Publications by authors named "Gabriela Simonova"

31 Publications

An Ovine Model of Haemorrhagic Shock and Resuscitation, to Assess Recovery of Tissue Oxygen Delivery and Oxygen Debt, and Inform Patient Blood Management.

Shock 2021 May 19. Epub 2021 May 19.

Australian Red Cross Lifeblood, Sydney, Australia Faculty of Medicine and Health, University of Sydney, Sydney, Australia Australian Red Cross Lifeblood, Brisbane, Australia Critical Care Research Group, The Prince Charles Hospital, Brisbane, Australia Faculty of Medicine, The University of Queensland, Brisbane, Australia Faculty of Health, Queensland University of Technology, Brisbane, Australia Medical Engineering Research Facility, Queensland University of Technology, Brisbane, Australia Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain Cardiovascular Research Institute, Basel, Switzerland Department of Thoracic and Cardiovascular Surgery, College of Medicine, Korea University, Seoul, Republic of Korea Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milano, Italy Sorbonne Université, INSERM, UMRS-1166, ICAN Institute of Cardiometabolism and Nutrition, Medical ICU, Pitié-Salpêtrière University Hospital, Paris, France School of Veterinary Science, The University of Queensland, Brisbane, Australia Department of Anesthesiology, Critical Care and Hyperbaric Medicine, Englewood Health, Englewood, USA TeamHealth, Englewood Health, Englewood, USA UF College of Medicine, University of Florida, Gainesville, USA Department of Anesthesiology, Medicine and Surgery, Icahn School of Medicine, Mount Sinai Hospital, New York, USA Department of Anesthesiology and Critical Care, Rutgers University, Newark, USA Faculty of Health, University of Technology, Sydney, Australia.

Background: Aggressive fluid or blood component transfusion for severe haemorrhagic shock may restore macrocirculatory parameters, but not always improve microcirculatory perfusion and tissue oxygen delivery. We established an ovine model of haemorrhagic shock to systematically assess tissue oxygen delivery and repayment of oxygen debt; appropriate outcomes to guide patient blood management.

Methods: Female Dorset-cross sheep were anaesthetised, intubated, and subjected to comprehensive macrohaemodynamic, regional tissue oxygen saturation (StO2), sublingual capillary imaging and arterial lactate monitoring, confirmed by invasive organ-specific microvascular perfusion, oxygen pressure and lactate/pyruvate levels, in brain, kidney, liver and skeletal muscle. Shock was induced by stepwise withdrawal of venous blood until mean arterial pressure (MAP) was 30mmHg, mixed venous oxygen saturation (SvO2) < 60%, and arterial lactate >4 mM. Resuscitation with PlasmaLyte® was dosed to achieve MAP > 65mmHg.

Results: Haemorrhage impacted primary outcomes between baseline and development of shock: MAP 89 ± 5 to 31 ± 5 mmHg (p < 0.01), SvO2 70 ± 7 to 23 ± 8% (p < 0.05), cerebral regional tissue oxygen saturation (StO2) 77 ± 11 to 65 ± 9% (p < 0.01), peripheral muscle StO2 66 ± 8 to 16 ± 9% (p < 0.01), arterial lactate 1.5 ± 1.0 to 5.1 ± 0.8 mM (p < 0.01), and base excess 1.1 ± 2.2 to -3.6 ± 1.7 mM (p < 0.05). Invasive organ-specific monitoring confirmed reduced tissue oxygen delivery; oxygen tension decreased and lactate increased in all tissues, but moderately in brain. Blood volume replacement with PlasmaLyte® improved primary outcome measures toward baseline, confirmed by organ-specific measures, despite haemoglobin reduced from baseline 10.8 ± 1.2 to 5.9 ± 1.1 g/dl post-resuscitation (p < 0.01).

Conclusion: Non-invasive measures of tissue oxygen delivery and oxygen debt repayment are suitable outcomes to inform Patient Blood Management of haemorrhagic shock, translatable for pre-clinical assessment of novel resuscitation strategies.
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http://dx.doi.org/10.1097/SHK.0000000000001805DOI Listing
May 2021

Stereotactic Radiosurgery for Differentiated Thyroid Cancer Brain Metastases: An International, Multicenter Study.

Thyroid 2021 May 11. Epub 2021 May 11.

Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.

Brain metastases (BM) from differentiated thyroid cancer are rare. Stereotactic radiosurgery (SRS) is commonly used for the treatment of BMs; however, the experience with SRS for thyroid cancer BMs remains limited. The goal of this international, multi-centered study was to evaluate the efficacy and safety of SRS for thyroid cancer BMs. From 10 institutions participating in the International Radiosurgery Research Foundation, we pooled patients with established papillary or follicular thyroid cancer diagnosis who underwent SRS for histologically confirmed or radiologically suspected BMs. We investigated patient overall survival (OS), local tumor control, and adverse radiation events (AREs). We studied 42 (52% men) patients who underwent SRS for 122 papillary (83%) or follicular (17%) thyroid cancer BMs. The mean age at SRS was 59.86 ± 12.69 years. The mean latency from thyroid cancer diagnosis to SRS for BMs was 89.05 ± 105.49 months. The median number of BMs per patient was 2 (range: 1-10 BMs). The median SRS treatment volume was 0.79 cm (range: 0.003-38.18 cm), and the median SRS prescription dose was 20 Gy (range: 8-24 Gy). The median survival after SRS for BMs was 14 months (range: 3-58 months). The OS was significantly shorter in patients harboring ≥2 BMs, when compared with patients with one BM (Log-rank = 5.452,  = 0.02). Two or more BMs (odds ratio [OR] = 3.688; confidence interval [CI]: 1.143-11.904;  = 0.03) and lower Karnofsky performance score at the time of SRS (OR = 0.807; CI: 0.689-0.945;  = 0.008) were associated with shorter OS. During post-SRS imaging follow-up of 25.21 ± 30.49 months, local failure (progression and/or radiation necrosis) of BMs treated with SRS was documented in five (4%) BMs at 7.2 ± 7.3 months after the SRS. At the last imaging follow-up, the majority of patients with available imaging data had stable intracranial disease (33%) or achieved complete (26%) or partial (24%) response. There were no clinical AREs. Post-SRS peritumoral T2/fluid attenuated inversion recovery signal hyperintensity was noted in 7% BMs. The SRS allows durable local control of papillary and follicular thyroid cancer BMs in the vast majority of patients. Higher number of BMs and worse functional status at the time of SRS are associated with shorter OS in patients with thyroid cancer BMs. The SRS is safe and is associated with a low risk of AREs.
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http://dx.doi.org/10.1089/thy.2020.0947DOI Listing
May 2021

Ovine red cell concentrates for transfusion research - is the storage lesion comparable to human red cell concentrates?

Vox Sang 2021 May 26;116(5):524-532. Epub 2020 Oct 26.

Research and Development, Australian Red Cross Lifeblood, Brisbane, QLD, Australia.

