Comparison of Operating Microscope and Exoscope in a Highly Challenging Experimental Setting

BACKGROUND: The use of a digital three-dimensional (3D) exoscope system in neurosurgery is increasing as an alternative to the operative microscope. The objective of this study was to compare a digital 3D exoscope system with a standard operating microscope as a neurosurgical visualization tool in a highly challenging experimental setting. METHODS: End-to-side bypass procedures, each at a depth of 9 cm, were performed in a simulation setting. The quality of the task and the depth effect, visualization, magnification, illumination, and ergonomics were evaluated. RESULTS: No major differences were noted between the microscope and the 3D exoscope in terms of the quality of the work. Working with the 3D exoscope was more time-consuming than working with the microscope. Changing the depth and focus was faster using the operative microscope. The 3D exoscope enabled higher magnification and offered better ergonomic features. CONCLUSIONS: In a highly challenging experimental setting, comparable procedural quality was found for the microscope and the 3D exoscope. Each visualization tool had advantages and disadvantages. Over time and with technologic advances, the digital 3D exoscope may become the main operative visualization system in microneurosurgery.Peer reviewe

Safety and feasibility of third-party multipotent adult progenitor cells for immunomodulation therapy after liver transplantation--a phase I study (MISOT-I)

BACKGROUND: Liver transplantation is the definitive treatment for many end-stage liver diseases. However, the life-long immunosuppression needed to prevent graft rejection causes clinically significant side effects. Cellular immunomodulatory therapies may allow the dose of immunosuppressive drugs to be reduced. In the current protocol, we propose to complement immunosuppressive pharmacotherapy with third-party multipotent adult progenitor cells (MAPCs), a culture-selected population of adult adherent stem cells derived from bone marrow that has been shown to display potent immunomodulatory and regenerative properties. In animal models, MAPCs reduce the need for pharmacological immunosuppression after experimental solid organ transplantation and regenerate damaged organs. METHODS: Patients enrolled in this phase I, single-arm, single-center safety and feasibility study (n=3-24) will receive 2 doses of third-party MAPCs after liver transplantation, on days 1 and 3, in addition to a calcineurin-inhibitor-free "bottom-up" immunosuppressive regimen with Basiliximab, mycophenolic acid, and steroids. The study objective is to evaluate the safety and clinical feasibility of MAPC administration in this patient cohort. The primary endpoint of the study is safety, assessed by standardized dose-limiting toxicity events. One secondary endpoint is the time until first biopsy-proven acute rejection, in order to collect first evidence of efficacy. Dose escalation (150, 300, 450, and 600 million MAPCs) will be done according to a 3 + 3 classical escalation design (4 groups of 3-6 patients each). DISCUSSION: If MAPCs are safe for patients undergoing liver transplantation in this study, a phase II/III trial will be conducted to assess their clinical efficacy

Treatment-emergent adverse events after infusion of adherent stem cells: the MiSOT-I score for solid organ transplantation

Background: Cellular therapy after organ transplantation is emerging as an intriguing strategy to achieve dose reduction of classical immunosuppressive pharmacotherapy. Here, we introduce a new scoring system to assess treatment-emergent adverse events (TEAEs) of adherent stem cell therapies in the clinical setting of allogeneic liver transplantation (e.g. the MiSOT-I trial Eudract CT: 200901779525). Methods: The score consists of three independent modalities (set of parameters) that focus on clinically relevant events early after intravenous or intraportal stem cell infusion: pulmonary toxicity, intraportal-infusional toxicity and systemic toxicity. For each modality, values between 0 (no TEAE) and 3 (severe TEAE) were defined. The score was validated retrospectively on a cohort of n=187 recipients of liver allografts not receiving investigational cell therapy between July 2004 and December 2010. These patients represent a control population for further trials. Score values were calculated for days 1, 4 and 10 after liver transplantation. Results: Grade 3 events were most commonly related to the pulmonary system (3.5% of study cohort on day 4). Almost no systemic-related TEAEs were observed during the study period. The relative frequency of grade 3 events never exceeded 5% over all modalities and time points. A subgroup analysis for grade 3 patients provided no descriptors associated with severe TEAEs. Conclusion: The MiSOT-I score provides an assessment tool to score specific adverse events that may occur after adherent stem cell therapy in the clinical setting of organ transplantation and is thus a helpful tool to conduct a safety study

Hybrid Capability to Integrate Multiple Treatment Modalities for Managing High-Grade Intracranial Dural Arteriovenous Fistulas

