Thrombin Generation as a Method to Identify the Risk of Bleeding in High Clinical-Risk Patients Using Dual Antiplatelet Therapy.

Background: Patients using dual antiplatelet therapy after percutaneous coronary intervention are at risk for bleeding. It is currently unknown whether thrombin generation can be used to identify patients receiving dual antiplatelet therapy with increased bleeding risk. Objectives: To investigate whether thrombin generation measurement in plasma provides additional insight into the assessment of bleeding risk for high clinical-risk patients using dual antiplatelet therapy. Methods: Coagulation factors and thrombin generation in platelet-poor plasma were measured in 93 high clinical-risk frail patients using dual antiplatelet therapy after percutaneous coronary intervention. During 12-month follow-up, clinically relevant bleedings were reported. Thrombin generation at 1 and 6 months after percutaneous coronary intervention was compared between patients with and without bleeding events. Results: One month after percutaneous coronary intervention, the parameters of thrombin generation, endogenous thrombin potential, peak height, and velocity index were significantly lower in patients with bleeding in the following months compared to patients without bleeding. At 6 months follow-up, endogenous thrombin potential, peak height, and velocity index were still (significantly) decreased in the bleeding group as compared to non-bleeders. Thrombin generation in the patients' plasma was strongly dependent on factor II, V, and VIII activity and fibrinogen. Conclusion: High clinical-risk patients using dual antiplatelet therapy with clinically relevant bleeding during follow-up show reduced and delayed thrombin generation in platelet-poor plasma, possibly due to variation in coagulation factors. Thus, impaired thrombin-generating potential may be a "second hit" on top of dual antiplatelet therapy, increasing the bleeding risk in high clinical-risk patients. Thrombin generation has the potential to improve the identification of patients using dual antiplatelet therapy at increased risk of bleeding.

Quality of life after esophageal replacement in children.

PURPOSE: Assessing quality of life (QoL) after esophageal replacement (ER) for long gap esophageal atresia (LGEA). METHODS: All patients after ER for LGEA with gastric pull-up (GPU n = 9) or jejunum interposition (JI n = 14) at the University Medical Center Groningen and Utrecht (1985-2007) were included. QoL was assessed with 1) gastrointestinal-related QoL using the Gastrointestinal Quality of Life Index (GIQLI)), 2) general QoL (Child Health questionnaire CHF87-BREF (children)/World Health Organization questionnaire WHOQOL-BREF (adults)), and 3) health-related QoL (HRQoL) (TNO AZL TACQoL/TAAQoL). Association of morbidity (heartburn, dysphagia, dyspnea on exertion, recurrent cough) and (HR)QoL was evaluated. RESULTS: Six patients after GPU (75%) and eight patients after JI (57%) responded to the questionnaires (mean age 15.7, SD 5.9, 12 male, two female). Mean gastrointestinal, general and health-related QoL total scores of the patients were comparable to healthy controls. However, young adults reported a worse physical functioning (p = 0.02) but better social functioning compared to peers (p = 0.01). Morbidity was not associated with significant differences in (HR)QoL. CONCLUSIONS: With the current validated QoL most patients after ER with GPU and JI for LGEA have normal generic and disease specific QoL scores. Postoperative morbidity does not seem to influence (HR)QoL. TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: III.

Atherothrombosis and Thromboembolism: Position Paper from the Second Maastricht Consensus Conference on Thrombosis.

Atherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin-angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet-fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia-reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C-based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.

Is complete surgical resection of stage 4 neuroblastoma a prerequisite for optimal survival or may >95 % tumour resection suffice?

Numerous studies have shown that for optimal survival in localized International Neuroblastoma Staging System stage 1-3 neuroblastoma, complete tumour resection (CR, macroscopic total tumour removal) is usually mandatory. In contrast, it is conceivable that in stage 4 disseminated disease, less extensive surgery [gross total resection (GTR), >95 % tumour removal] may suffice. This review shows substantial survival benefit in studies reporting on stage 4 patients undergoing CR, but also in studies reporting on patients undergoing GTR. Comparison between these studies is severely hampered by treatment heterogeneity. We found only four studies that explicitly compared survival between patients undergoing either CR or GTR. Two of these studies showed favourable results for patients treated with CR, while the other two did not show differences in survival.

Diagnosis and subsequent US-guided percutaneous drainage of an adrenal abscess in a 5-week-old infant.