Background And Objectives: Sheep are increasingly being used as a large in vivo animal model of blood transfusion because they provide several advantages over small animals. Understanding the effects of storage duration on ovine (ov) red cell concentrates (RCCs) and how these changes compare with stored human (hu) RCCs is necessary to facilitate clinical translation of research findings.

Materials And Methods: OvRCCs (n = 5) collected and processed in standard human blood collection packs, and equivalent huRCCs provided by Australian Red Cross Lifeblood (n = 5), were stored at 2-6°C for 42 days, with samples collected weekly. Haemolysis index was determined by measuring supernatant haemoglobin concentration. Biochemical parameters were evaluated using a blood gas analyser. Energy metabolites and biologically active lipids were measured using commercial assays. Osmotic fragility was determined by lysis in various saline concentrations. Extracellular vesicles were characterized by nanoparticle tracking analysis.

Results: Ovine red blood cells (RBCs) are double in number, smaller in size and more fragile than human RBCs. Haematological values were unchanged throughout storage. In contrast, biochemical and metabolic values, and haemolysis index in three of the five ovRCCs exceeded huRCCs licensing criteria by day 42. Accumulation of extracellular vesicles and biologically active lipids was comparable between huRCCs and ovRCCs.

Conclusion: This study documents similarities and differences in the storage lesion of ovRCCs and huRCCs. This new information will guide the design of ovine transfusion models to enhance translation of findings to human transfusion settings.
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http://dx.doi.org/10.1111/vox.13020DOI Listing
May 2021

Development and validation of ELISAs for the quantitation of interleukin (IL)-1β, IL-6, IL-8 and IL-10 in ovine plasma.

J Immunol Methods 2020 11 20;486:112835. Epub 2020 Aug 20.

Critical Care Research Group, The Prince Charles Hospital, Brisbane, Australia; Faculty of Medicine, University of Queensland, Brisbane, Australia. Electronic address:

There is growing evidence that inflammation underpins many common diseases. Inflammatory/immunomodulatory/immune mediators, such as cytokines, are key modulators of inflammation and mediate both immune cell recruitment and complex intracellular signalling pathways. Ovine models of disease are increasingly utilized in pre-clinical research, however existing methods for measuring cytokine levels are limited. We established and validated enzyme-linked immunosorbent assays (ELISAs) targeting interleukin (IL)-1β, IL-6, IL-8 and IL-10 in sheep plasma. These ELISAs showed high sensitivity and specificity with intra- and inter-assay CV's below 10%, and recovery rates between 82 and 123%. Sensitivity for IL-1β, IL-6, IL-8 and IL-10 were 117.6 pg/mL, 443.1 pg/mL, 30.9 pg/mL, and 64.3 pg/mL, respectively. ELISA test result reproducibility decreased significantly after 12 weeks of plasma storage at -80 °C. Therefore, for accurate cytokine measurements, plasma samples need to be tested within three months of sample collection to account for cytokine protein degradation. These ELISAs offer a reliable and convenient method to identify inflammatory cytokine changes in sheep, allowing key insights into the disease pathogenesis of these ruminants.
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http://dx.doi.org/10.1016/j.jim.2020.112835DOI Listing
November 2020

Outcomes of stereotactic radiosurgery for pilocytic astrocytoma: an international multiinstitutional study.

J Neurosurg 2019 Nov 29:1-9. Epub 2019 Nov 29.

13Rose-Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland, Ohio.

Objective: The current standard initial therapy for pilocytic astrocytoma is maximal safe resection. Radiation therapy is considered for residual, recurrent, or unresectable pilocytic astrocytomas. However, the optimal radiation strategy has not yet been established. Here, the authors describe the outcomes of stereotactic radiosurgery (SRS) for pilocytic astrocytoma in a large multiinstitutional cohort.

Methods: An institutional review board-approved multiinstitutional database of patients treated with Gamma Knife radiosurgery (GKRS) between 1990 and 2016 was queried. Data were gathered from 9 participating International Radiosurgery Research Foundation (IRRF) centers. Patients with a histological diagnosis of pilocytic astrocytoma treated using a single session of GKRS and with at least 6 months of follow-up were included in the analysis.

Results: A total of 141 patients were analyzed in the study. The median patient age was 14 years (range 2-84 years) at the time of GKRS. The median follow-up was 67.3 months. Thirty-nine percent of patients underwent SRS as the initial therapy, whereas 61% underwent SRS as salvage treatment. The median tumor volume was 3.45 cm3. The tumor location was the brainstem in 30% of cases, with a nonbrainstem location in the remainder. Five- and 10-year overall survival rates at the last follow-up were 95.7% and 92.5%, respectively. Five- and 10-year progression-free survival (PFS) rates were 74.0% and 69.7%, respectively. On univariate analysis, an age < 18 years, tumor volumes < 4.5 cm3, and no prior radiotherapy or chemotherapy were identified as positive prognostic factors for improved PFS. On multivariate analysis, only prior radiotherapy was significant for worse PFS.

Conclusions: This represents the largest study of single-session GKRS for pilocytic astrocytoma to date. Favorable long-term PFS and overall survival were observed with GKRS. Further prospective studies should be performed to evaluate appropriate radiosurgery dosing, timing, and sequencing of treatment along with their impact on toxicity and the quality of life of patients with pilocytic astrocytoma.
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http://dx.doi.org/10.3171/2019.9.JNS191335DOI Listing
November 2019

Pre-clinical study protocol: Blood transfusion in endotoxaemic shock.

MethodsX 2019 9;6:1124-1132. Epub 2019 May 9.

Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.

The Surviving Sepsis Campaign (SCC) and the American College of Critical Care Medicine (ACCM) guidelines recommend blood transfusion in sepsis when the haemoglobin concentration drops below 7.0 g/dL and 10.0 g/dL respectively, while the World Health Organisation (WHO) guideline recommends transfusion in septic shock 'if intravenous (IV) fluids do not maintain adequate circulation', as a supportive measure of last resort. Volume expansion using crystalloid and colloid fluid boluses for haemodynamic resuscitation in severe illness/sepsis, has been associated with adverse outcomes in recent literature. However, the volume expansion effect(s) following blood transfusion for haemodynamic circulatory support, in severe illness remain unclear with most previous studies having focused on evaluating effects of either different RBC storage durations (short versus long duration) or haemoglobin thresholds (low versus high threshold) pre-transfusion. •We describe the protocol for a pre-clinical randomised controlled trial designed to examine haemodynamic effect(s) of early volume expansion using packed RBCs (PRBCs) transfusion (before any crystalloids or colloids) in a validated ovine-model of hyperdynamic endotoxaemic shock.•Additional exploration of mechanisms underlying any physiological, haemodynamic, haematological, immunologic and tissue specific-effects of blood transfusion will be undertaken including comparison of effects of short (≤5 days) versus long (≥30 days) storage duration of PRBCs prior to transfusion.
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http://dx.doi.org/10.1016/j.mex.2019.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529713PMC
May 2019

Fluid resuscitation with 0.9% saline alters haemostasis in an ovine model of endotoxemic shock.

Thromb Res 2019 Apr 12;176:39-45. Epub 2019 Feb 12.

