3D-printing of the elbow in complex posttraumatic elbow-stiffness for preoperative planning, surgery-simulation and postoperative control.

BACKGROUND: Restoration of mobility of the elbow after post-traumatic elbow stiffening due to osteophytes is often a problem. METHODS: The anatomical structures were segmented within the CT-scan. Afterwards, the Multi Jet Fusion 3D-printing was applied to create the model made of biocompatible and steam-sterilizable plastic. Preoperative simulation of osteophyte resection at the 3D-model was performed as well as the direct comparison with the patient anatomy intraoperatively. RESULTS: The patient-specific was very helpful for the preoperative simulation of the resection of elbow osteophytes. The 3D anatomical representation improved the preoperative plan its implementation. A high degree of fidelity was found between the 3D Printed Anatomical representation and the actual joint pathology. CONCLUSIONS: Arthrolysis of complex post-traumatic bony changes is an important indication for the use of 3D models for preoperative planning. Due to the use of 3D printing and software simulation, accurate resection planning is feasible and residual bony stiffening can be avoided. 3D printing models can lead to an improvement in surgical quality.

RNA sequencing of glioblastoma tissue slice cultures reveals the effects of treatment at the transcriptional level.

One of the major challenges in cancer research is finding models that closely resemble tumors within patients. Human tissue slice cultures are a promising approach to provide a model of the patient's tumor biology ex vivo. Recently, it was shown that these slices can be successfully analyzed by whole transcriptome sequencing as well as automated histochemistry, increasing their usability as preclinical model. Glioblastoma multiforme (GBM) is a highly malignant brain tumor with poor prognosis and little is known about its genetic background and heterogeneity regarding therapy success. In this study, tissue from the tumors of 25 patients with primary GBM was processed into slice cultures and treated with standard therapy (irradiation and temozolomide). Total RNA sequencing and automated histochemistry were performed to enable analysis of treatment effects at a transcriptional and histological level. Slice cultures from long-term survivors (overall survival [OS] > 24 months) exhibited more apoptosis than cultures from patients with shorter OS. Proliferation within these slices was slightly increased in contrast to other groups, but not significantly. Among all samples, 58 protein-coding genes were upregulated and 32 downregulated in treated vs. untreated slice cultures. In general, an upregulation of DNA damage-related and cell cycle checkpoint genes as well as enrichment of genotoxicity pathways and p53-dependent signaling was found after treatment. Overall, the current study reproduces knowledge from former studies regarding the feasibility of transcriptomic analyses and automated histology in tissue slice cultures. We further demonstrate that the experimental data merge with the clinical follow-up of the patients, which improves the applicability of our model system.

Causes and Predictors of Unplanned Readmission in Cranial Neurosurgery.

OBJECTIVE: A better understanding of the risks and reasons for unplanned readmission is an essential component in reducing costs in the health care system and in optimizing patient safety and satisfaction. The reasons for unplanned readmission vary between different disciplines and procedures. The aim of this study was to identify reasons for readmission in view of different diagnoses in cranial neurosurgery. METHODS: In this single-center retrospective study, adult patients after neurosurgical treatment were analyzed and grouped according to the indication based on International Classification of Diseases and Related Health Problems, Tenth Revision, German Modification diagnosis codes. The main outcome measure was unplanned readmission within 30 days of discharge. Further logistic regression models were performed to identify factors associated with unplanned rehospitalization. RESULTS: Of the 2474 patients analyzed, 183 underwent unplanned rehospitalization. Readmission rates differed between the diagnosis groups, with 9.19% in neoplasm, 8.26% in hydrocephalus, 5.76% in vascular, 6.13% after trauma, and 8.05% in the functional group. Several causes were considered to be preventable, such as wound healing disorders, seizures, or social reasons. Younger age, length of first stay, surgical treatment, and side diagnoses were predictors for unplanned readmission. Diagnoses with an increased risk of readmission were glioblastoma, traumatic subdural hematoma, or chronic subdural hematoma. CONCLUSIONS: Reasons and predictors for an unplanned readmission differ considerably among the index diagnosis groups. In addition to well-known reasons for readmission, we identified social indication, meaning a lack of home care, which is particularly prevalent in oncologic and elderly patients. A transitional care program could benefit these vulnerable patients.