Adrenal abscess is an uncommon finding in neonates and young infants. It may have a fatal outcome if inadequately treated. This case report describes the successful diagnosis and treatment of a left-sided adrenal abscess in a 5-week-old girl. Abdominal US and antigranulocyte antibody-scintigraphy showed an encapsulated suprarenal mass with debris suspicious for an adrenal abscess. Treatment is generally surgical. In this case, however, we performed US-guided percutaneous drainage combined with intravenous antibiotic treatment. The child recovered fully.

Laparoscopic treatment of gastric and duodenal perforation in children after blunt abdominal trauma.

Minimal invasive surgery has not yet gained wide acceptation for the care of patients that sustained an abdominal trauma. We describe the complete laparoscopic surgical treatment of two patients after a single blunt abdominal trauma. One patient sustained a handle bar injury and presented with a gastric perforation. The other sustained a duodenal rupture by falling on a sharp edge of a table. The patients were assessed and treated laparoscopically. The perforations were identified and closed. Both patients had an uneventful postoperative recovery. Therapeutic laparoscopic treatment of patients with upper gastrointestinal perforation is feasible. We would recommend this approach to experienced laparoscopic surgeons in hemodynamically stable patients.

A mucinous cystadenoma in the mesentery of the right hemicolon.

Cysts of the mesentery, retroperitoneum and omentum are rare. We present a patient with a mucinous cystadenoma in the mesentery of the right hemicolon. The exact aetiology of these cysts at the aforementioned sites is still unclear. Adenocarcinomas can arise in mucinous cystadenomas. Therefore, in our opinion, to prevent spillage the right approach is to primarily perform a laparatomy instead of attempting to remove these lesions laparoscopically, even if clinical and radiological signs of malignancy are absent.

[Diagnostic image (384). A woman with a swelling in the groin after a trauma]. / Diagnose in beeld (384). Een vrouw met een zwelling in de lies na een trauma.

A 59-year-old woman presented with persistent pain in the right hip and a hump in de groin area after a mild trauma due to a fall on the handlebars ofa bicycle. Iliopsoas bursitis was diagnosed.

High steady-state levels of p53 are not a prerequisite for tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.

CTLs specific to p53 were previously shown to efficiently eradicate p53-overexpressing tumor cells in vitro as well as in vivo. In this report, we demonstrate that these CTLs can also eliminate tumors that display moderate or even low levels of p53. Neither high steady-state levels of p53 nor elevated p53 synthesis is a prerequisite for recognition of tumors by p53-specific CTLs. Instead, our data show that a high p53 turnover rate is an important factor in determining the sensitivity of tumor cells to p53-specific CTLs. Our data suggest that p53 turnover is related to the MHC class I-restricted presentation of p53-derived epitopes at the tumor cell surface and indicate that CTL-mediated immunotherapy that targets p53 can be applied to a wider range of tumors than has thus far been anticipated.

Characteristics of tumor infiltration by adoptively transferred and endogenous natural-killer cells in a syngeneic rat model: implications for the mechanism behind anti-tumor responses.

Interleukin-2-activated, cultured NK cells (A-NK) cells were adoptively transferred into a syngeneic rat liver-tumor model. The kinetics of tumor infiltration by NK cells, originating either from adoptively transferred or from endogenous sources, the localization of these cells in the tumor, and their interactions with extracellular-matrix proteins were studied by immunohistochemistry and transmission-electron microscopy. The adoptive transfer of A-NK cells via the hepatic artery and s.c. injections of IL-2 into rats bearing subcapsularly induced CC531 liver tumors, but also IL-2 monotherapy, resulted in a significant increase of the number of NK cells both at the tumor border and in the tumor center. The majority of tumor-infiltrating NK cells was present in the tumor stroma and only occasionally was an NK cell observed in a tumor nodule in direct contact with tumor cells. Observations by electron microscopy suggested that matrix proteins, abundantly present in the tumor stroma but absent in the tumor nodules, provide a substrate for migration of infiltrating cells, whereas tight structures of matrix proteins surrounding tumor nodules provide a barrier for establishment of direct NK-cell-to-tumor-cell-contact. Our results suggest that direct NK-cell-to-target-cell-contact-mediated lysis is of minor importance for attaining an anti-tumor effect in this model. We hypothesize that treatment of tumor-bearing rats with A-NK cells and/or IL-2 initiates a cascade of events (e.g., secretion of tumor-killing cytokines and/or infiltration of other immune cells) ultimately leading to tumor regression.