Tuning Mesopore Accessibility of Ce0.18Zr0.64Y0.15La0.03O2-δ by Hydrothermal Post-treatment─A Case Study for Ceria-Based Oxidation Storage Materials.

The connectivity and thermal stability of pores in heterogeneous, mesoporous metal oxide catalysts are key properties controlling their (long-term) efficacy. In this study, we investigate the influence of pH and temperature during a common hydrothermal aftertreatment step in the synthesis of mesoporous CexZr1-x-y-zYyLazO2-δ oxides obtained from molecular precursors via hydrothermal synthesis. This study has a strong focus on the methodological approach, elucidating whether and how even the smallest changes in morphology and connectivity may be unraveled and related to the underlying chemical processes to uncover key parameters for the ongoing improvement of material properties. Deep insights into the mesopore space were obtained by state-of-the-art physisorption (including hysteresis scanning), electron tomography, and small-angle X-ray scattering (SAXS) analysis. We also provide a simple tool to simulate SAXS curves from electron tomography data that allow direct comparison to experimentally obtained SAXS curves. Furthermore, the impact on surface-bound nitrate groups and the development during calcination were studied in detail by thermogravimetric analysis coupled with mass spectrometry. The key observations indicate a significant increase in thermal stability at temperatures as high as 1050 °C and improved mesopore accessibility with an increase in pH of the aftertreatment solution. The combined observations from the employed methods suggest a pH-dependent removal of surface-bound nitrate groups as well as a dissolution and reprecipitation-based fusing of the primary particles that constitute the mesopore skeleton. This transformation yields a mechanically and thermally stronger mesopore space with the capability to endure high temperatures.

Biomarker-guided intervention to prevent acute kidney injury after major surgery (BigpAK-2 trial): study protocol for an international, prospective, randomised controlled multicentre trial.

INTRODUCTION: Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation. METHODS AND ANALYSIS: The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage. ETHICS AND DISSEMINATION: The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research. TRIAL REGISTRATION NUMBER: NCT04647396.

Effects of Hydrothermal Treatment on Mesopore Structure and Connectivity in Doped Ceria-Zirconia Mixed Oxides.

Pore size and pore connectivity control diffusion-based transport in mesopores, a crucial property governing the performance of heterogeneous catalysts. In many cases, transition-metal oxide catalyst materials are prepared from molecular precursors involving hydrothermal treatment followed by heat treatment. Here, we investigate the effects of such a hydrothermal aftertreatment step, using an aqueous ammonia solution, on the disordered mesopore network of CexZr1-x-y-zYyLazO2-δ mixed oxides. This procedure is a common synthesis step in the preparation of such ceria-based oxygen storage materials applied in three-way catalysis, employed to improve the materials' thermal stability. We perform state-of-the-art Ar-physisorption analysis, especially advanced hysteresis scanning, to paint a detailed picture of the alterations in mesopore space caused by the hydrothermal aftertreatment and subsequent aging at 1050 °C. Furthermore, we investigate the network characteristics by electron tomography in combination with suitable statistical analysis, enabling a consistent interpretation of the desorption scans (physisorption). The results indicate that the hydrothermal aftertreatment enhances the mesopore connectivity of the continuous 3D network by widening pores and especially necks, hence facilitating accessibility to the particles' internal surface area and the ability to better withstand high temperatures.

Microvascular and proteomic signatures overlap in COVID-19 and bacterial sepsis: the MICROCODE study.

AIMS: Although coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients. METHODS AND RESULTS: This multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p < 0.0001) in COVID-19. CONCLUSION: Our data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes.

Development of Pore Morphology During Nitrate Group Removal by Calcination of Mesoporous CexZr1-x-y-zYyLazO2-δ Powders.