Critical Care Research Group, Prince Charles Hospital, Brisbane, Australia; University of Queensland, Brisbane, Australia. Electronic address:

Introduction: Fluid resuscitation is a cornerstone of severe sepsis management, however there are many uncertainties surrounding the type and volume of fluid that is administered. The entire spectrum of coagulopathies can be seen in sepsis, from asymptomatic aberrations to fulminant disseminated intravascular coagulation (DIC). The aim of this study was to determine if fluid resuscitation with saline contributes to the haemostatic derangements in an ovine model of endotoxemic shock.

Materials And Methods: Twenty-one adult female sheep were randomly divided into no endotoxemia (n = 5) or endotoxemia groups (n = 16) with an escalating dose of lipopolysaccharide (LPS) up to 4 μg/kg/h administered to achieve a mean arterial pressure below 60 mmHg. Endotoxemia sheep received either no bolus fluid resuscitation (n = 8) or a 0.9% saline bolus (40 mL/kg over 60 min) (n = 8). No endotoxemia, saline only animals (n = 5) underwent fluid resuscitation with a 0.9% bolus of saline as detailed above. Hemodynamic support with vasopressors was initiated if needed, to maintain a mean arterial pressure (MAP) of 60-65 mm Hg in all the groups.

Results: Rotational thromboelastometry (ROTEM®) and conventional coagulation biomarker tests demonstrated sepsis induced derangements to secondary haemostasis. This effect was exacerbated by saline fluid resuscitation, with low pH (p = 0.036), delayed clot initiation and formation together with deficiencies in naturally occurring anti-coagulants antithrombin (p = 0.027) and Protein C (p = 0.001).

Conclusions: Endotoxemia impairs secondary haemostasis and induces changes in the intrinsic, extrinsic and anti-coagulant pathways. These changes to haemostasis are exacerbated following resuscitation with 0.9% saline, a commonly used crystalloid in clinical settings.
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http://dx.doi.org/10.1016/j.thromres.2019.02.015DOI Listing
April 2019

Gamma knife radiosurgery for local recurrence of glioblastoma.

Neuro Endocrinol Lett 2018 Oct;39(4):281-287

Department of Medical Physics, Na Homolce Hospital, Prague, Czech Republic.

Objective: Local recurrence of glioblastoma is observed in most patients after standard oncologic treatment (surgery, chemotherapy and radiotherapy). Stereotactic radiosurgery with the Leksell Gamma Knife (SRS with LGK) was used to treat recurrent tumors in selected cases, and retrospective analysis of treatment outcome was performed.

Methods: Altogether 126 patients were treated for glioblastoma at our center from 1992-2014. Sixty-nine patients (55%) were male and 57 (45%) female, with a median age of 56 years (range 17-80 years). Prior to LGK radiosurgery, 123 (98%) underwent surgery, 126 (100%) radiotherapy and 116 (92%) chemotherapy. The median Karnofsky score before LGK radiosurgery was 90% (range 50-100), and the median time from GBM diagnosis to LGK radiosurgery was 12 months (range 1-96 months). The median tumor volume was 3.75 cm3 (range 0.04-37.10 cm3). LGK radiosurgery was performed in a single fraction with a median minimal tumor dose of 12 Gy (range 10-25 Gy) on a median 50% (range 40-86%) isodose line. Two and more LGK radiosurgeries were performed in 19 (15%) cases, a median interval of 9.6 months (range 2-45 months) from the initial LGK radiosurgery. The median prescribed dose in these patients was 12.6 Gy (range 10-15 Gy), and the median volume 5.8 cm3 (range 0.1-13.7 cm3).

Results: The median survival from GBM diagnosis was 20 months (range 6-237 months). The median survival after LGK radiosurgery was 7 months (range 1-223 months). The one year survival after LGK radiosurgery was 27%, 2 years 8%, and more than 3 years 4%. Tumor regression on MR images was observed in 17% of patients at a median interval of 7 months. The median interval to tumor progression on MR images after LGK treatment was 8.5 months. No treatment-related radionecrosis with expansive behaviour was detected after radiosurgery.

Conclusion: We show that LGK radiosurgery is a safe palliative treatment modality in patients with recurrent GBM.
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October 2018

Inflammation and lung injury in an ovine model of fluid resuscitated endotoxemic shock.

Respir Res 2018 Nov 22;19(1):231. Epub 2018 Nov 22.

Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Rd, Brisbane, Australia.

Background: Sepsis is a multi-system syndrome that remains the leading cause of mortality and critical illness worldwide, with hemodynamic support being one of the cornerstones of the acute management of sepsis. We used an ovine model of endotoxemic shock to determine if 0.9% saline resuscitation contributes to lung inflammation and injury in acute respiratory distress syndrome, which is a common complication of sepsis, and investigated the potential role of matrix metalloproteinases in this process.

Methods: Endotoxemic shock was induced in sheep by administration of an escalating dose of lipopolysaccharide, after which they subsequently received either no fluid bolus resuscitation or a 0.9% saline bolus. Lung tissue, bronchoalveolar fluid (BAL) and plasma were analysed by real-time PCR, ELISA, flow cytometry and immunohistochemical staining to assess inflammatory cells, cytokines, hyaluronan and matrix metalloproteinases.

Results: Endotoxemia was associated with decreased serum albumin and total protein levels, with activated neutrophils, while the glycocalyx glycosaminoglycan hyaluronan was significantly increased in BAL. Quantitative real-time PCR studies showed higher expression of IL-6 and IL-8 with saline resuscitation but no difference in matrix metalloproteinase expression. BAL and tissue homogenate levels of IL-6, IL-8 and IL-1β were elevated.

Conclusions: This data shows that the inflammatory response is enhanced when a host with endotoxemia is resuscitated with saline, with a comparatively higher release of inflammatory cytokines and endothelial/glycocalyx damage, but no change in matrix metalloproteinase levels.
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http://dx.doi.org/10.1186/s12931-018-0935-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249903PMC
November 2018

Stereotactic Radiosurgery for Intracranial Ependymomas: An International Multicenter Study.

Neurosurgery 2019 01;84(1):227-234

Department of Neurological Surgery, Center for Image-Guided Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Stereotactic radiosurgery (SRS) is a potentially important option for intracranial ependymoma patients.

Objective: To analyze the outcomes of intracranial ependymoma patients who underwent SRS as a part of multimodality management.

Methods: Seven centers participating in the International Gamma Knife Research Foundation identified 89 intracranial ependymoma patients who underwent SRS (113 tumors). The median patient age was 16.3 yr (2.9-80). All patients underwent previous surgical resection and radiation therapy (RT) of their ependymomas and 40 underwent previous chemotherapy. Grade 2 ependymomas were present in 42 patients (52 tumors) and grade 3 ependymomas in 48 patients (61 tumors). The median tumor volume was 2.2 cc (0.03-36.8) and the median margin dose was 15 Gy (9-24).

