Multiple formin proteins participate in glioblastoma migration.

BACKGROUND: The prognosis of glioblastoma remains poor, related to its diffuse spread within the brain. There is an ongoing search for molecular regulators of this particularly invasive behavior. One approach is to look for actin regulating proteins that might be targeted by future anti-cancer therapy. The formin family of proteins orchestrates rearrangement of the actin cytoskeleton in multiple cellular processes. Recently, the formin proteins mDia1 and mDia2 were shown to be expressed in glioblastoma in vitro, and their function could be modified by small molecule agonists. This finding implies that the formins could be future therapeutic targets in glioblastoma. METHODS: In cell studies, we investigated the changes in expression of the 15 human formins in primary glioblastoma cells and commercially available glioblastoma cell lines during differentiation from spheroids to migrating cells using transcriptomic analysis and qRT-PCR. siRNA mediated knockdown of selected formins was performed to investigate whether their expression affects glioblastoma migration. Using immunohistochemistry, we studied the expression of two formins, FHOD1 and INF2, in tissue samples from 93 IDH-wildtype glioblastomas. Associated clinicopathological parameters and follow-up data were utilized to test whether formin expression correlates with survival or has prognostic value. RESULTS: We found that multiple formins were upregulated during migration. Knockdown of individual formins mDia1, mDia2, FHOD1 and INF2 significantly reduced migration in most studied cell lines. Among the studied formins, knockdown of INF2 generated the greatest reduction in motility in vitro. Using immunohistochemistry, we demonstrated expression of formin proteins FHOD1 and INF2 in glioblastoma tissues. Importantly, we found that moderate/high expression of INF2 was associated with significantly impaired prognosis. CONCLUSIONS: Formins FHOD1 and INF2 participate in glioblastoma cell migration. Moderate/high expression of INF2 in glioblastoma tissue is associated with worse outcome. Taken together, our in vitro and tissue studies suggest a pivotal role for INF2 in glioblastoma. When specific inhibiting compounds become available, INF2 could be a target in the search for novel glioblastoma therapies.

Sleep of professional athletes: Underexploited potential to improve health and performance.

Sleep disorders have become increasingly prevalent affecting health and working ability. Restorative sleep may be considered important for athletes' successful recovery and performance. However, some athletes seem to experience major problems in sleeping. Thus far, there is limited scientific information about their sleep. This study aimed to evaluate the quality of sleep and the prevalence of sleep disorders as well as the impact of a structured sleep counselling protocol in professional athletes. A total of 107 professional ice hockey players participated in the study. The exploratory observational 1-year follow-up study consisted of questionnaire-based sleep assessment followed by general sleep counselling and, when needed, polysomnography and an individual treatment plan. One in every four players was found to have a significant problem in sleeping. All athletes considered sleep essential for their health and three in every four players considered that counselling would improve their performance. Counselling and individual treatment were found to improve significantly the quality of sleep with the mean alteration of 0.6 (95% CI 0.2-1.0, P = 0.004) in a scale from 0 to 10. Our results support that sleep problems are common in professional athletes. However, systematic examination, counselling and individual treatment planning can improve the quality of their sleep.

Caring communication - The impact of interpersonal communication between physician and patient. Can smileys measure the quality of communication?

The importance of communication in medical practice is widely recognized, but what is good communication in patient encounter? Feedback and surveys based on patient experience or "smileys" provide a narrow and often too insignificant view of communication. In addition to patient experience, communication benefits the information gathering by the physician and the patient, the patient's ability to promote his/her recovery, the physician's coping with workload, and the effectiveness of health care. In order to evaluate communication and improve it, one has to recognize the criteria and objectives of good communication. Medical communication that supports the rehabilitation of patients is reasonably good and responsible communication.

Serum levels of GFAP and EGFR in primary and recurrent high-grade gliomas: correlation to tumor volume, molecular markers, and progression-free survival.