Here, we present a study of the development of the micro- and mesoporosity of a CexZr1-x-y-zYyLazO2-δ oxygen storage material upon treatment at temperatures up to 1050 °C. The investigated powder, obtained from nitrate-based metal oxide precursors in a specially developed hydrothermal synthesis, is highly crystalline, features a high surface area and does not show phase segregation at high temperatures. By employing an advanced methodology, consisting of state-of-the-art argon physisorption, thermogravimetric analysis coupled with mass spectrometry (TG-MS) and X-ray powder diffraction (XRD) along with Raman spectroscopy, we correlate the stability of the mesopore system to the presence of surface-bound nitrate groups introduced during synthesis, which prevent sintering up to a temperature of 600 °C. In addition, the connectivity of mesopores was further studied by hysteresis scanning within the argon physisorption measurements. These advanced physisorption experiments suggest a three-dimensionally interconnected pore system and, in turn, a 3D network of the material itself on the nanometer scale which appears to be beneficial to endow the mesopore space with enhanced stability against sintering and mesopore collapse once the removal of nitrate groups is completed.

Analysis of spinal cord blood supply combining vascular corrosion casting and fluorescence microsphere technique: A feasibility study in an aortic surgical large animal model.

INTRODUCTION: Spinal cord ischemia after cardiovascular interventions continues to be a devastating problem in modern surgery. The role of intraspinal vascular networks and anterior radiculomedullary arteries (ARMA) in preventing spinal cord ischemia is poorly understood. MATERIALS AND METHODS: Landrace pigs (n = 30, 35.1 ± 3.9 kg) underwent a lateral thoracotomy. Fluorescent microspheres were injected into the left atrium and a reference sample was aspirated from the descending aorta. Repeated measurements of spinal cord and renal cortical blood flow from the left and right kidneys with three different microsphere colors in five pigs were taken to validate reproducibility. Spinal cord blood flow to the upper thoracic (T1-T4), mid-thoracic (T5-T8), lower thoracic (T9-T13), and lumbar (L1-L3) levels were determined. After euthanasia, we carried out selective vascular corrosion cast and counted the left and right ARMAs from levels T1-T13. RESULTS: Blood flow analysis of the left and right kidneys revealed a strong correlation (r = .94, p < .001). We detected more left than right ARMAs, with the highest prevalence at T4 (p < .05). The mean number of ARMAs was 8 ± 2. Their number in the upper thoracic region ranged from 2 to 7 (mean of 5 ± 1), while in the lower thoracic region they ranged from 0 to 5 (mean of 3 ± 1 [p < .001]). CONCLUSIONS: This study shows that combining fluorescence microsphere technique and vascular corrosion cast is well suited for assessing the blood flow and visualizing the arteries at the same time.

Microvascular dysfunction in COVID-19: the MYSTIC study.

RATIONALE: Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. OBJECTIVES: To comprehensively characterize and quantify microvascular alterations in patients with COVID-19. METHODS: Hospitalized adult patients with moderate-to-severe or critical COVID-19 (n = 23) were enrolled non-consecutively in this prospective, observational, cross-sectional, multi-center study. Fifteen healthy volunteers served as controls. All participants underwent intravital microscopy by sidestream dark field imaging to quantify vascular density, red blood cell velocity (VRBC), and glycocalyx dimensions (perfused boundary region, PBR) in sublingual microvessels. Circulating levels of endothelial and glycocalyx-associated markers were measured by multiplex proximity extension assay and enzyme-linked immunosorbent assay. MEASUREMENTS AND MAIN RESULTS: COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4-6 µm), and also significant reductions of VRBC. Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality. CONCLUSIONS: Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19.

Age-Dependent Presentation and Clinical Course of 1465 Patients Aged 0 to Less than 18 Years with Ovarian or Testicular Germ Cell Tumors; Data of the MAKEI 96 Protocol Revisited in the Light of Prenatal Germ Cell Biology.