Results: Forty-seven (53%) patients were alive and 42 (47%) patients died at the last follow-up. The overall survival after SRS was 86% at 1 yr, 50% at 3 yr, and 44% at 5 yr. Smaller total tumor volume was associated with longer overall survival (P = .006). Twenty-two patients (grade 2: n = 9, grade 3: n = 13) developed additional recurrent ependymomas in the craniospinal axis. The progression-free survival after SRS was 71% at 1 yr, 56% at 3 yr, and 48% at 5 yr. Adult age, female sex, and smaller tumor volume indicated significantly better progression-free survival. Symptomatic adverse radiation effects were seen in 7 patients (8%).

Conclusion: SRS provides another management option for residual or recurrent progressive intracranial ependymoma patients who have failed initial surgery and RT.
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http://dx.doi.org/10.1093/neuros/nyy082DOI Listing
January 2019

Evidence of altered haemostasis in an ovine model of venovenous extracorporeal membrane oxygenation support.

Crit Care 2017 07 29;21(1):191. Epub 2017 Jul 29.

Critical Care Research Group, University of Queensland and the Prince Charles Hospital, Brisbane, Australia.

Background: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality used in the management of cardiopulmonary failure that is refractory to conventional medical and surgical therapies. The major problems clinicians face are bleeding and clotting, which can occur simultaneously. To discern the impact of pulmonary injury and ECMO on the host's haemostatic response, we developed an ovine model of smoke-induced acute lung injury (S-ALI) and ECMO. The aims of this study were to determine if the ECMO circuit itself altered haemostasis and if this was augmented in a host with pulmonary injury.

Methods: Twenty-seven South African meat merino/Border Leicester Cross ewes underwent instrumentation. Animals received either sham injury (n = 12) or S-ALI (n = 15). Control animal groups consisted of healthy controls (ventilation only for 24 h) (n = 4), ECMO controls (ECMO only for 24 h) (n = 8) and S-ALI controls (S-ALI but no ECMO for 24 h) (n = 7). The test group comprised S-ALI sheep placed on ECMO (S-ALI + ECMO for 24 h) (n = 8). Serial blood samples were taken for rotational thromboelastometry, platelet aggregometry and routine coagulation laboratory tests. Animals were continuously monitored for haemodynamic, fluid and electrolyte balances and temperature. Pressure-controlled intermittent mandatory ventilation was used, and mean arterial pressure was augmented by protocolised use of pressors, inotropes and balanced fluid resuscitation to maintain mean arterial pressure >65 mmHg.

Results: Rotational thromboelastometry, platelet aggregometry and routine coagulation laboratory tests demonstrated that S-ALI and ECMO independently induced changes to platelet function, delayed clot formation and reduced clot firmness. This effect was augmented with the combination of S-ALI and ECMO, with evidence of increased collagen-induced platelet aggregation as well as changes in factor VIII (FVIII), factor XII and fibrinogen levels.

Conclusions: The introduction of an ECMO circuit itself increases collagen-induced platelet aggregation, decreases FVIII and von Willebrand factor, and induces a transient decrease in fibrinogen levels and function in the first 24 h. These changes to haemostasis are amplified when a host with a pre-existing pulmonary injury is placed on ECMO. Because patients are often on ECMO for extended periods, longer-duration studies are required to characterise ECMO-induced haemostatic changes over the long term. The utility of point-of-care tests for guiding haemostatic management during ECMO also warrants further exploration.
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http://dx.doi.org/10.1186/s13054-017-1788-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534117PMC
July 2017

Histology-Stratified Tumor Control and Patient Survival After Stereotactic Radiosurgery for Pineal Region Tumors: A Report From the International Gamma Knife Research Foundation.

World Neurosurg 2017 Nov 24;107:974-982. Epub 2017 Jul 24.

Division of Neurosurgery, Department of Surgery, Université de Sherbrooke, Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada. Electronic address:

Background: Pineal region tumors represent a rare and histologically diverse group of lesions. Few studies are available to guide management and the outcomes after stereotactic radiosurgery (SRS).

Methods: Patients who underwent SRS for a pineal region tumor and for whom at least 6 months of imaging follow-up was available were retrospectively assessed in 5 centers. Data were collected from the medical record and histology level analyses were performed, including actuarial tumor control and survival analyses.

Results: A total of 70 patients were treated between 1989 and 2014 with a median follow-up of 47 months. Diagnoses were pineocytoma (37%), pineoblastoma (19%), pineal parenchymal tumor of intermediate differentiation (10%), papillary tumor of the pineal region (9%), germinoma (7%), teratoma (3%), embryonal carcinoma (1%), and unknown (14%). Median prescription dose was 15 Gy at the 50% isodose line. Actuarial local control and survival rates were 81% and 76% at 20 years for pineocytoma, 50% and 56% at 5 years for pineal parenchymal tumor of intermediate differentiation, 27% and 48% at 5 years for pineoblastoma, 33% and 100% at 5 years for papillary tumor of the pineal region, 80% and 80% at 20 years for germinoma, and 61% and 67% at 5 years for tumors of unknown histology. New focal neurological deficit, Parinaud syndrome, and hydrocephalus occurred in 9%, 7%, and 3% of cases, respectively.

Conclusions: SRS is a safe modality for the management of pineal region tumors. Its specific role is highly dependent on tumor histology. As such, all efforts should be made to obtain a reliable histologic diagnosis.
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http://dx.doi.org/10.1016/j.wneu.2017.07.097DOI Listing
November 2017

Inflammation and lung injury in an ovine model of extracorporeal membrane oxygenation support.

Am J Physiol Lung Cell Mol Physiol 2016 12 4;311(6):L1202-L1212. Epub 2016 Nov 4.

Critical Care Research Group, University of Queensland and the Prince Charles Hospital, Brisbane, Australia.

Extracorporeal membrane oxygenation (ECMO) is a life-saving treatment for patients with severe refractory cardiorespiratory failure. Exposure to the ECMO circuit is thought to trigger/exacerbate inflammation. Determining whether inflammation is the result of the patients' underlying pathologies or the ECMO circuit is difficult. To discern how different insults contribute to the inflammatory response, we developed an ovine model of lung injury and ECMO to investigate the impact of smoke-induced lung injury and ECMO in isolation and cumulatively on pulmonary and circulating inflammatory cells, cytokines, and tissue remodeling. Sheep receiving either smoke-induced acute lung injury (S-ALI) or sham injury were placed on veno-venous (VV) ECMO lasting either 2 or 24 h, with controls receiving conventional ventilation only. Lung tissue, bronchoalveolar fluid, and plasma were analyzed by RT-PCR, immunohistochemical staining, and zymography to assess inflammatory cells, cytokines, and matrix metalloproteinases. Pulmonary compliance decreased in sheep with S-ALI placed on ECMO with increased numbers of infiltrating neutrophils, monocytes, and alveolar macrophages compared with controls. Infiltration of neutrophils was also observed with S-ALI alone. RT-PCR studies showed higher expression of matrix metalloproteinases 2 and 9 in S-ALI plus ECMO, whereas IL-6 was elevated at 2 h. Zymography revealed higher levels of matrix metalloproteinase 2. Circulating plasma levels of IL-6 were elevated 1-2 h after commencement of ECMO alone. These data show that the inflammatory response is enhanced when a host with preexisting pulmonary injury is placed on ECMO, with increased infiltration of neutrophils and macrophages, the release of inflammatory cytokines, and upregulation of matrix metalloproteinases.
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http://dx.doi.org/10.1152/ajplung.00296.2016DOI Listing
December 2016

Stereotactic Radiosurgery for Brainstem Metastases: An International Cooperative Study to Define Response and Toxicity.

