trials have confirmed that the antithrombotic efficacy of the LMWH is at least equal, if not superior, to that of nonfractioned heparin, though without reducing the frequency of hemorrhagic complications in the prevention of postoperative phlebitis. A limited number of randomized clinical trials suggests that the LMWH might also be as effective as NFH, as expected at doses about 3 times as high as those used for prophylaxis.     

Cancer and thrombosis

The risk of venous thromboembolic events (VTE) in patients with cancer is well established. Malignancy screening in patients who present with their first episode of VTE is recommended only if the history or physical findings are suggestive of an underlying problem, however. Thrombotic events remain a significant cause of death in cancer patients and their treatment remains a major challenge in the management of cancer. Low-molecular-weight heparins are safe, effective options for treatment and prophylaxis and may prolong survival in this patient population. It remains to be seen, however, if this treatment will influence cancer outcomes.     

Cancer stem cells in colorectal cancer from pathogenesis to therapy: Controversies and perspectives

Colorectal cancer remains one of the most common and lethal malignancies worldwide despite the use of various therapeutic strategies.A better understanding of the mechanisms responsible for tumor initiation and progression is essential for the development of novel,more powerful therapies.The traditional,so-called"stochastic model"of tumor development,which assumes that each cancer cell is tumorigenic,has been deeply challenged during the past decade by the identification of cancer stem cells(CSCs),a biologically distinct subset of cells within the bulk of tumor mass.This discovery led to the development of the hierarchical model of tumorigenesis which assumes that only CSCs have the ability to initiate tumor growth,both at primary and metastatic sites.This model implies that the elimination of all CSCs is fundamental to eradicate tumors and that failure to do so might be responsible for the occurrence of relapses and/or metastases frequently observed in the clinical management of colorectal cancer patients.Identification and isolation of CSCs is essential for a better understanding of their role in the tumorigenetic process and for the development of CSC-specific therapies.Several methods have been used for this purpose and many efforts have been focused on the identification of specific CSC-surface markers.This review provides an overview of the proposed roles of CSC in human colorectal tumorigenesis focusing on the most important molecules identified as CSC-specific markers in colorectal cancer and on the potential strategies for the development of CSC-targeted therapy.     

Efficacy of rituximab in primary immune thrombocytopenia: an analysis of adult pretreated patients from everyday hematological practice

Although rituximab has seen increasing use in the treatment of immune thrombocytopenia (ITP) for many years, its therapeutic role in this disease remains unclear. We retrospectively analyzed data of all patients with ITP treated with rituximab (375?mg/m² once weekly for four consecutive weeks) and consecutively entered the findings into the databases of six large academic centers in the Czech Republic. A total of 114 patients were included in the analysis. All of the patients received rituximab as a second or additional line of therapy. The overall response rate (ORR) after rituximab therapy was 72?% [48?% complete response (CR), 24?% partial response (PR)] at month 6, and 69?% (45?% CR, 24?% PR) at month 12. For the group of patients with newly diagnosed (acute) ITP, the results of treatment were significantly better than for the group of patients with persistent or chronic ITP; nonetheless, this group of patients was far too small (n?=?18) for our findings to be generalized. Multivariate analysis revealed that the ORR was significantly influenced primarily by the number of therapies prior to rituximab (the more previous therapies, the worse treatment response). The results of our analysis ??from everyday hematological practice?? confirm the high efficiency of rituximab treatment in pretreated adult patients with ITP.     

