The Haemostasis Traffic Light, a user-centred coagulation management tool for acute bleeding situations: a simulation-based randomised dual-centre trial.

The Haemostasis Traffic Light is a cognitive aid with a user-centred design to enhance and simplify situation awareness and decision-making during peri-operative bleeding. Its structure helps to prioritise therapeutic interventions according to the pathophysiology and the severity of the bleeding. This investigator-initiated, randomised, prospective, international, dual-centre study aimed to validate the Haemostasis Traffic Light by adapting it to the local coagulation protocols of two university hospitals. Between 9 January and 12 May 2020, we recruited 84 participants at the University Hospital Zurich, Switzerland, and the Italian Hospital of Buenos Aires, Argentina. Each centre included 21 resident and 21 staff anaesthetists. Participants were randomly allocated to either the text-based algorithm or the Haemostasis Traffic Light. All participants managed six bleeding scenarios using the same algorithm. In simulated bleeding scenarios, the design of the Haemostasis Traffic Light algorithm enabled more correctly solved cases, OR (95%CI) 7.23 (3.82-13.68), p < 0.001, and faster therapeutic decisions, HR (95%CI) 1.97 (1.18-3.29, p = 0.010). In addition, the tool improved therapeutic confidence, OR (95%CI) 4.31 (1.67-11.11, p = 0.003), and reduced perceived work-load coefficient (95%CI) -6.1 (-10.98 to -1.22), p = 0.020). This study provides empirical evidence for the importance of user-centred design in the development of haemostatic management protocols.

Efficacy of quadruple treatment on different types of pre-operative anaemia: secondary analysis of a randomised controlled trial.

In patients with pre-operative anaemia undergoing cardiac surgery, combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12 and oral folic acid reduces allogeneic blood product transfusions. It is unclear if certain types of anaemia particularly benefit from this treatment. We performed a post-hoc analysis of anaemic patients from a randomised trial on the 'Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery'. We used linear regression analyses to examine the efficacy of a combination anaemia treatment compared with placebo on the following deficiencies, each representing a part of the combination treatment: ferritin and transferrin saturation; endogenous erythropoietin; holotranscobalamine; and folic acid in erythrocytes. Efficacy was defined as change in reticulocyte count from baseline to the first, third and fifth postoperative days and represented erythropoietic activity in the immediate peri-operative recovery phase. In all 253 anaemic patients, iron deficiency was the most common cause of anaemia. Treatment significantly increased reticulocyte count in all regression analyses on postoperative days 1, 3 and 5 (all p < 0.001). Baseline ferritin and endogenous erythropoietin were negatively associated with change in reticulocyte count on postoperative day 5, with an unstandardised regression coefficient B of -0.08 (95%CI -0.14 to -0.02) and -0.14 (95%CI -0.23 to -0.06), respectively. Quadruple anaemia treatment was effective regardless of the cause of anaemia and its effect manifested early in the peri-operative recovery phase. The more pronounced a deficiency was, the stronger the subsequent boost to erythropoiesis may have been.

Improving decision making through presentation of viscoelastic tests as a 3D animated blood clot: the Visual Clot.

Point-of-care viscoelastic coagulation tests are used increasingly and enable physicians to run precise whole blood coagulation diagnostics. However, the somewhat complicated and abstract presentation of results may hinder these advantages. For this reason, we developed the Visual Clot as an alternative mode of presentation for thrombelastometric data. An algorithm takes existing parameters from rotational thromboelastometry and creates a visual representation in the form of an animated blood clot named 'Visual Clot'. In a prospective international dual-centre study, 60 physicians were presented with rotational thromboelastometry results in the standard way or as a Visual Clot. They were then asked to make therapeutic decisions based on pathological findings. Overall proportion of correct therapeutic decisions was median (IQR [range] 100 (83-100 [39-100]) % for Visual Clot vs. 44 (25-50 [0-83]) % for standard rotational thromboelastometry presentation of results, p < 0.001. Mixed regression models yielded a mean OR (95%CI) 22.1 (13.4-36.5), p < 0.001 for correct decisions with the Visual Clot compared with standard rotational thromboelastometry, with an 18.7 (16.4-21.1), p < 0.001 second decrease in decision time. Perceived cognitive work-load was lower, and participants rated their diagnostic confidence to be higher with the Visual Clot, both p < 0.001. Although correct interpretation of standard rotational thromboelastometry results depended on previous rotational thromboelastometry knowledge and experience, Visual Clot interpretation did not. The Visual Clot improved rotational thromboelastometry-based therapeutic decisions, as pathologies can be recognised more rapidly and accurately. These findings underline the significance of an alternative additional visualisation technique that simplifies the interpretation of abstract standard data.

