An Injury-like Signature of the Extracellular Glioma Metabolome.

Aberrant metabolism is a hallmark of malignancies including gliomas. Intracranial microdialysis enables the longitudinal collection of extracellular metabolites within CNS tissues including gliomas and can be leveraged to evaluate changes in the CNS microenvironment over a period of days. However, delayed metabolic impacts of CNS injury from catheter placement could represent an important covariate for interpreting the pharmacodynamic impacts of candidate therapies. Intracranial microdialysis was performed in patient-derived glioma xenografts of glioma before and 72 h after systemic treatment with either temozolomide (TMZ) or a vehicle. Microdialysate from GBM164, an IDH-mutant glioma patient-derived xenograft, revealed a distinct metabolic signature relative to the brain that recapitulated the metabolic features observed in human glioma microdialysate. Unexpectedly, catheter insertion into the brains of non-tumor-bearing animals triggered metabolic changes that were significantly enriched for the extracellular metabolome of glioma itself. TMZ administration attenuated this resemblance. The human glioma microdialysate was significantly enriched for both the PDX versus brain signature in mice and the induced metabolome of catheter placement within the murine control brain. These data illustrate the feasibility of microdialysis to identify and monitor the extracellular metabolome of diseased versus relatively normal brains while highlighting the similarity between the extracellular metabolome of human gliomas and that of CNS injury.

Technologically Comprehensive Reconstruction of Fronto-Orbito-Sphenoidal Craniofacial Fibrous Dysplasia.

Craniofacial fibrous dysplasia (CFD) is a benign bone condition that presents unique challenges due to its proximity to vital organs, esthetic significance, and variability in each case. Consequently, a meticulous and personalized surgical approach becomes imperative. Diverse techniques and technologies have been employed sporadically to tackle various aspects of CFD. Our approach includes a comprehensive integration of emerging methods and technologies, encompassing presurgical strategizing, three-dimensional computer-aided manufacturing (3D-CAM), intraoperative navigation systems, and a prefabricated drilling guide in a fronto-orbito-sphenoidal CFD case. This combined strategy is aimed at effectively addressing the complexities of this demanding ailment. Moreover, a collaborative team consisting of plastic surgeons, neurosurgeons, and oculoplastic surgeons cooperates to orchestrate the procedure. Embracing a multidisciplinary team and a holistic technological strategy appears to be the key to addressing the multifaceted challenges posed by intricate conditions like CFD.

Plasma exchange as a tool for removal of bevacizumab: Highlighting application for urgent surgery.

Background: Bevacizumab is commonly used to manage cerebral edema associated with brain tumors. However, its long half-life poses challenges for patients requiring urgent surgery due to wound complications. We present a case of utilizing therapeutic plasma exchange (TPE) to remove bevacizumab in a patient with recurrent glioblastoma requiring urgent surgery. Methods: A 58-year-old male with recurrent glioblastoma, IDH-wildtype, presented with clinical and radiographic concern for ventriculitis requiring urgent wound washout only 4 days after his last bevacizumab infusion. TPE was performed for 3 sessions after surgery using a centrifugation-based cell separator. Replacement fluids included normal serum albumin, normal saline, and fresh frozen plasma. Bevacizumab levels were quantified using an enzyme-linked immunoabsorbent assay before and after each TPE session. Results: TPE effectively removed bevacizumab, enabling safe surgery without new complications. Plasma bevacizumab levels decreased from 1087.63 to 145.35 ng/mL (13.4% of original) by the end of the last TPE session. This decline is consistent with nearly 3 half-lives, which compares favorably to the expected timeline of natural decline given the 21-day half-life. Conclusions: We report a complex clinical scenario of a patient requiring urgent wound washout 4 days after last bevacizumab infusion for CNS infection. Surgery was successfully performed without new complications with use of TPE to remove bevacizumab immediately following surgery. This case highlights the feasibility of this approach, which may be utilized effectively in patients requiring surgery after having recently received bevacizumab.

Blood-brain barrier disruption defines the extracellular metabolome of live human high-grade gliomas.