Deep sequencing and automated histochemistry of human tissue slice cultures improve their usability as preclinical model for cancer research.

Cancer research requires models closely resembling the tumor in the patient. Human tissue cultures can overcome interspecies limitations of animal models or the loss of tissue architecture in in vitro models. However, analysis of tissue slices is often limited to histology. Here, we demonstrate that slices are also suitable for whole transcriptome sequencing and present a method for automated histochemistry of whole slices. Tumor and peritumoral tissue from a patient with glioblastoma was processed to slice cultures, which were treated with standard therapy including temozolomide and X-irradiation. Then, RNA sequencing and automated histochemistry were performed. RNA sequencing was successfully accomplished with a sequencing depth of 243 to 368 x 106 reads per sample. Comparing tumor and peritumoral tissue, we identified 1888 genes significantly downregulated and 2382 genes upregulated in tumor. Treatment significantly downregulated 2017 genes, whereas 1399 genes were upregulated. Pathway analysis revealed changes in the expression profile of treated glioblastoma tissue pointing towards downregulated proliferation. This was confirmed by automated analysis of whole tissue slices stained for Ki67. In conclusion, we demonstrate that RNA sequencing of tissue slices is possible and that histochemical analysis of whole tissue slices can be automated which increases the usability of this preclinical model.

Two cases of atypical meningioma with pulmonary metastases: a comparative cytogenetic analysis of chromosomes 1p and 22 and a review of the literature.

We present two cases of atypical meningioma WHO grade II with a history of multiple local recurrences and late pulmonary metastases. Comparative cytogenetic analyses on 1p and 22q confirmed clonal origin of the primary intracranial meningiomas and the pulmonary metastases in both cases. These cases illustrate the importance of close neuroradiological follow-up to detect tumor recurrence in patients with atypical meningiomas WHO grade II even with clinically stable disease and should sensitize clinicians to late extracranial metastases of these tumors, especially to the lung. In an effort to elucidate common clinical features of metastatic meningiomas, especially to the lung, the literature was reviewed from 1995 to 2014, identifying a total of 45 published cases.

Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex.

A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.

The influence of immunosuppressive drugs on neural stem/progenitor cell fate in vitro.

In allogenic and xenogenic transplantation, adequate immunosuppression plays a major role in graft survival, especially over the long term. The effect of immunosuppressive drugs on neural stem/progenitor cell fate has not been sufficiently explored. The focus of this study is to systematically investigate the effects of the following four different immunotherapeutic strategies on human neural progenitor cell survival/death, proliferation, metabolic activity, differentiation and migration in vitro: (1) cyclosporine A (CsA), a calcineurin inhibitor; (2) everolimus (RAD001), an mTOR-inhibitor; (3) mycophenolic acid (MPA, mycophenolate), an inhibitor of inosine monophosphate dehydrogenase and (4) prednisolone, a steroid. At the minimum effective concentration (MEC), we found a prominent decrease in hNPCs' proliferative capacity (BrdU incorporation), especially for CsA and MPA, and an alteration of the NAD(P)H-dependent metabolic activity. Cell death rate, neurogenesis, gliogenesis and cell migration remained mostly unaffected under these conditions for all four immunosuppressants, except for apoptotic cell death, which was significantly increased by MPA treatment.

Automation in surgery: the impact of navigated-control assistance on performance, workload, situation awareness, and acquisition of surgical skills.