Impact of a Patient Blood Management monitoring and feedback programme on allogeneic blood transfusions and related costs.

A Patient Blood Management programme was established at the University Hospital of Zurich, along with a monitoring and feedback programme, at the beginning of 2014 with a first analysis reported in 2015. Our study aimed to investigate the further impact of this Patient Blood Management monitoring and feedback programme on transfusion requirements and related costs. We included adult patients discharged between 2012 and 2017. A total of 213,882 patients underwent analysis: 66,659 patients in the baseline period (2012-2013); 35,309 patients in the year after the introduction of the Patient Blood Management monitoring and feedback programme (2014) and 111,914 patients in the continued sustainability period (2015-2017). The introduction of the Patient Blood Management monitoring and feedback programme reduced allogeneic blood product transfusions by 35%, from 825 units per 1000 hospital discharges in 2012 to 536 units in 2017. The most sustained effect was an approximately 40% reduction in red blood cell transfusions, from 535 per 1000 discharges to 319 units. Fewer patients were transfused in the periods after the introduction of the Patient Blood Management monitoring and feedback programme (6251 (9.4%) vs. 2932 (8.3%) vs. 8196 (7.3%); p < 0.001). Compared with 2012, the yearly OR for being exposed to any blood transfusion declined steadily after the introduction of the Patient Blood Management monitoring and feedback programme to 0.64 (95%CI 0.61-0.68; p < 0.001) in 2017. For patients requiring extracorporeal membrane oxygenation, transfusion requirements were also sustainably reduced. This reduction in allogeneic blood transfusions led to savings of 12,713,754 Swiss francs (£ 9,497,000 sterling; EUR 11,100,000; US$ 12,440,000) in blood product acquisition costs over 4 years. In-hospital mortality was not affected by the programme. The Patient Blood Management monitoring and feedback programme sustainably reduced transfusion requirements and related costs, without affecting in-hospital mortality.

The importance of genetic susceptibility in Dupuytren's disease.

Dupuytren's disease (DD) is a progressive fibromatosis that causes the formation of nodules and cords in the palmar aponeurosis leading to flexion contracture of affected fingers. The etiopathogenesis is multifactorial with a strong genetic predisposition. It is the most frequent genetic disorder of connective tissues. We have collected clinical data from 736 unrelated individuals with DD who underwent surgical treatment from Germany and Switzerland. We evaluated a standardised questionnaire, assessed the importance of different risk factors and compared subgroups with and without positive family history. We found that family history clearly had the strongest influence on the age at first surgery compared to environmental factors, followed by male sex. Participants with a positive family history were on average 55.9 years of age at the first surgical intervention, 5.2 years younger than probands without known family history (p = 6.7 × 10(-8) ). The percentage of familial cases decreased with age of onset from 55% in the 40-49 years old to 17% at age 80 years or older. Further risk factors analysed were cigarettes, alcohol, diabetes, hypertension, and epilepsy. Our data pinpoint the importance of genetic susceptibility for DD, which has long been underestimated.

[Sclerotization of orbital lymphangioma with OK-432]. / Sklerosierung orbitaler Lymphangiome mit OK-432.

Orbital lymphangiomas are mostly congenital, apparent vascular space-occupying lesions, which can lead to disfiguring swelling of the periorbital soft tissues, ocular motility disorders, optic nerve compression and keratopathy. The treatment is challenging because the disease is principally incurable. Lymphangiomatous tissue can be surgically partially reduced or treated by intralesional injection of various sclerosants. In this review we report the successful use of OK-432 for destruction of a macrocystic orbital lymphangioma.

[Medication-based therapy of infantile hemangioma and lymphatic malformations]. / Medikamentöse Behandlungsansätze für infantile Hämangiome und lymphatische Malformationen.

The therapy of vascular tumors and malformations should be interdisciplinary and performed according to available guidelines. Infantile hemangiomas (IH) are the most frequent vascular tumors of childhood and do not require treatment in most cases. If the IH is complicated by its location (e.g. facial or genital) or if the lesion threatens to cause loss of function, small localized IH should be treated by laser- or cryotherapy. If the IH is diffuse or rapidly growing it can be successfully treated using the ß blocker propranolol. The mechanism underlying the efficacy of this medication-based therapy is not completely understood and this still represents an experimental therapy. The results of molecular studies on vascular malformations have indicated new strategies for medical therapies. However, lymphatic malformations (LM) are still treated by surgery where possible, or sclerotherapy. Further investigations are necessary to determine whether new drugs such as the mTOR inhibitor rapamycin may be effective for treatment of diffuse LM. First case reports seem to be promising.