Int J Radiat Oncol Biol Phys 2016 10 15;96(2):280-288. Epub 2016 Jun 15.

Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia; Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia.

Purpose: To pool data across multiple institutions internationally and report on the cumulative experience of brainstem stereotactic radiosurgery (SRS).

Methods And Materials: Data on patients with brainstem metastases treated with SRS were collected through the International Gamma Knife Research Foundation. Clinical, radiographic, and dosimetric characteristics were compared for factors prognostic for local control (LC) and overall survival (OS) using univariate and multivariate analyses.

Results: Of 547 patients with 596 brainstem metastases treated with SRS, treatment of 7.4% of tumors resulted in severe SRS-induced toxicity (grade ≥3, increased odds with increasing tumor volume, margin dose, and whole-brain irradiation). Local control at 12 months after SRS was 81.8% and was improved with increasing margin dose and maximum dose. Overall survival at 12 months after SRS was 32.7% and impacted by age, gender, number of metastases, tumor histology, and performance score.

Conclusions: Our study provides additional evidence that SRS has become an option for patients with brainstem metastases, with an excellent benefit-to-risk ratio in the hands of experienced clinicians. Prior whole-brain irradiation increases the risk of severe toxicity in brainstem metastasis patients undergoing SRS.
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http://dx.doi.org/10.1016/j.ijrobp.2016.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014646PMC
October 2016

Leksell Gamma Knife treatment for pilocytic astrocytomas: long-term results.

J Neurosurg Pediatr 2016 Jul 18;18(1):58-64. Epub 2016 Mar 18.

Departments of 1 Stereotactic and Radiation Neurosurgery and.

OBJECTIVE The purpose of this study was to evaluate long-term treatment results, radiation-related toxicity, and prognostic factors for the progression-free survival (PFS) of patients with pilocytic astrocytomas treated by means of stereotactic radiosurgery with a Leksell Gamma Knife. METHODS A total of 25 patients with pilocytic astrocytomas underwent Gamma Knife surgery during the period 1992-2002. The median target volume was 2700 mm(3) (range 205-25,000 mm(3)). The 18 patients treated with 5 daily fractions received a median minimum target dose of 25 Gy. Doses for the 2 patients treated with 10 fractions over 5 days (2 fractions delivered on the same day at least 6 hours apart) were 23 and 28 Gy. For the 5 patients treated with a single fraction, the minimum target dose ranged from 13 to 20 Gy (median 16 Gy). RESULTS Complete regression occurred in 10 patients (40%) and partial regression in 10 patients (40%). The 10-year overall survival rate was 96% and the 10-year PFS rate was 80%. Target volume appeared to be a significant prognostic factor for PFS (p = 0.037). Temporary Grade 3 toxicity appeared in 2 patients (8%), and these patients were treated with corticosteroids for 2 months. Permanent Grade 4 toxicity appeared in 2 patients (8%) and was associated with neurocognitive dysfunction. In these 2 individuals, the neurocognitive dysfunction was also felt to be in part the result of the additional therapeutic interventions (4 in one case and 6 in the other) required to achieve durable control of their tumors. CONCLUSIONS Radiosurgery represents an alternative treatment modality for small residual or recurrent volumes of pilocytic astrocytomas and provides long-term local control. Target volume appears to be the most important factor affecting PFS.
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http://dx.doi.org/10.3171/2015.10.PEDS14443DOI Listing
July 2016

The impact of acute lung injury, ECMO and transfusion on oxidative stress and plasma selenium levels in an ovine model.

J Trace Elem Med Biol 2015 Apr 17;30:4-10. Epub 2015 Jan 17.

Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Chermside, Queensland, Australia; Adult Intensive Care Service, The Prince Charles Hospital, Chermside, Queensland, Australia. Electronic address:

The purpose of this study was to determine the effects of smoke induced acute lung injury (S-ALI), extracorporeal membrane oxygenation (ECMO) and transfusion on oxidative stress and plasma selenium levels. Forty ewes were divided into (i) healthy control (n=4), (ii) S-ALI control (n=7), (iii) ECMO control (n=7), (iv) S-ALI+ECMO (n=8) and (v) S-ALI+ECMO+packed red blood cell (PRBC) transfusion (n=14). Plasma thiobarbituric acid reactive substances (TBARS), selenium and glutathione peroxidase (GPx) activity were analysed at baseline, after smoke injury (or sham) and 0.25, 1, 2, 6, 7, 12 and 24h after initiation of ECMO. Peak TBARS levels were similar across all groups. Plasma selenium decreased by 54% in S-ALI sheep (1.36±0.20 to 0.63±0.27μmol/L, p<0.0001), and 72% in sheep with S-ALI+ECMO at 24h (1.36±0.20 to 0.38±0.19, p<0.0001). PRBC transfusion had no effect on TBARS, selenium levels or glutathione peroxidase activity in plasma. While ECMO independently increased TBARS in healthy sheep to levels which were similar to the S-ALI control, the addition of ECMO after S-ALI caused a negligible increase in TBARS. This suggests that the initial lung injury was the predominant feature in the TBARS response. In contrast, the addition of ECMO in S-ALI sheep exacerbated reductions in plasma selenium beyond that of S-ALI or ECMO alone. Clinical studies are needed to confirm the extent and duration of selenium loss associated with ECMO.
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http://dx.doi.org/10.1016/j.jtemb.2015.01.004DOI Listing
April 2015

Leksell Gamma Knife radiosurgery of the jugulotympanic glomus tumor: long-term results.

J Neurosurg 2014 Dec;121 Suppl:198-202

Departments of 1 Stereotactic and Radiation Neurosurgery.

Object: Glomus tumors usually display indolent behavior, and the effectiveness of radiation in stopping their growth can be assessed after long-term follow-up. Currently only midterm results of radiosurgery are available, so the authors included patients treated by Gamma Knife at least 10 years ago in this study to obtain a perspective of long-term results.

Methods: During the period from 1992 to 2003, the Gamma Knife was used to treat 46 patients with glomus tumors. The age of the patients ranged from 21 to 79 years (median 56 years). Gamma Knife radiosurgery was the primary treatment in 17 patients (37%). Open surgery preceded radiosurgery in 46% of cases, embolization in 17%, and fractionated radiotherapy in 4%. The volume of the tumor ranged from 0.2 to 24.3 cm(3) (median 3.6 cm(3)). The minimal dose to the tumor margin ranged between 10 and 30 Gy (median 20 Gy).