OBJECTIVE: To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT). METHODS: Patients <18 years with ovarian and testicular GCT (respectively OGCT and TGCT) were prospectively registered according to the guidelines of MAKEI 96. After resection of the primary tumor, patients staged ≥II received risk-stratified cisplatin-based combination chemotherapy. Patients were analyzed in respect to age (six age groups divided into 3-year intervals), histology, stage, and therapy. The primary end point was overall survival. RESULTS: Between January 1996 and March 2016, the following patients were registered: 1047 OGCT, of those, 630 had ovarian teratoma (OTER) and 417 had malignant OGCT (MOGCT); and 418 TGCT, of those, 106 had testicular teratoma (TTER) and 312 had malignant TGCT (MTGCT). Only in MTGCT, older age correlated with a higher proportion of advanced tumors. All 736 teratomas and 240/415 stage I malignant gonadal GCT underwent surgery and close observation alone. In case of watchful waiting, the progression rate of OGCT was higher than that of TGCT. However, death from disease was reported in 8/417 (1.9%) MOGCT and 8/312 (2.6%) MTGCT irrespective of adjuvant chemotherapy and repeated surgery. CONCLUSIONS: The different pathogenesis and histogenesis of gonadal GCT reflects sex- and age-specific patterns that define clinically relevant risk groups. Therefore, gender and age should be considered in further research on the biology and clinical practice of pediatric gonadal GCT.

Modifiable Risk Factors for Delayed Graft Function After Deceased Donor Kidney Transplantation.

PURPOSE: Delayed graft function is a major complication after kidney transplantation affecting patients' long-term outcome. The aim of this study was to identify modifiable risk factors for delayed graft function after deceased donor kidney transplantation. METHODS: This is a single-center retrospective cohort study of a university transplantation center. Univariate and multivariate step-wise logistic regression analysis of patient-specific and procedural risk factors were conducted. RESULTS: We analyzed 380 deceased donor kidney transplantation patients between October 30, 2008 and December 30, 2017. The incidence of delayed graft function was 15% (58/380). Among the patient-specific risk factors recipient diabetes (2.8 [1.4-5.9] odds ratio [OR] [95% confidence interval [CI]]), American Society of Anesthesiologist score of 4 (2.7 [1.2-6.5] OR [95% CI]), cold ischemic time >13 hours (2.8 [1.5-5.3] OR [95% CI]) and donor age >55 years (1.9 [1.01-3.6] OR [95% CI]) revealed significance. The significant intraoperative, procedural risk factors included the use of colloids (3.9 [1.4-11.3] OR [95% CI]), albumin (3.0 [1.2-7.5] OR [95% CI]), crystalloids >3000 mL (3.1 [1.2-7.5] OR [95% CI]) and mean arterial pressure <80 mm Hg at the time of reperfusion (2.4 [1.2-4.8] OR [95% CI]). CONCLUSION: Patients undergoing deceased donor kidney transplantation with a mean arterial pressure >80 mm Hg at the time of transplant reperfusion without requiring excessive fluid therapy in terms of colloids, albumin or crystalloids >3000 mL are less likely to develop delayed graft function.

New insights into spinal cord ischaemia after thoracic aortic procedures: the importance of the number of anterior radiculomedullary arteries for surgical outcome.

OBJECTIVES: Anterior radiculomedullary arteries (ARMAs) link dorsal segmental arteries and the intraspinal compartment of the spinal collateral network. The number of thoracic ARMA is highly variable from one person to another. The impact of the number of ARMAs on spinal cord perfusion during thoracic aortic procedures is unknown. We investigated the influence of the number of thoracic ARMAs on spinal cord perfusion in an aortic surgical large animal model. METHODS: Twenty-six pigs were included (20 treatment animals, 6 sham animals, weight 34 ± 3 kg). The animals underwent ligation of the left subclavian artery and the thoracic segmental arteries via a left lateral thoracotomy with normothermia. After sacrifice, complete body perfusion with coloured cast resin was performed and the number of thoracic ARMAs was documented at autopsy. End points were spinal cord perfusion pressure, cerebrospinal fluid pressure, spinal cord blood flow (microspheres) and neurological outcome. Observation time was 3 h post-ligation. RESULTS: The numbers of thoracic ARMAs ranged between 3 (n = 1) and 13 (n = 1). The mean number was 8. Animals were grouped according to number of thoracic ARMA: 6-7 (5 animals), 8-10 (8 animals) and 11-13 (5 animals). A large number of thoracic ARMAs was linked to (i) a lower drop in spinal cord blood flow from baseline to post-clamp, (ii) the presence and increased magnitude of hyperaemia evident 3 h post-clamp (P < 0.001) and (iii) the presence of early hyperaemia starting immediately post-clamp in animals with 11 or more ARMA (P < 0.001). CONCLUSIONS: We showed that a large number of thoracic ARMA protects against spinal cord injury during descending aortic surgical procedures.1.