BACKGROUND: An integrated multimodality approach can be effective in treatment of high-grade dural arteriovenous fistulas. Nevertheless, this requires a high level of efficient cooperation between different departments, underlying a degree of bias in the decisional process. In comparison, hybrid capability, integrating these modalities in one hand, may allow aggregating multimodality treatment strategies by pooling their individual benefits, leading to a more holistic view of the consequences of each modality. METHODS: We retrospectively reviewed 18 cases of dural arteriovenous fistulas subjected to a hybrid treatment approach at the Diakonieklinikum Jung-Stilling, Siegen, Germany, between March 2008 and January 2017. Nine cases were excluded. We selected 4 cases that highlight different aspects of hybrid capability for illustrative purposes. RESULTS: Hybrid capability allows treatment of a dural arteriovenous fistula based on the individual clinical situation of the patient and features of the lesion, free of interdepartmental bias. The surgeon maintains a level of flexibility that enables him or her to move from a minimally invasive endovascular approach to a maximally invasive surgical access according to the specific situation. Hybrid capability can lead to a highly efficient treatment regimen with palliation of symptoms and complete obliteration of the fistula, improving performance in these complex pathologies. CONCLUSIONS: Hybrid capability has great potential in the treatment of complex neurovascular lesions. It remains to be seen if a single surgeon with hybrid capability can supersede the current multidepartmental practice and achieve better outcomes.Peer reviewe

3D Vision Sensing for Grasp Planning: A New, Robust and Affordable Structured Light Approach

In this paper we present a new approach to 3D shape acquisition. This implementation enables a robot arm to move the scan unit over the object without the scan unit being tracked. The chosen structured light approach uses an initially unknown white noise pattern that can easily be projected with any fixed pattern projection system. Object points are acquired on the basis of finding correspondences in the pattern in the camera image of the current scene. This is achieved by using a fast SSD correlation algorithm. In the current test setup we are using a standard video beamer and a standard digital camera, but we have also set up a scan head for fixation on a robots ’ wrist. The special requirements of this miniaturized system will be explained as well as our implementation. Our approach reduces hardware complexity to a minimum using only one calibrated camera and one calibrated fixed pattern projector. In this paper we present the whole system also including the calibration procedure. The focus will be on the hardware setup, but we also give an introduction to the software methods used

Treatment-emergent adverse events after infusion of adherent stem cells: the MiSOT-I score for solid organ transplantation

BACKGROUND: Cellular therapy after organ transplantation is emerging as an intriguing strategy to achieve dose reduction of classical immunosuppressive pharmacotherapy. Here, we introduce a new scoring system to assess treatment-emergent adverse events (TEAEs) of adherent stem cell therapies in the clinical setting of allogeneic liver transplantation (for example, the MiSOT-I trial Eudract CT: 2009-017795-25). METHODS: The score consists of three independent modalities (set of parameters) that focus on clinically relevant events early after intravenous or intraportal stem cell infusion: pulmonary toxicity, intraportal-infusional toxicity and systemic toxicity. For each modality, values between 0 (no TEAE) and 3 (severe TEAE) were defined. The score was validated retrospectively on a cohort of n=187 recipients of liver allografts not receiving investigational cell therapy between July 2004 and December 2010. These patients represent a control population for further trials. Score values were calculated for days 1, 4, and 10 after liver transplantation. RESULTS: Grade 3 events were most commonly related to the pulmonary system (3.5% of study cohort on day 4). Almost no systemic-related TEAEs were observed during the study period. The relative frequency of grade 3 events never exceeded 5% over all modalities and time points. A subgroup analysis for grade 3 patients provided no descriptors associated with severe TEAEs. CONCLUSION: The MiSOT-I score provides an assessment tool to score specific adverse events that may occur after adherent stem cell therapy in the clinical setting of organ transplantation and is thus a helpful tool to conduct a safety study

Assessing the impact of transgenerational epigenetic variation on complex traits

Loss or gain of DNA methylation can affect gene expression and is sometimes transmitted across generations. Such epigenetic alterations are thus a possible source of heritable phenotypic variation in the absence of DNA sequence change. However, attempts to assess the prevalence of stable epigenetic variation in natural and experimental populations and to quantify its impact on complex traits have been hampered by the confounding effects of DNA sequence polymorphisms. To overcome this problem as much as possible, two parents with little DNA sequence differences, but contrasting DNA methylation profiles, were used to derive a panel of epigenetic Recombinant Inbred Lines (epiRILs) in the reference plant Arabidopsis thaliana. The epiRILs showed variation and high heritability for flowering time and plant height (~30%), as well as stable inheritance of multiple parental DNA methylation variants (epialleles) over at least eight generations. These findings provide a first rationale to identify epiallelic variants that contribute to heritable variation in complex traits using linkage or association studies. More generally, the demonstration that numerous epialleles across the genome can be stable over many generations in the absence of selection or extensive DNA sequence variation highlights the need to integrate epigenetic information into population genetics studies