OBJECTIVE: Human performance consequences of a new technology of image-guided navigation (IGN) support for surgeons are investigated. BACKGROUND: Navigated control (NC) represents an advancement of IGN technology. In contrast to currently available pointer-based systems, it represents a higher degree of automation that supports processes not only of information analysis and integration but also of intraoperative decision making. METHOD: In the first experiment, 14 surgical novices performed a simulated mastoidectomy with and without NC support. Effects of provision of the system were analyzed with respect to different measures of surgical performance and outcome, workload, and situation awareness. In the second experiment, 21 advanced medical students were trained to perform a mastoidectomy by practicing it either with or without NC support. It was investigated to what extent the provision of the system during practice would affect the acquisition of surgical skills. RESULTS: The results reveal that NC support can reduce both the risk of intraoperative injuries and complications as well as the physiological effort of surgeons. "Cost effects" compared to a conventional (i.e., not supported) surgery emerged with respect to the time needed for the surgery, increased subjective workload, reduced spare capacity, and a reduced level of situation awareness. However, no significant effects on processes of skill acquisition were found. CONCLUSION: NC systems can contribute to improved patient safety. Most of the cost effects seem to be related not to the basic principle of NC but to its current technological implementation. APPLICATION: The results have consequences for the design and clinical use of automated navigation support.

Assessment of neuropsychological parameters and quality of life to evaluate outcome in patients with surgically treated supratentorial meningiomas.

OBJECTIVE: According to current outcomes research programs, assessment of a broad spectrum of parameters, including quality of life indices, is required to adequately reflect the results of a given treatment. We performed a comprehensive evaluation in patients after supratentorial meningioma surgery in a retrospective study. METHODS: In 91 consecutive patients, outcome was assessed in individual sessions in patients' homes an average of 15 months (standard deviation, +/- 3.6 months) after surgery. The survey included tests of cognitive performance, coping strategies, satisfaction with life, and a structured interview. RESULTS: We found a significant negative correlation between patient age and cognitive performance (P < 0.001), with a major decline beginning at the age of 55 years. Despite normal cognitive performance, 73% of younger patients (younger than 55 years) compared with 20% of older patients (P < 0.001) were not satisfied with life. As a major problem, 68% of younger patients described an inability to accept having this severe disease as a young person. Patients living as singles had a higher frequency of depressive coping (P < 0.05) and less satisfaction with life (P < 0.05). CONCLUSION: Comprehensive evaluation after meningioma surgery is required to prevent poor long-term results after apparently successful surgery. In our study, tests and structured interviews revealed different aspects, especially concerning patient age. Because demographic variables clearly influenced satisfaction with life, evaluation of quality of life must account for these factors to improve comparison of different studies. However, prospective studies with larger cohorts and control groups are required to prove our hypotheses.

Induction of gliosarcoma and atypical meningioma 13 years after radiotherapy of residual pilocytic astrocytoma in childhood.

BACKGROUND: Malignant transformation of pilocytic astrocytomas in children is rare and often linked to previous radiotherapy. METHODS AND RESULTS: We report a patient who underwent subtotal resection of a right temporal and insular pilocytic astrocytoma at age 8 in 1988 followed by high-dose radiation therapy. A local recurrence, grade WHO III, with signs of focal sarcomatous transformation, was subtotally resected 13 years later in 2001. A new and fast growing right frontal meningioma, grade WHO II, was removed in 2003. In 2004 a second glioma recurrence was partially resected, this time graded gliosarcoma WHO IV. The patient was treated thereafter with repeated courses of temozolomide. Another tumor mass reduction in 2005 was followed by stereotactic radiotherapy. Nevertheless, he deceased 3 months later. CONCLUSION: Most of the reported cases of malignant transformation of pilocytic astrocytomas received radiation therapy beforehand. Irradiation-induced meningiomas in children are known to occur, however not following radiotherapy of low-grade hemispheric gliomas. The presented case illustrates why adjuvant radiotherapy of residual pilocytic astrocytoma in children is not recommended anymore. For children who underwent radiotherapy in the past, we recommend MRI surveillance on a yearly basis far beyond 10 years, even in those who seem to have achieved total remission.

The navigation-controlled drill in temporal bone surgery: a feasibility study.