Evaluation of the prognostic meaning of C-reactive protein (CRP) in children and adolescents with classical Hodgkin's lymphoma (HL).

BACKGROUND: In adult cancer patients the negative predictive value of elevated CRP levels has been described for several malignancies. Only few studies have analyzed the prognostic role of CRP in children and adolescents with classical HL. In these studies elevated CRP levels correlate with the presence of classical risk factors and adverse outcome. PATIENTS AND METHODS: The prognostic role of CRP for patients with classical HL admitted to the GPOH-HD-2002 study was analyzed retrospectively. RESULTS: CRP levels were documented for 369 of 573 patients. Significant (p<0.05) increased median CRP levels were found in the presence of B-Symptoms (25.7 vs. 5.1 mg/l), extranodal involvement (21.5 vs. 7.5 mg/l), elevated erythrocyte sedimentation rate (ESR, 13.0 vs. 1.0 mg/l) and stage III/IV disease (15.5 vs. 5.3 mg/l). 83.9% of patients with elevated and 45.8% of patients with normal CRP had an ESR >30 mm/h. CONCLUSION: Elevated CRP levels were associated with classical risk factors of HL. CRP and ESR may reflect different biological processes. CRP was prognostic within early stage TG-1 patients treated with reduced treatment, but not within advanced stage TG-2+3.

[Therapy of tumors of the anterior orbit]. / Therapie anterior gelegener Orbitatumoren.

Tumors of the orbit are diagnosed on clinical and neuroradiological criteria. A biopsy may histologically confirm uncertain mass lesions. The patients' age and medical history predispose for certain tumor entities among the rather heterogenous spectrum of possible diagnoses. The therapy depends on the degree of malignancy and its location within the orbit. Among the different options, surgical excision is the most common followed by radiation therapy either in combination with surgery or alone. Chemotherapy plays a subsidiary role in certain lymphomas or metastases. This review covers the surgical techniques and treatment principles for tumors of the anterior orbit, explains radiotherapy techniques and briefly covers chemotherapy. Pediatric tumors of the orbit are covered separately.

Successful treatment of ulcerated haemangioma with propranolol.

BACKGROUND: Ulceration is a frequent complication of proliferating haemangioma. METHODS: Four patients with ulcerated hemangioma aged 2, 4, 5 months and 5 weeks were treated with 2 mg/kg KG propranolol. RESULTS: Efficacy and safety of propranolol were excellent in all four cases. CONCLUSIONS: Propranolol may be the first-choice therapy for ulcerated haemangioma.

[Metronomic chemotherapy in pediatric oncology: hype or hope?]. / Chimiothérapie métronomique en oncologie pédiatrique : effet de mode ou espoir réel ?

Angiogenesis is crucial for the growth of cancer. As such, it has become an established target in fighting cancer. Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potential novel approach to controlling advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has the property of killing resistant cancer cells while significantly reducing undesirable toxic side effects. We review the data regarding the use of metronomic chemotherapy in children with cancer and discuss its potential uses and limits.

Gallium assisted plasma enhanced chemical vapor deposition of silicon nanowires.

Silicon nanowires have been grown with gallium as catalyst by plasma enhanced chemical vapor deposition. The morphology and crystalline structure has been studied by electron microscopy and Raman spectroscopy as a function of growth temperature and catalyst thickness. We observe that the crystalline quality of the wires increases with the temperature at which they have been synthesized. The crystalline growth direction has been found to vary between <111> and <112>, depending on both the growth temperature and catalyst thickness. Gallium has been found at the end of the nanowires, as expected from the vapor-liquid-solid growth mechanism. These results represent good progress towards finding alternative catalysts to gold for the synthesis of nanowires.

[Potential role of antiangiogenic treatment in neuroblastoma]. / Neuroblastome : intérêt des traitements anti-angiogéniques.