Results: One patient was lost for follow-up after radiosurgery. Clinical follow-up was available in 45 patients and 44 patients were followed with MRI in a follow-up period that ranged from 12 to 217 months (median 118 months). Neurological deficits improved in 19 (42%) of 45 patients and deteriorated in 2 patients (4%). Tumor size decreased in 34 (77%) of 44 patients with imaging follow-up, while an increase in volume was observed in 1 patient (2%) 182 months after radiosurgery and Gamma Knife treatment was repeated. One patient underwent another Gamma Knife treatment for secondary induced meningioma close to the glomus tumor 98 months after initial radiosurgical treatment. Seven patients died 22-96 months after radiosurgery (median 48 months), all for unrelated reasons.

Conclusions: Radiosurgery has proved to be a safe treatment with a low morbidity rate and a reliable long-term antiproliferative effect.
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http://dx.doi.org/10.3171/2014.7.GKS14923DOI Listing
December 2014

A comprehensive study of ovine haemostasis to assess suitability to model human coagulation.

Thromb Res 2014 Aug 27;134(2):468-73. Epub 2014 May 27.

Critical Care Research Group, The University of Queensland and The Prince Charles Hospital, Brisbane, QLD, Australia; School of Health and Sports Science, University of Sunshine Coast, Sippy Downs, QLD, Australia.

Introduction: Similarities in size, anatomy and physiology have supported the use of sheep to model a wide range of human diseases, including coagulopathy. However, coagulation studies involving sheep are limited by the absence of high quality data defining normal ovine coagulation and fibrinolysis.

Materials And Methods: Full blood examination, routine and specialised coagulation tests, rotational thromboelastometry and whole blood platelet aggregometry was performed on 50 healthy Samm & Border Leicester Cross ewes and compared to corresponding human ranges. Intraspecies breed and gender variability was investigated by comparison to a smaller population of 13 healthy Merino wethers.

Results: Ovine coagulation was similar to human according to routine coagulation methods (PT, aPTT, TCT, Fib(C)) and some specialised coagulation tests (vWF, AT, Plasmin Inh). Despite these similarities, ovine secondary haemostasis demonstrated substantial differences to that of human. Rapid initiation of the contact activation pathway, high levels of FVIII, low Protein C, greater overall clot firmness and a reduced capacity for clot lysis was documented in sheep. In addition, ADP and collagen agonists precipitated a reduced primary haemostatic response in sheep relative to human. Intraspecies differences in whole blood platelet aggregometry between the cohorts of sheep indicate the need for breed-specific normal ranges.

Conclusions: The application of a board spectrum of coagulation assays has enabled elucidation of the similarities as well as differences between ovine and human coagulation. The new knowledge generated from this study will guide the design of future translational coagulation studies in ovine models.
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http://dx.doi.org/10.1016/j.thromres.2014.05.026DOI Listing
August 2014

Optimal management of the critically ill: anaesthesia, monitoring, data capture, and point-of-care technological practices in ovine models of critical care.

Biomed Res Int 2014 25;2014:468309. Epub 2014 Mar 25.

Critical Care Research Group Laboratory, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4032, Australia ; The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia ; Innovative Cardiovascular Engineering and Technology Laboratory, The Prince Charles Hospital, Chermside, Brisbane, QLD 4032, Australia.

Animal models of critical illness are vital in biomedical research. They provide possibilities for the investigation of pathophysiological processes that may not otherwise be possible in humans. In order to be clinically applicable, the model should simulate the critical care situation realistically, including anaesthesia, monitoring, sampling, utilising appropriate personnel skill mix, and therapeutic interventions. There are limited data documenting the constitution of ideal technologically advanced large animal critical care practices and all the processes of the animal model. In this paper, we describe the procedure of animal preparation, anaesthesia induction and maintenance, physiologic monitoring, data capture, point-of-care technology, and animal aftercare that has been successfully used to study several novel ovine models of critical illness. The relevant investigations are on respiratory failure due to smoke inhalation, transfusion related acute lung injury, endotoxin-induced proteogenomic alterations, haemorrhagic shock, septic shock, brain death, cerebral microcirculation, and artificial heart studies. We have demonstrated the functionality of monitoring practices during anaesthesia required to provide a platform for undertaking systematic investigations in complex ovine models of critical illness.
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http://dx.doi.org/10.1155/2014/468309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982457PMC
January 2015

Gamma knife radiosurgery of brain cavernomas.

Acta Neurochir Suppl 2013 ;116:107-11

Hospital Na Homolce, Roentgenova 2, Prague, 150 30, Czech Republic.

Purpose: Radiosurgery of cavernomas should prevent rebleeding, growth of the lesion, and deterioration of clinical symptoms. However, there is no direct diagnostic tool to verify the endpoints of treatment. At present, the positive effects of radiosurgery are identified by clinical observation and analysis of imaging changes on magnetic resonance imaging during a sufficiently long follow-up period.

Methods: Between 1992 and 2000, a total of 112 patients with brain cavernomas were treated with Gamma Knife radiosurgery at our center. In all, 59 patients experienced bleeding before radiosurgery; the remainder did not. The median age of patients was 42 years, the median volume of the cavernomas was 0.9 cm(3), and the median applied marginal dose was 16 Gy.

Results: After a 2-year latent interval after treatment (median follow-up 84 months), the risk of bleeding in the group of patients with bleeding before radiosurgery had decreased from 3.7 % to 0.2 %. For the patients without bleeding before radiosurgery, the annual risk of bleeding was 0.8 %. The cavernoma size decreased in 53.0 % of cases and increased in 6.4 %. Epilepsy, if present before the treatment, was alleviated in 45 % of cases. The risks of temporary or permanent morbidity caused by radiosurgery were 14.6 % and 0.9 %, respectively.

Conclusion: Radiosurgery of cavernomas was associated with a low risk of permanent morbidity. The risk of rebleeding after the 2-year latent interval after radiosurgery had decreased. Treatment of cavernomas with no history of bleeding was halted at our center.
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http://dx.doi.org/10.1007/978-3-7091-1376-9_17DOI Listing
June 2013

[Significance of radiosurgery in the treatment of brain metastases].

Cas Lek Cesk 2011 ;150(4-5):273-7

Oddeleni stereotaktické a radiarní neurochirurgie Nemocnice Na Homolce, Praha.

Brain metastases are diagnosed in about 30% adult patients with generalized carcinomas, their accompanying severe neurological symptoms cause worsening quality of patient's life. The development of magnetic resonance imaging and stereotactically guided radiosurgery and radiotherapy enable to apply relatively high doses to well defined intracranial target volumes. Progression free survival after irradiation of brain lesions depends on several prognostic factors. Radiosurgery using gamma knife is an effective treatment with low rate of postradiation complications.
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June 2011

[Significance of radiosurgery for the treatment of meningiomas].

Cas Lek Cesk 2011 ;150(4-5):250-3

Oddelení stereotaktické a radiacni neurochirurgie, Nemocnice Na Homolce, Praha.