Challenges in everyday surgical practice: synchronous bilobar hepatic colorectal metastases--newer multimodality approach

BACKGROUND/AIMS: This study was designed to assess the efficacy of two-stage liver surgery and hepatic directed chemo-biological therapy in treatment of synchronous bilobar hepatic metastases of colorectal origin. METHODOLOGY: A total of thirty-two patients were included in this study that were diagnosed to have colorectal carcinoma with synchronous bilobar hepatic metastases. During stage one surgery along with excision of primary colorectal carcinoma; ligation and transection of main portal branch on side of bulky metastases disease (right branch in 28 and left in 4 patients) was performed. The metastatic nodules in the opposite lobe were ablated by microwave therapy and a hepatic arterial jet port catheter was introduced via the gastroduodenal artery for liver directed chemo-biological therapy. The catheter was connected to a subcutaneously placed port. Three cycles of chemotherapeutic drugs and Avastin (Bevacizumab) were given via hepatic arterial infusion (HAI) at intervals of twenty-five days. During the second stage surgery hepatic resection was carried out followed by continuation of hepatic arterial infusion of chemobiological drugs as adjuvant therapy. RESULTS: In the follow-up period of 31 months, 1-year survival of 100% and 2-year survival of 80% with a mean 28 months survival was noted. CONCLUSIONS: Combined approach of ligating the portal branch, microwave ablation, hepatic regional chemo-biological therapy and staged liver surgery (a multimodality approach) in the treatment of advanced liver metastatic disease synchronous with colorectal cancer is an effective method of treatment which improves the overall survival and quality of life of the patient with hepatic bilobar metastases synchronous with colorectal carcinoma. Avastin, a monoclonal antibody against vascular endothelial growth factor; used for inhibition of tumor growth has shown its efficacy in early results and holds good promise for the future.     

Applicability of decision analysis to everyday clinical practice

Objective: To determine whether decision analysis is applicable to routine management of suspected pulmonary embolism in an emergency care setting. Design: Controlled feasibility trial. Setting: Emergency center of a university hospital. Patients: Outpatients (n=84) admitted with clinical and scintigraphic evidence of pulmonary embolism. Interventions: Patients were treated either with the usual clinical work up for pulmonary embolism (control group) or using a decision analysis model with three options: no action; angiography followed by treatment if positive; treatment without angiography. Results: All six senior residents in the decision analysis group agreed to fully participate for the 16 months of the study. Summarizing the decision analysis model in a graph was critical to obtain acceptance from all the physicians. Decision analysis (n=43) and control (n=41) patients underwent similar numbers of angiographies. However, angiographies for patients who had intermediate clinical probabilities of pulmonary embolism, between 25 and 75%, were more frequent in the decision analysis group (9/13=69%) than in the control group (7/20=35%). Agreement between clinical probability and lung-scan result was stronger in the decision analysis group. Conclusions: Decision analysis was successfully used to manage all patients suspected of having pulmonary embolism admitted to an emergency center during the 16-month trial. There was no insuperable obstacle to acceptance of clinical decision analysis by the physicians. Decision analysis may have resulted in a better discrimination between low and intermediate clinical probabilities of pulmonary embolism.     

Arterial thrombosis associated with adjuvant chemotherapy for breast carcinoma: a Cancer and Leukemia Group B Study

PURPOSE: Multiagent chemotherapy and chemohormonal therapy for breast cancer are associated with an increased risk for venous thromboembolic complications. We observed instances of arterial thrombosis in two studies of breast cancer involving multiagent chemotherapy for stages II and III disease. Our purpose in this study was to determine the incidence of this complication and whether it appeared to be related to the chemotherapy or was a random event. PATIENTS AND METHODS: Episodes of arterial thrombotic events were identified from record reviews of 1,014 assessable patients with breast cancer entered on two Cancer and Leukemia Group B protocols. Details of the kind of arterial event, when it occurred, the outcome, and the occurrence of metastases were analyzed. RESULTS: Thirteen (1.3%) patients had an arterial thrombosis: six (5.3%) of 113 patients with stage III disease and seven (0.8%) of 901 patients with stage II disease. Four of these patients had a peripheral arterial thrombosis and nine had strokes (four were fatal). All these events occurred while the patients were receiving adjuvant chemotherapy. Only one additional arterial event (a stroke approximately four years later) has occurred in this patient group after chemotherapy was completed. CONCLUSION: Arterial thrombosis is also associated with multiagent chemotherapy in patients with breast cancer. The mechanism is unknown.