Focus on new drug development over the last few years has yielded new agents that differ from unspecific classical chemotherapeutics and ionizing radiation, while still targeting the cancer cell itself. Antiangiogenesis is a totally distinct approach targeting the tumor's blood vessels. This concept has now found its eligibility for the treatment of several adult solid tumors: the human antivascular endothelial growth factor (VEGF) antibody bevacizumab, as well as the VEGF receptor tyrosine kinase inhibitors, sunitinib and sorafinib, have recently been licensed by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of colorectal, renal, and lung cancer. Other antiangiogenic drugs are under preclinical and early clinical evaluation. However, what do we know of the use of these drugs in pediatric solid tumors, such as sarcomas and embryonal and neuronal tumors? For some time now, neuroblastoma has been shown to be dependent on angiogenesis. However, the first preclinical data on antiangiogenic drugs in neuroblastoma have not been published until recently, and clinical trials with antiangiogenic agents in neuroblastoma treatment protocols are scarce. This review adresses current knowledge on the important role and mechanisms of angiogenesis in neuroblastoma and summarizes available preclinical and clinical results of antiangiogenic agents used to treat neuroblastoma. Our review clearly demonstrates that clinical trials are urgently needed to bring forward promising antiangiogenesis concepts in neuroblastoma therapy.

First description of three patients with multifocal lymphangiomatosis and protein-losing enteropathy following palliation of complex congenital heart disease with total cavo-pulmonary connection.

The objective was to identify abdominal lymphatic malformations in pediatric patients with protein-losing enteropathy after palliation of complex congenital heart disease with total cavo-pulmonary connection (TCPC). In 2006, we performed complete hemodynamic and laboratory workup and thoracic and abdominal MRT screens in three patients who newly presented with symptoms of protein-losing enteropathy. All three patients, aged 3, 5, and 7 years, showed excellent TCPC hemodynamics with central venous pressures of 10-13 mm Hg. None of the patients had right-to-left overflow. All three patients showed extensive thoracic and mesenterial lymphangiomatosis. One patient died after 18 months of therapy, which included long-term parenteral nutrition, somatostatin, subcutaneous heparin injections, and frequent albumin and immunoglobulin substitution. The other two patients are in stable condition. Lymphangiomatosis might play an unknown role in the pathogenesis of protein-losing enteropathy after TCPC. It remains unclear whether lymphangiomatosis is a primary congenital disease related to the cardiac disease or if it is triggered by repeated surgery or venous congestion. The presence of lymphangiomatosis should be given diagnostic and therapeutic consideration in TCPC patients in the future.

Response of progressive fibromatosis to therapy with liposomal doxorubicin.

BACKGROUND: Patients with fibromatosis not amenable to surgery may suffer from high morbidity. Various chemotherapeutic regimens have been tried in these patients with limited success. Here, we report on the successful use of pegylated liposomal doxorubicin in the treatment of 4 patients with unresectable fibromatosis in unfavorable localizations. PATIENTS AND METHODS: 3 children and 1 adult with progressive fibromatosis were treated with 3-weekly cycles of chemotherapy with liposomal doxorubicin (dose range 20-50 mg/m2 per day every 21 days). Tumors were located at the nasal cavity, fossa infratemporalis, oral cavity, abdomen, and fossa supraclavicularis and were unresectable. 3 of the 4 patients had been heavily pretreated with various chemotherapeutic agents. Objective tumor response was monitored by magnetic resonance imaging and possible cardiotoxicity by echocardiography at regular intervals. RESULTS: A tumor response was obtained in all 4 patients. All patients showed normal cardiac function after completion of chemotherapy as evaluated by left ventricular shortening fraction. Severe neutropenia was not observed. CONCLUSION: Pegylated liposomal doxorubicin is a therapeutic option in patients with progressive unresectable fibromatosis in unfavorable localizations.

Parkes Weber or Klippel-Trenaunay syndrome? Non-invasive diagnosis with MR projection angiography.

Klippel-Trenaunay and Parkes Weber (Klippel-Trenaunay-Weber) syndromes consist of vascular malformations of the capillary, venous and lymphatic systems combined with soft tissue and bone hypertrophy of the affected extremity. Klippel-Trenaunay syndrome is a pure low-flow condition, while Parkes Weber syndrome is characterized by significant arteriovenous fistulas. The distinction of both entities is relevant, since the prognosis and therapeutic strategies differ significantly. Our purpose is to demonstrate that thick-slice dynamic magnetic resonance projection angiography (MRPA) is a non-invasive tool to detect arteriovenous shunting in Parkes Weber syndrome. Four patients underwent MR imaging and MRPA. MRPA demonstrated arteriovenous shunting in three patients. Arteriovenous shunting was characterized by early appearing draining veins. The time of arrival between normal arteries and pathological veins varied between less than 0.5 and 1.0 s. Therefore, the diagnosis in these cases could be specified as Parkes Weber syndrome. In all these cases, arteriovenous shunting was confirmed by intraarterial digital subtraction angiography. One patient showed normal results in MRPA and could be diagnosed as having Klippel-Trenaunay syndrome.