Spinal ischaemia after thoracic endovascular aortic repair with left subclavian artery sacrifice: is there a critical stent graft length?

OBJECTIVES: Thoracic endovascular aortic repair (TEVAR) is used for treatment of thoracic aortic pathologies, but the covered stent graft can induce spinal ischaemia depending on the length used. The left subclavian artery contributes to spinal cord collateralization and is frequently occluded by the stent graft. Our objective was to investigate the impact of covered stent graft length on the risk of spinal ischaemia in the setting of left subclavian artery sacrifice. METHODS: Twenty-six pigs (German country race, mean body weight 36 ± 4 kg) underwent simulated descending aortic TEVAR via left lateral thoracotomy, with left subclavian artery and thoracic segmental artery occlusion in normothermia. Animals were assigned to treatment groups according to simulated stent graft length: TEVAR to T8 (n = 4), TEVAR to T9 (n = 4), TEVAR to T10 (n = 4), TEVAR to T11 (n = 7) and TEVAR to T12 (n = 1) and a sham group (n = 6). End points included spinal cord perfusion pressure, cerebrospinal fluid pressure and spinal cord blood flow using fluorescent microspheres. RESULTS: There were no group differences in spinal cord perfusion pressure drop or in spinal cord perfusion pressure regeneration potential at 3 h after the procedure: from a baseline average of 75 mmHg (95% confidence interval 71-83 mmHg) to 73 mmHg (67-75 mmHg) at 3 h in Group T10 versus from a baseline average of 67 mmHg (95% CI 50-81 mmHg) to 65 mmHg (95% confidence interval 48-81 mmHg) in Group T8. There were no differences in the spinal cord blood flow courses over time in the different groups nor was there any difference in cerebrospinal fluid pressure levels and cerebrospinal fluid pressure dynamics between groups. However, we did observe local blood flow distribution to the spinal cord that was inhomogeneous depending on the distance between the simulated stent graft end and the first thoracic anterior radiculomedullary artery. CONCLUSIONS: The risk of spinal ischaemia after serial segmental artery occlusion does not depend on the distal extent of the aortic repair alone. Future attempts to allow patient risk stratification for spinal ischaemia need to focus on anterior radiculomedullary artery anatomy together with the extent of planned aortic repair.

Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial.

BACKGROUND: Following promising results to increase survival and reduce treatment burden in intracranial non-germinomatous germ cell tumors (NGGCTs), we conducted a European study using dose-intense chemotherapy followed by risk-adapted radiotherapy. METHODS: All patients received 4 courses of cisplatin/etoposide/ifosfamide. Non-metastatic patients then received focal radiotherapy only (54 Gy); metastatic patients received 30 Gy craniospinal radiotherapy with 24 Gy boost to primary tumor and macroscopic metastatic sites. RESULTS: Patients with localized malignant NGGCT (n = 116) demonstrated 5-year progression-free survival (PFS) and overall survival (OS) of 0.72 ± 0.04 and 0.82 ± 0.04, respectively. Primary tumor sites were: 67 pineal, 35 suprasellar, 5 bifocal, 9 others. One patient died postsurgery in clinical remission; 3 patients progressed during treatment and 27 (23%) relapsed afterward. Fourteen were local, 6 combined, and 7 distant relapses (outside radiation field). Seventeen of the 27 relapsed patients died of disease. Patients with metastatic disease (n = 33) demonstrated 5-year PFS and OS of 0.68 ± 0.09 and 0.75 ± 0.08, respectively; 1 patient died following progression on treatment and 9 (27%) relapsed afterward (5 local, 1 combined, 3 distant). Only one metastatic patient with recurrence was salvaged. Multivariate analysis identified diagnostic alpha-fetoprotein level (serum and/or cerebrospinal fluid level >1000 ng/mL, 19/149 patients, of whom 11 relapsed; P < 0.0003) and residual disease following treatment, including after second-look surgery (n = 52/145 evaluable patients, 26 relapsed; P = 0.0002) as significant prognostic indicators in this cohort. CONCLUSION: In localized malignant NGGCT, craniospinal radiotherapy could be avoided without increased relapses outside the radiotherapy field. Chemotherapy and craniospinal radiotherapy remain the gold standard for metastatic disease.