Our aim was to study the association of two potential serum biomarkers glial fibrillary acidic protein (GFAP) and epidermal growth factor receptor (EGFR) with prognostic markers such as IDH1 mutation, tumor burden, and survival in patients with high-grade gliomas (HGG). Additionally, our objective was to evaluate the potential of serum EGFR as a surrogate marker for EGFR status in the tumor. Pre-operative serum samples were prospectively collected from patients with primary (n = 17) or recurrent (n = 10) HGG. Serum GFAP and EGFR levels were determined by ELISA and studied for correlation with molecular markers including EGFR amplification, tumor volume in contrast-enhanced T1-weighted MRI, and progression-free survival (PFS). Pre-operative serum GFAP level of ≥0.014 ng/ml was 86 % sensitive and 85 % specific for the diagnosis of glioblastoma. High GFAP was related to the lack of IDH1 mutation (P = 0.016), high Ki67 proliferation index (P < 0.001), and poor PFS (HR 5.9, CI 1.2-29.9, P = 0.032). Serum GFAP correlated with enhancing tumor volume in primary (r = 0.64 P = 0.005), but also in recurrent HGGs (r = 0.76 P = 0.011). In contrast, serum EGFR levels did not differ between HGG patients and 13 healthy controls, and were not related to EGFR status in the tumor. We conclude that high serum GFAP associates with IDH1 mutation-negative HGG, and poor PFS. Correlation with tumor burden in recurrent HGG implicates the potential of serum GFAP for detection of tumor recurrence. Our results suggest that circulating EGFR is not derived from glioma cells and cannot be used as a marker for EGFR status in the tumor.

Paediatric cranial defect reconstruction using bioactive fibre-reinforced composite implant: early outcomes.

BACKGROUND: In children, approximately half of cryopreserved allograft bone flaps fail due to infection and resorption. Synthetic materials offer a solution for allograft bone flap resorption. Fibre-reinforced composite with a bioactive glass particulate filling is a new synthetic material for bone reconstruction. Bioactive glass is capable of chemically bonding with bone and is osteoinductive, osteoconductive and bacteriostatic. Fibre-reinforced composite allows for fabricating thin (0.8 mm) margins for implant, which are designed as onlays on the existing bone. Bioactive glass is dissolved over time, whereas the fibre-reinforced composite serves as a biostable part of the implant, and these have been tested in preclinical and adult clinical trials. In this study, we tested the safety and other required properties of this composite material in large skull bone reconstruction with children. METHOD: Eight cranioplasties were performed on seven patients, aged 2.5-16 years and having large (>16 cm(2)) skull bone defects. The implant used in this study was a patient-specific, glass-fibre-reinforced composite, which contained a bioactive glass particulate compound, S53P4. RESULTS: During follow-up (average 35.1 months), one minor complication was observed and three patients needed revision surgery. Two surgical site infections were observed. After treatment of complications, a good functional and cosmetic outcome was observed in all patients. The implants had an onlay design and fitted the defect well. In clinical and imaging examinations, the implants were in the original position with no signs of implant migration, degradation or mechanical breakage. CONCLUSIONS: Here, we found that early cranioplasty outcomes with the fibre-reinforced composite implant were promising. However, a longer follow-up time and a larger group of patients are needed to draw firmer conclusions regarding the long-term benefits of the proposed novel biomaterial and implant design. The glass-fibre-reinforced composite implant incorporated by particles of bioactive glass may offer an original, non-metallic and bioactive alternative for reconstruction of large skull bone defects in a paediatric population.

Superspreading of SARS-CoV-2 at a choir rehearsal in Finland-A computational fluid dynamics view on aerosol transmission and patient interviews.

