Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Explicit Finite Element Models Accurately Predict Subject-Specific and Velocity-Dependent Kinetics of Sideways Fall Impact

The majority of hip fractures in the elderly are the result of a fall from standing or from a lower height. Current injury models focus mostly on femur strength while neglecting subject-specific loading. This article presents an injury modeling strategy for hip fractures related to sideways falls that takes subject-specific impact loading into account. Finite element models (FEMs) of the human body were used to predict the experienced load and the femoral strength in a single model. We validated these models for their predicted peak force, effective pelvic stiffness, and fracture status against matching ex vivo sideways fall impacts (n = 11) with a trochanter velocity of 3.1 m/s. Furthermore, they were compared to sideways impacts of volunteers with lower impact velocities that were previously conducted by other groups. Good agreement was found between the ex vivo experiments and the FEMs with respect to peak force (root mean square error [RMSE] = 10.7%, R² = 0.85) and effective pelvic stiffness (R² = 0.92, RMSE = 12.9%). The FEMs were predictive of the fracture status for 10 out of 11 specimens. Compared to the volunteer experiments from low height, the FEMs overestimated the peak force by 25% for low BMI subjects and 8% for high BMI subjects. The effective pelvic stiffness values that were derived from the FEMs were comparable to those derived from impacts with volunteers. The force attenuation from the impact surface to the femur ranged between 27% and 54% and was highly dependent on soft tissue thickness (R² = 0.86). The energy balance in the FEMS showed that at the time of peak force 79% to 93% of the total energy is either kinetic or was transformed to soft tissue deformation. The presented FEMs allow for direct discrimination between fracture and nonfracture outcome for sideways falls and bridge the gap between impact testing with volunteers and impact conditions representative of real life falls. © 2019 American Society for Bone and Mineral Research.     

C-arm-based mobile computed tomography: a comparison with established imaging on the basis of simulated treatments of talus neck fractures in a cadaveric study.

OBJECTIVE: To analyse the image quality and diagnostic effectiveness of a new C-arm-based 3D imaging method (C-arm-CT) for intraoperative evaluation of screw osteosyntheses adjacent to a peripheral joint. MATERIALS AND METHODS: Insertion of screws into four cadaveric specimens simulated the surgical treatment of talus neck fractures. Ten orthopedic surgeons and 10 radiologists evaluated X-ray, C-arm fluoroscopy, C-arm-CT and CT images. RESULTS: The best image quality was obtained with X-rays (p < 0.001), followed by C-arm fluoroscopy (2D) and CT, with the C-arm-CT (3D) being rated lowest (p < 0.001). The most correct diagnoses were obtained with CT and C-arm-CT (with no statistical difference between them), while C-arm-fluoroscopy was inferior (p < 0.001) and X-rays were the worst (p < 0.05). CONCLUSIONS: Even if the image quality of C-arm-CT is definitely inferior to that of CT, screw misplacements can be reliably detected using C-arm-CT. As compared to the current standard procedures (intraoperative fluoroscopy and postoperative radiography), C-arm-CT performed better. C-arm-CT is ideally suited to the intraoperative diagnosis of high-contrast inquiries like bone fragments and OS material, especially at the extremities. Coupling of the new 3D imaging to existing navigation systems is possible. C-arm-CT will support the further development and implementation of open and minimally invasive surgical procedures.     

A randomised trial of ultrasonic dissection versus electrocoagulation to reduce lymphatic complications after surgery for recurrent sapheno-femoral incompetence.

OBJECTIVE: Prospectively to compare lymphatic drainage after ultrasonic dissection, an electrocoagulation technique and sharp dissection in the groin during surgery for recurrent sapheno-femoral incompetence. DESIGN: Prospective, randomised study comparing three surgical techniques. METHODS: Thirty-six consecutive patients undergoing surgery for recurrent sapheno-femoral incompetence were randomised. Twelve patients underwent dissection with ultrasound, 12 with electrocoagulation and 12 controls had sharp dissection with ligation of scar and lymphatic tissue using absorbable suture material. RESULTS: The mean drain output per patient was 13.5 ml in the ultrasonic group, 15.4 ml in the electrocoagulation group and 8.3 ml in the suture ligation group. Six minor cases of lymphatic leakage occurred in the ultrasonic group. This resulted in no clinical problem. There were no other significant differences between the three groups. CONCLUSIONS: There is no detectable advantage for the use of ultrasound or electrocoagulation in recurrent saphenous high ligation compared to sharp dissection.     

A modified Viernstein and Kelly surgical technic for correcting chronic recurrent peroneal tendon dislocation

An operative technique modified after Viernstein and Kelly for the treatment of chronic, recurrent peronal tendon dislocation is presented, which has been performed successfully in 15 cases. Principal elements of this technique are an improvement of the bony containment of the tendons within the shallowed, malleolar sulcus and the use of the outer layer of the dislocation pouch as superior retinaculum. This is achieved by inserting the outer layer underneath a dorsally displaced, bony lamella of the outer malleolus.     

Akathisia as a side effect of antipsychotic treatment with quetiapine in a patient with Parkinson's disease.

Due to its low profile for extrapyramidal side-effects, quetiapine has become an alternative to clozapine in the treatment of dopamimetic psychosis in patients with Parkinson's disease (PD). We describe the case of a patient with PD who developed severe akathisia, a common complication with classical antipsychotics, with quetiapine.     

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Low frequency of p53 gene mutation in tumors induced by aflatoxin B1 in nonhuman primates.

Aflatoxin B1 has been suggested as a causative agent for a G to T mutation at codon 249 in the p53 gene in human hepatocellular carcinomas from southern Africa and Qidong in China. To test this hypothesis, nine tumors induced by aflatoxin B1 in nonhuman primates were analyzed for mutations in the p53 gene. These included four hepatocellular carcinomas, two cholangiocarcinomas, a spindle cell carcinoma of the bile duct, a hemangioendothelial sarcoma of the liver, and an osteogenic sarcoma of the tibia. None of the tumors showed changes at the third position of codon 249 by cleavage analysis of the HaeIII enzyme site at codon 249. A point mutation was identified in one hepatocellular carcinoma at the second position of codon 175 (G to T transversion) by sequencing analysis of the four conserved domains (II to V) in the p53 gene. These data suggest that mutations in the p53 gene are not necessary in aflatoxin B1 induced hepatocarcinogenesis in nonhuman primates. The occurrence of mutation in codon 249 of the p53 gene in selective samples of human hepatocellular cancers may indicate involvement of environmental carcinogens other than aflatoxin B1 or that hepatitis B virus-related hepatitis is a prerequisite for aflatoxin B1 induction of G to T transversion in codon 249.