Treatment of intracranial meningiomas in the light of their benignity (90%) should ensure minimal risk of recurrence, avoid new neurological deficit and preserve quality of life. Stereotactic radiosurgery has proved its long-term effectiveness and safety with a low complication rate. It can be applied as a method of choice for meningiomas in locations that are too risky for microsurgical removal, meningiomas that usually do not exceed 3 cm in diameter and in patients, who are not candidates for microsurgery because of associated disease. It is a part of multimodal treatment for recurrence after operative resection or after partial removal of large meningiomas, where radical surgery represents a high risk of postoperative morbidity and mortality. Indication of radiosurgical treatment of intracranial meningiomas should be considered for each patient individually in order to choose methods or their combination with the lowest risk of complications.
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June 2011

Repeated treatment of vestibular schwannomas after gamma knife radiosurgery.

Acta Neurochir (Wien) 2009 Apr 11;151(4):317-24; discussion 324. Epub 2009 Mar 11.

Stereotactic and radiation neurosurgery, Na Homolce Hospital, Roentgenova 2, Prague, Czech Republic.

Purpose: When gamma knife radiosurgery (GKS) does not achieve control of the growth of a tumour, the need to repeat treatment is considered. The results and risks of repeat treatment of patients with a vestibular schwannoma were reviewed to assess its efficacy and safety.

Methods: Between 1992 and 2001, we treated 351 patients with a vestibular schwannoma by GKS, control of the growth of the tumour was not achieved in 32. 26 patients underwntrepeat GKS and five patients had an open microsurgical operation and one stereotactic aspiration of a tumour cyst.

Results: Twenty-four of 26 patients were followed up after the repeat GKS for a median of 43 months. 15 tumours became smaller, seven remained unchanged and two enlarged. After the second GKS one patient's hearing deteriorated, one developed facial weakness and three facial spasms. One patient required insertion of ventriculo-peritoneal drainage. An operation to radically resect the tumour was performed in five patients after the first GKS and for a subtotal removal in one after repeated GKS.

Conclusions: In the small proportion of patients (9%) in whom initial GKS does not control the growth of a vestibular schwannoma, most can be controlled by further GKS with a very low risk of a complications.
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http://dx.doi.org/10.1007/s00701-009-0254-0DOI Listing
April 2009

Gamma Knife surgery for benign meningioma.

J Neurosurg 2007 Aug;107(2):325-36

Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic.

Object: Meningioma is the most frequent benign tumor treated with Gamma Knife surgery (GKS); however, the assessment of its efficacy and safety in slow-growing tumors is an ongoing process, requiring analysis of long-term results.

Methods: Three hundred sixty-eight patients harboring 400 meningiomas treated between 1992 and 1999 at Na Homolce Hospital were evaluated. The median patient age was 57 years (range 18-84 years). The median tumor volume was 4.4 cm3 (range 0.11-44.9 cm3). The median tumor margin dose to the 50% isodose line was 12.55 Gy (range 6.5-24 Gy). Descriptive analysis was performed in 331 patients (90%); 325 patients had a follow-up longer than 24 months (median 60 months), and six patients were included because of posttreatment complications. The volume of treated tumors decreased in 248 cases (69.7%), remained the same in 99 (27.8%), and increased in nine (2.5%). The actuarial tumor control rate was 97.9% at 5 years post-GKS. Perilesional edema after radiosurgery was confirmed on neuroimaging in 51 patients (15.4%). The temporary and permanent morbidity rates after radiosurgery were 10.2 and 5.7%, respectively.

Results: A significantly higher incidence of tumor volume increase was observed in men compared with women and in tumors treated with a margin dose lower than 12 Gy. Significant risk factors for edema included an age greater than 60 years, no previous surgery, perilesional edema before radiosurgery, a tumor volume greater than 10 cm3, a tumor location in the anterior fossa, and a margin dose greater than 16 Gy.

Conclusions: Stereotactic radiosurgery is a safe method of treatment for meningiomas. A minimum margin dose of 12 to 16 Gy seems to represent the therapeutic window for benign meningiomas with a high tumor control rate in a mid-term follow-up period.
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http://dx.doi.org/10.3171/JNS-07/08/0325DOI Listing
August 2007

Arteriovenous malformations after Leksell gamma knife radiosurgery: rate of obliteration and complications.

Neurosurgery 2007 Jun;60(6):1005-14; discussion 1015-6

Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic.

Objective: Although relevant information exists regarding the chance of obliterating arteriovenous malformations (AVMs) using radiosurgery, the overall chance of cure after gamma knife radiosurgery is usually only extrapolated from a portion of all monitored patients. This chance and the risks involved in radiosurgery, including repeat treatment when necessary in a defined population of treated patients, were analyzed in our study.

Methods: Between October 1992 and June 2000, gamma knife radiosurgery was performed on 330 patients with AVMs. The volume of the AVM nidus ranged from 0.15 to 28.6 cm (median, 3.9 cm). When complete obliteration was not achieved within 3 years, repeat radiosurgery was performed on 76 patients. The volume of the nidus for the second treatment ranged from 0.09 to 16.8 cm (median 2.9 cm). The result was reviewed in 300 (91%) patients after the first round of treatment and in 68 (89.5%) after the second round of treatment.

Results: AVM obliteration was achieved in 222 (74%) patients after the first round of radiosurgery and in 47 (69%) after the second. The overall chance of cure was 92% (269 patients). Final angiography verified complete obliteration by 12 to 96 months (median, 25 mo) after initial radiosurgery. Smaller volume AVMs and the application of a higher radiation dose resulted in a higher chance of obliteration. The risk of rebleeding after radiosurgery was 2.1% annually until full obliteration, and the overall mortality from rebleeding was 1%. The risk of permanent morbidity after the first and second radiosurgery treatments were 2.7 and 2.9%, respectively. The cumulative risk of morbidity in both groups of patients was 3.4%.

Conclusion: Although one-quarter of the patients required that the treatment be repeated, gamma knife radiosurgery can offer a high cure rate for patients treated for AVMs with a low risk of morbidity and mortality from rebleeding during the latent period.
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http://dx.doi.org/10.1227/01.NEU.0000255474.60505.4ADOI Listing
June 2007

Gamma knife surgery of brain cavernous hemangiomas.

J Neurosurg 2005 Jan;102 Suppl:207-13

Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic.

Object: The authors conducted a study to record more detailed information about the natural course and factors predictive of outcome following gamma knife surgery (GKS) for cavernous hemangiomas.

Methods: One hundred twelve patients with brain cavernous hemangiomas underwent GKS between 1993 and 2000. The median prescription dose was 16 Gy. One hundred seven patients were followed for a median of 48 months (range 6-114 months). The rebleeding rate was 1.6%, which is not significantly different with that prior to radiosurgery (2%). An increase in volume was observed in 1.8% of cases and a decrease in 45%. Perilesional edema was detected in 27% of patients, which, together with the rebleeding, caused a transient morbidity rate of 20.5% and permanent morbidity rate of 4.5%. Before radiosurgery 39% of patients suffered from epilepsy and this improved in 45% of them. Two patients with brainstem cavernous hemangiomas died due to rebleeding. Rebleeding was more frequent in female middle-aged patients with a history of bleeding, a larger lesion volume, and a prescription dose below 13 Gy. Edema after GKS occurred more frequently in patients who had surgery, a larger lesion volume, and in those in whom the prescription dose was more than 13 Gy.