Spinal Ischemia in Thoracic Aortic Procedures: Impact of Radiculomedullary Artery Distribution.

BACKGROUND: The aim of this study was to assess the influence of thoracic anterior radiculomedullary artery (tARMA) distribution on spinal cord perfusion in a thoracic aortic surgical model. METHODS: Twenty-six pigs (34 ± 3 kg; study group, n = 20; sham group, n = 6) underwent ligation of the left subclavian artery and thoracic segmental arteries. End points were spinal cord perfusion pressure (SCPP), regional spinal cord blood flow (SCBF), and neurologic outcome with an observation time of 3 hours. tARMA distribution patterns tested for an effect on end points included (1) maximum distance between any 2 tARMAs within the treated aortic segment (0 or 1 segment = small-distance group; >1 segment = large-distance group) and (2) distance between the end of the treated aortic segment and the first distal tARMA (at the level of the distal simulated stent-graft end = group 0; gap of 1 or more segments = group ≥1). RESULTS: The number of tARMA ranged from 3 to 13 (mean, 8). In the large-distance group, SCBF dropped from 0.48 ± 0.16 mL/g/min to 0.3 ± 0.08 mL/g/min (p < 0.001). We observed no detectable SCBF drop in the small-distance group: 0.2 ± 0.05 mL/g/min at baseline to 0.23 ± 0.05 mL/g/min immediately after clamping (p = 0.147). SCBF increased from 0.201 ± 0.055 mL/g/min at baseline to 0.443 ± 0.051 mL/g/min at 3 hours postoperatively (p < 0.001) only in the small-distance group. CONCLUSIONS: We demonstrate experimental data showing that distribution patterns of tARMAs correlate with the degree of SCBF drop and insufficient reactive parenchymal hyperemia in aortic procedures. Individual ARMA distribution patterns along the treated aortic segment could help us predict the individual risk of spinal ischemia.

Treatment and outcomes of UK and German patients with relapsed intracranial germ cell tumors following uniform first-line therapy.

We aimed to retrospectively assess treatments/outcomes, including the value of high-dose-chemotherapy and autologous-stem-cell-rescue (HDC + AuSCR) and re-irradiation, in a large, European patient-cohort with relapsed intracranial germ-cell-tumors (GCTs) receiving uniform first-line therapy, including radiotherapy as standard-of-care. Fifty-eight UK/German patients (48 male/10 female) with relapsed intracranial-GCTs [13 germinoma/45 non-germinomatous GCT (NGGCT)] treated 1996-2010 as per the SIOP-CNS-GCT-96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five-year overall-survival (OS) for the whole-group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard-dose-chemotherapy (SDC) and re-irradiation or HDC + AuSCR with/without re-irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non-protocol adherence, five teratoma, five palliation). Five-year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2-26%). By treatment received, 5-year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0-0%) and 14% (3-36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5-year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re-irradiation or HDC + AuSCR with/without re-irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa-based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible.

Immediate Spinal Cord Collateral Blood Flow During Thoracic Aortic Procedures: The Role of Epidural Arcades.