BACKGROUND: This study examines the feasibility of a navigation-controlled (NC) drill for surgery on the petrosal bone in an experimental environment. According to the principle of NC, the drill is to be switched off automatically once the borders of the workspace are exceeded during a mastoidectomy. MATERIALS AND METHODS: The registration is based on an optical navigation system with navigation software (MiMed). As surgery engine, the Unidrive-system (Karl Storz GmbH & CO. Kg, Tuttlingen, Germany) was integrated. The definition of the workspace was performed manually in axial computed tomography (CT) slices of the petrosal bone phantom. The mastoidectomy on the model was accomplished in three runs with 10 trial surgeons altogether (5 experienced [exp.] in otologic (ear) surgery, 5 inexperienced [nonexp.]). During each run, the following were logged: the total length of time for the procedure as well as the number and extent of injuries to the risk structures (facial nerve, horizontal semicircular canal, sigmoid sinus). The resultant petrosal bone cavities were measured on the CT. RESULTS: The time for the segmentation of the workspace for the mastoidectomy amounted to 17 minutes. The mean value of the drilling (e.g., milling) performance ranges from 6.61 mm3/s (group 1 [nonexp. + NC]), 9.62 mm3/s (group 2 [exp. w/o NC]), to 10.08 mm3/s (group 3 [exp. + NC]). The relative deviation to the segmented volume amounts to +7.4% (794.3 mm3) for group 1, -39.9% for group 2, and -34% (3,647.0 mm3) for group 3. In the groups with NC guidance of the drill, no damage to a risk structure could be logged. In the group of exp. ear surgeons without NC assistance, one injury to the facial nerve in the petrosal bone phantom occurred. DISCUSSION: The results that follow prove the fundamental feasibility of an NC drill for surgery of the petrosal bone using the example of the simple mastoidectomy in the laboratory test. When using NC, tissue resection is faster, more precise, and has fewer related complications than the same procedure without. The results offer a very promising basis for the introduction of a newly conceived system to the procedure of NC surgery on the petrosal bone. The device configuration used here was originally conceived for NC guidance of a shaver in functional endoscopic sinus surgery. Individual errors will have to be mitigated through the new version of the control unit presently in development.

Evaluation of a navigation system for ENT with surgical efficiency criteria.

The aim of this study is the evaluation of a navigation system (NaviBase) for ENT surgery. For this purpose, a new methodology for the evaluation of surgical and ergonomic system properties has been developed. The practicability of the evaluation instruments will be examined using the example of the overall assessment of the system in comparison with the current surgical standard and with other systems using clinical efficiency criteria. The evaluation is based on 102 ENT surgical applications; of these, 89 were functional endoscopic sinus surgeries (FESS). The evaluation of surgical and ergonomic performance factors was performed by seven ENT surgeons. To evaluate surgical system properties, the Level of Quality (LOQ) in 89 cases of the FESS was determined. It compares the existing information of the surgeon with that of the navigation system on a scale of 0 to 100 and with a mean value of 50 and places it in a relationship to the clinical impact. The intraoperative change of the planned surgical strategy (Change of Surgical Strategy) was documented. The ergonomic factors of the system with the categories of Overall Confidence (Trust), awareness of the situation (Situation Awareness), influence on the operating team, requirements for specific skills (Skill Set Requirement), and cognitive load (Workload Shift) were recorded for all surgical procedures as Level of Reliance (LOR). In the evaluation of the surgical system properties, an average evaluation of the quality of the information, as an LOQ of 63.59, resulted. Every second application of the navigation system (47.9%), on average, led to a change in the surgical strategy. An extension/enhancement of the indication of the endonasal approach through the use of the navigation system was shown in 7 of 102 (6.8%) cases. The completion of the resection in the FESS was rated by 74% of group I and 11% of group II as better in comparison with the standard approach. Total confidence shows a positive evaluation of 3.35 in the LOR. To supplement the evaluation of the navigation system, the technical parameters were included. The maximum deviation, Amax, of the displayed position of the reference value amounted to 1.93 mm. The average deviation was at 1.29 mm with an SD above all values, sd, of 0.29. The subsequent economic evaluation resulted in an effective average extra expenditure of time of 1.35 minutes per case. The overall evaluation of the system imparts application-relevant information beyond the technical details and permits comparability between different assistance systems.