The extracellular microenvironment modulates glioma behaviour. It remains unknown if blood-brain barrier disruption merely reflects or functionally supports glioma aggressiveness. We utilised intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions of gliomas and evaluated the global extracellular metabolome via ultra-performance liquid chromatography tandem mass spectrometry. Among 162 named metabolites, guanidinoacetate (GAA) was 126.32x higher in enhancing tumour than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumour than brain. With exception of GAA, and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumour and brain microdialysate were modest and less consistent. The enhancing, but not the non-enhancing glioma metabolome, was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies will determine how the altered extracellular metabolome impacts glioma behaviour.

Reconstruction of the plantar toe with a distal reverse instep sensory island flap.

BACKGROUND: Plantar toe ulcers are a challenging surgical problem. There are several methods for reconstruction, but no attention has been given to the preservation of sensation. This report proposes a method to provide protective sensation for the reconstructed area. PATIENTS AND METHODS: The ulcers of seven patients ranged from 2 × 3 to 7 × 3 cm with defects of the plantar first toe and distal metatarsus, including four burns, a trauma, a diabetic ulcer, and a neuropathy injury reconstructed with a distal reverse instep sensory island (DRISI) flap. The patients were 21-38 years old. The second metatarsus medial nerve was co-opted using the end-to-side method to the adjacent lateral nerve, then its proximal stump provided the donor nerve for the sensation of the flap. Patients were assessed in terms of protective sensory functions, including touch, pain, dermatomeric somatosensory-evoked potentials (SEP), thermal sensation and Semmes-Weinstein monofilament (SWM) light touch. RESULTS: The flaps ranged from 2 × 3 to 7 × 3 cm. All transferred flaps to the plantar first toe survived. No complications were observed at the donor and flap sites. Patients were followed-up 8-24 months. Except for two cases, all nerves of the donor and flap sites exhibited protective sensation, including positive SEP responses between 44 and 50 ms and positive SWM responses ≤ 3.84. CONCLUSION: The DRISI flap can be used for the reconstruction of various plantar first toe defects with acceptable protective sensation. End-to-side neurorrhaphy provides a sensory nerve end to subsequent end to end co-optation to the flap nerve for protective sensation.

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures.

BACKGROUND: Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA) make it as a good candidate for designing and development of the new anticonvulsant medications. METHODS: Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection of the screened compounds to mice. RESULTS: Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tert-Butylcyclo-hexanecarboxylic acid showed significant activity with ED50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM. CONCLUSION: Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA.

Comparison of a distal end-to-side neurorrhaphy with a proximal-distal end-to-side neurorrhaphy: in a rat model.

BACKGROUND: Peripheral nerve injuries have severe consequences on quality of life, especially in cases with extensive or old injuries when standard nerve repair is impossible and proposed repair methods are not completely satisfactory. Terminolateral neurorrhaphy is a practical and advantageous technique for nerve repair; therefore, we developed a nerve function study to evaluate advantages of proximal stump coaptation in end-to-side nerve repair method. METHODS: Three experimental groups were studied: In group A, the proximal and distal stumps of the transected peroneal nerve were sutured to the posterior tibialis nerve in left side and right side left intact; in group B, a classic end-to-side neurorrhaphy was performed; and group C was without neurorrhaphy as the control group. Five months later, visual functional assessment of sciatic nerves was performed to assess the statistic sciatic index (SSI). RESULTS: The surgical procedures caused an ipsilateral rehabilitation in groups A and B compared with the control group (p < 0.05). Although comparison of intermediate toe spread factor of distal-proximal nerve repair and distal nerve repair (DNR) was not statistically significant, toe spread factor and subsequently SSI comparisons showed significant statistical difference (p < 0.05). DISCUSSION: Contribution of proximal nerve stump to DNR improved functional recovery of motor neurons in an end-to-side cooptation method in rat lower extremity. Some of possible explanations for positive results could be the presence of more neuroattractive substances and use of donor nerve epineurium as a neuropermissive bridge for the regenerated axons.