The objective of this study was to investigate the functional differences between paraspinal and intraspinal compartments of the spinal collateral network and the importance of circular epidural arcades in thoracic aortic surgery. N = 33 pigs (mean body weight: 34 ± 3kg) were included. A single-inlet-model of spinal collateral flow was created: paraspinal inflow into the collateral network was isolated by cephalad and caudal interruption of inflow into epidural arcades using laminectomies. Animals were assigned to treatment groups (Treatment "open" [patent epidural arcades, n = 10] and Treatment "closed" [closed epidural arcades, n = 10]) and Sham groups (Sham "open" n = 8 and Sham "closed" n = 5). Treatment was a simulated Frozen Elephant Trunk procedure with occlusion of left subclavian and thoracic segmental arteries under mild permissive hypothermia. Observation time was 3 hours. Endpoints were motor and somatosensory evoked potentials (motor evoked potentials and sensory evoked potentials), spinal cord perfusion pressure, cerebrospinal fluid pressure, regional spinal cord blood flow, and neurologic outcome. Animals with interrupted inflow into epidural arcades (Group Treatment "closed") had higher cerebrospinal fluid pressure levels (P < 0.05), were not able to maintain sufficient spinal cord perfusion pressure during Frozen Elephant Trunk procedure (P < 0.001) and did not generate reactive hyperemia as did group Treatment "open." spinal cord blood flow was strongly decreased in group Treatment "closed" (P < 0.001) at 0 hour, did not recover out to 3 hours of observation and 90% of the animals suffered flaccid paraplegia (P < 0.05). Immediate spinal cord backup blood flow is almost exclusively delivered using the system of epidural arcades in the immediate setting, serving as an immediate backup system. Intraspinal arcades are responsible for generating sufficient intraspinal perfusion pressures, reactive hyperemia, and spinal cord integrity. Paraspinal collaterals might need to undergo arteriogenesis, and thus serve as a long-term backup system.

Ovarian Sertoli Leydig cell tumours in children and adolescents: an analysis of the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT).

OBJECTIVE: To analyse ovarian Sertoli-Leydig cell tumours (SLCTs) for potential prognostic markers and their use for treatment stratification. PATIENTS: Forty-four patients were included. Patients were prospectively reported to the German MAKEI (Maligne Keimzelltumoren) studies (n=23), French TGM protocols (n=10), Italian Rare Tumour Project (TREP) registry (n=6), and the Polish Pediatric Rare Tumour Study group (n=5). Tumours were classified according to World Health Organisation (WHO) and staged according to International Federation of Gynecological Oncology (FIGO). RESULTS: Median age was 13.9 (0.5-17.4) years. All patients underwent resection by tumour enucleation (n=8), ovariectomy (n=17), adenectomy isolated (n=18) or with hysterectomy (n=1). FIGO-stage: Ia 24pts., Ic 17pts., II/III 3pts. One patient had bilateral tumours. Four patients (stage Ia: 3, stage Ic: 1) developed a metachronous contralateral tumour. Otherwise, all stage Ia patients remained in complete remission. Among 20 patients with incomplete resection or tumour spread (stage Ic-III), eight relapsed, and five patients died. Eleven patients were initially treated with two to sixcycles of cisplatin-based chemotherapy. Of these, seven patients are in continuous remission. Poor histological differentiation was associated with higher relapse rate (5/13) compared to intermediate (3/18) and high differentiation (0/4). Tumours with retiform pattern or heterologous elements showed a high relapse rate, too (5/11). After a median follow-up of 62 months, event-free survival is 0.70±0.07, relapse-free survival 0.81±0.06 and overall survival 0.87±0.05. CONCLUSIONS: Prognosis of SLCTs is determined by stage and histopathologic differentiation. Complete resection with careful avoidance of spillage is a prerequisite of cure. The impact of chemotherapy in incompletely resected and advanced stage tumours remains to be evaluated.

Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single-institution, phase 2 study.