Conclusions: Gamma knife surgery of cavernous hemangiomas can produce an acceptable rate of morbidity, which can be reduced by using a lower margin dose. Lesion regression was observed in many patients. Radiosurgery seems to remain a suitable treatment modality in carefully selected patients.
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http://dx.doi.org/10.3171/jns.2005.102.s_supplement.0207DOI Listing
January 2005

Low-grade gliomas treated by fractionated gamma knife surgery.

J Neurosurg 2005 Jan;102 Suppl:19-24

Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic.

Object: The authors sought to evaluate local tumor control, complications, and progression-free survival in patients harboring low-grade gliomas who were treated with Leksell gamma knife surgery (GKS).

Methods: During a 6-year period 70 patients were treated for verified low-grade gliomas (Grade I or II) by GKS. Statistical analysis was based on 68 patients; two patients were lost to follow up. The median patient age was 17 years. The median target volume was 4200 mm.3 The median prescription dose was 25 Gy. The median number of fractions was five. Ninety-five percent of patients were treated in five daily fractions. Partial or complete tumor regression was achieved in 83% of patients with a median time to response of 18 months. There was moderate acute or late toxicity in not more than 5% of patients. In this series the progression-free survival was 92% at 3 years and 88% at 5 years.

Conclusions: Relatively high local tumor control with minimal complications was achieved.
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http://dx.doi.org/10.3171/jns.2005.102.s_supplement.0019DOI Listing
January 2005

Radiosurgery in the treatment of malignant brain tumors.

Expert Rev Anticancer Ther 2003 Dec;3(6):879-90

Department of Stereotactic and Radiation Neurosurgery, Hospital Na Homolce, Prague, Czech Republic.

Brain metastases are an attractive target for radiosurgery. Over a period of 6 years, 400 patients with brain metastases have been treated with radiosurgery. Of these patients, 61% had solitary brain metastases and 39% had multiple brain metastases. Local control was achieved in 90% and improvement of severe neurological symptoms in 76%. The median survival time was 8 months. The significant prognostic factors for survival in patients with solitary brain metastases were age, Karnofsky performance status, severity of symptoms, extent of progressive malignant disease outside the brain, histology, interval between diagnosis of primary tumor and brain metastasis, and minimum applied dosage. The significant prognostic factors in patients with multiple brain metastases were sex, Karnofsky performance status and presence of progressive disease outside the brain.
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http://dx.doi.org/10.1586/14737140.3.6.879DOI Listing
December 2003

Leksell gamma knife treatment of uveal melanoma.

J Neurosurg 2002 Dec;97(5 Suppl):635-9

Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic.

Object: The purpose of this study was to analyze treatment results, radiation-induced side effects, and prognostic survival factors for patients with uveal melanoma.

Methods: Eighty-one patients with uveal melanoma were treated using the Leksell gamma knife during a period of 6 years (1996-2001). There were 45 men and 36 women with a median age of 59 years (range 22-85 years). Seventy-five of these patients underwent minimal follow up 10 months after treatment. After patient eye immobilization, magnetic resonance (MR) imaging was performed to enable stereotactic localization. A scoring system was used to measure radiation side effects. The median target volume was 640 mm3, and the median applied minimal dose was 31.4 Gy. All patients were examined by an ophthalmologist and with MR imaging at regular intervals. Factors influencing posttreatment survival and side effects were statistically analyzed.

Conclusions: Local tumor control in the 75 patients who underwent minimal follow up after 10 months was achieved in 63 patients (84%), whereas progression was observed in 12 patients (16%). The most frequent side effect was secondary glaucoma, which was detected in 18 patients (25%). The incidence of this side effect was significantly higher when the total volume of peripheral isodose was greater than 1000 mm3 (p = 0.015). Toxicity in the optic nerve here was also significantly higher when the maximum dose to this structure was higher than 9 Gy (p = 0.011), in the cornea when the maximum dose was higher than 15 Gy (p = 0.010), and in the lens when the maximum dose was higher than 10 Gy (p = 0.035). Altogether three pretreatment variables (patient age, tumor location, and dissemination of the disease) and one treatment variable (the minimum dose applied) were identified as having a significant influence on a patient's survival.
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http://dx.doi.org/10.3171/jns.2002.97.supplementDOI Listing
December 2002

Brain metastases after stereotactic radiosurgery using the Leksell gamma knife: can FDG PET help to differentiate radionecrosis from tumour progression?

Eur J Nucl Med Mol Imaging 2003 Jan 5;30(1):96-100. Epub 2002 Nov 5.

Department of Nuclear Medicine - PET Centre, Na Homolce Hospital, Roentgenova 2, 150 30 Prague 5, Czech Republic.

Stereotactic radiosurgery (SRS) using the Leksell gamma knife promotes acute and chronic local changes in glucose metabolism. We have been able to find very few papers on Medline on the subject of assessment of metastases by 2-[(18)F]fluoro-2-deoxy- D-glucose positron emission tomography (FDG PET) after SRS. The aim of this work was to specify the additional value of FDG PET, in comparison with magnetic resonance imaging (MRI), in differentiating SRS-induced radionecrosis from viable brain metastasis in a clinical setting. Fifty-seven metastases in 25 patients were treated by SRS. An average of 33 weeks later, all the patients underwent FDG PET. At the same time (SD=2 weeks) all the patients underwent MRI. The sensitivity, specificity and accuracy of both FDG PET and MRI examinations were calculated with reference to clinical and radiological follow-up or biopsies. The additional value derived from use of FDG PET after MRI was assessed and progression-free survival rates were compared. The difference in progression-free survival rates between the negative and positive subgroups was significant ( P=0.0005) for MRI and even more so ( P<0.00001) for FDG PET. Sensitivity, specificity and accuracy were 75% (6/8), 93.9% (46/49) and 91.2% (52/57) for FDG PET, and 100% (8/8), 65.3% (32/49) and 70.2% (40/57) for MRI. In the subgroup of patients with positive or non-diagnostic MRI, the probability of presence of a viable tumour was only 32% (8/25). This probability increased to 100% (5/5) when subsequent FDG PET was positive and decreased to 11.1% (2/18) when FDG PET was negative. The frequency of a viable neoplasm was significantly different ( P=0.001) in the FDG PET negative and positive subgroups. MRI and FDG PET both have an important predictive value for persistent viable metastases after treatment by SRS. Neither sensitive but non-specific MRI nor specific but insensitive FDG PET is reliable on its own. While FDG PET significantly improved the diagnostic accuracy in the subgroup of patients with positive and non-diagnostic MRI, it provided no additional value in the MRI-negative subgroup.
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http://dx.doi.org/10.1007/s00259-002-1011-2DOI Listing
January 2003