BACKGROUND: Although the survival of children and adolescents with malignant germ-cell tumours has improved greatly in recent years, the outcome remains poor for those with refractory or recurrent malignant germ-cell tumours. We aimed to determine whether objective tumour response could be achieved in patients with refractory or recurrent malignant germ-cell tumours with PEI-regional deep hyperthermia as salvage treatment. METHODS: Patients with refractory or recurrent non-testicular malignant germ-cell tumours after standard cisplatin-based chemotherapy were treated prospectively with PEI chemotherapy (cisplatin 40 mg/m(2), delivered intravenously on days 1 and 4; etoposide 100 mg/m(2), intravenously on days 1-4; and ifosfamide 1800 mg/m(2), intravenously on days 1-4) plus simultaneous 1-h regional deep hyperthermia (41-43°C) on days 1 and 4. Patients received three to four treatment courses at 21-day intervals until residual tumour resection was possible; they subsequently received one or two additional courses of PEI-regional deep hyperthermia. Local radiotherapy was given for incompletely resected tumours. Chemotherapy and hyperthermia toxic effects were assessed using WHO grading. The primary endpoint was the proportion of patients who had an objective response as assessed with Response Evaluation Criteria in Solid Tumors version 1.0 guidelines. Secondary endpoints were the event-free survival and overall survival after 5 years. This ongoing PEI-regional deep hyperthermia study (Hyper-PEI protocol) is registered at the German Cancer Society, number 50-2732. FINDINGS: 44 patients aged 7 months to 21 years (median 2 years 7 months) with refractory or recurrent malignant germ-cell tumours (nine patients with poor response, 23 patients with first relapse, 12 patients with multiple relapses) were included in this study. We identified 34 yolk sac tumours, eight embryonal carcinomas, one choriocarcinoma, and one dysgerminoma by histology analysis. Of the 35 patients who had sufficient clinical and radiographical data available for response assessment, 30 (86%) had an objective response to treatment (16 patients had complete remission and 14 had partial remission). 5-year event-free survival was 62% (95% CI 45-75), and 5-year overall survival was 72% (95% CI 55-83). The median follow-up of surviving patients was 82 months (range 9-195). WHO grade 3-4 neutropenia and thrombocytopenia occurred in all 181 chemotherapy cycles. Granulocytopenic fever, which required intercurrent hospital admission, was noted in 29 (66%) of 44 patients after 53 (29%) of 181 courses. Five patients experienced treatment-related grade-3 acute renal toxic effects. INTERPRETATION: A multimodal strategy integrating PEI-regional deep hyperthermia and tumour resection with or without radiation can successfully treat children and adolescents with refractory or recurrent malignant non-testicular germ-cell tumours. The long-term prognosis of patients with poor response or after first relapse was almost similar to those receiving first-line treatment. This strategy merits further investigation. FUNDING: Deutsche Krebshilfe eV, Bonn, Elterninitiative Kinderkrebsklinik Düsseldorf eV, the Barbara and Hubertus-Trettnerstiftung, and the Marie Quendt Fund.

Rotavirus disease in Germany--a prospective survey of very severe cases.

OBJECTIVE: Rotavirus (RV) gastroenteritis is a notifiable disease in Germany. The reports to the authorities contain few data concerning the severity of disease. The aims of this study were to determine incidence and outcome of very severe cases of RV disease. METHODS: Cases of very severe RV disease were collected by the German Paediatric Surveillance Unit for rare diseases (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland) using anonymous questionnaires based on hospitalized patients between April 2009 and March 2011. Inclusion criteria were detection of RV antigen in feces, patient aged 0-16 years and 1 or more of the following criteria: intensive care treatment, hypernatremia or hyponatremia (>155 mmol/L or <125 mmol/L), clinical signs of encephalopathy (somnolence, seizures, apnea) and RV-associated death. RESULTS: During 2 years, 130 cases of very severe RV disease were reported, 101 of 130 were verified. Seventeen patients had nosocomial infection, of whom 14 were neonates in intensive care. Among those, 12 infants had verified or suspected necrotizing enterocolitis. Eighty-four community-acquired cases were reported, median age was 10.5 months (0-108 months). The median hospital stay was 6 days, and 48 patients needed intensive care treatment. Among children less than 5 years of age, the yearly incidence of community-acquired very severe RV disease was 1.2 of 100,000 (95% confidence interval: 0.9-1.4/100,000). A total of 26 of 84 and 10 of 84 patients had severe hypernatremia or hyponatremia, respectively, and 58 of 84 patients had signs of encephalopathy. Three deaths were reported (1 nosocomial and 2 community acquired). CONCLUSIONS: RV infection in Germany can have a life-threatening course. A substantial number are nosocomial infections.