INTRODUCTION: COVID-19 pandemic has highlighted the role of aerosol transmission and the importance of superspreading events. We analyzed a choir rehearsal in November 2020, where all participants, except one who had recently earlier recovered from COVID-19, were infected. We explore the risk factors for severe disease in this event and model the aerosol dispersion in the rehearsal room. MATERIALS AND METHODS: Characteristics of participants were collected by interviews and supplemented with patient records. A computational simulation of aerosol distribution in the rehearsal room and the efficacy of potential safety measures was conducted using the Large-Eddy Simulation approach. Infection risk was studied by analyzing quanta emission and exposure with the Wells-Riley equation. RESULTS: The simulation showed that airborne transmission likely explains this mass contagion event. Every singer was exposed to the virus in only 5 min from the beginning of the rehearsal, and maximum concentration levels were reached at 20 min the concentration levels started to approach a steady state after 20 min. Although concentration differences existed in the room, risk levels near (1 m) and far (5 m) from the aerosol source were similar for certain singers. Modeling indicated infection risk levels of 70-100% after one hour; the risk would have been considerably reduced by wearing high-filtration respirators. Age and pre-existing comorbidities predicted more severe disease. The high incidence of illness may be partly attributed to the relatively high median age of individuals. Additionally, those admitted to the hospital had multiple underlying health conditions that predispose them to more severe disease. CONCLUSIONS: Airborne transmission and indoor space can explain this mass exposure event. High-filtration respirators could have prevented some infections. The importance of safety distances diminishes the longer the indoor event. The concept of safety distance is challenging, as our study suggests that long range airborne transmission may occur in indoor events with extended duration. We encourage informing the public, especially persons at risk, of safety measures during epidemics.

Hyperspectral image reconstruction from colored natural flame luminosity imaging in a tri-fuel optical engine.

The detection of chemiluminescence from various radicals and molecules in a hydrocarbon flame can provide valuable information on the rate of local heat release, combustion stability, and combustion completeness. In this study, chemiluminescence from the combustion process is detected using a high-speed color camera within the broadband spectrum of visible light. Whereon, a novel hyperspectral reconstruction approach based on the physically plausible spectral reconstruction (PPSR) is employed to reconstruct the spectral chemiluminescence signals from 400 to 700 nm with a resolution of 10 nm to provide 31 different spectral channels. The reconstructed key chemiluminescence signals (e.g., CH*, CH2O*, C2*, and CO2*) from the color images are further analyzed to characterize the chemical kinetics and combustion processes under engine conditions. The spectral chemiluminescence evolution with engine crank angle is identified to comprehend the effect of H2 fraction on flame characteristics and combustion kinetics. Additionally, in this study, a detailed kinetic mechanism is adopted to deepen the theoretical understanding and describe the spectral chemiluminescence from H2/CH4 and H2/CH4/n-dodecane flames at relevant conditions for various species including OH*, CH*, C2*, and CO2*. The results indicate that the PPSR is an adequately reliable approach to reconstructing spectral wavelengths based on chemiluminescence signals from the color images, which can potentially provide qualitative information about the evolution of various species during combustion. Here, the reconstructed chemiluminescence images show less than 1% errors compared to the raw images in red, green, and blue channels. Furthermore, the reconstructed chemiluminescence trends of CH*, CH2O*, C2*, and CO2* show a good agreement with the detailed kinetics 0D simulation.

Motor dysfunction as a primary symptom predicts poor outcome: multicenter study of glioma symptoms.

Background and objectives: The objectives of this study were to investigate the prognostic value of primary symptoms and leading symptoms in adult patients with diffuse infiltrating glioma and to provide a clinical perspective for evaluating survival. Methods: This study included a retrospective cohort from two tertiary university hospitals (n = 604, 2006-2013, Tampere University Hospital and Turku University Hospital) and a prospective cohort (n = 156, 2014-2018, Tampere University Hospital). Preoperative symptoms were divided into primary and leading symptoms. Results were validated with the newer WHO 2021 classification criteria. Results: The most common primary symptoms were epileptic seizure (30.8% retrospective, 28.2% prospective), cognitive disorder (13.2% retrospective, 16.0% prospective), headache (8.6% retrospective, 12.8% prospective), and motor paresis (7.0% retrospective, 7.1% prospective). Symptoms that predicted better survival were epileptic seizure and visual or other sense-affecting symptom in the retrospective cohort and epileptic seizure and headache in the prospective cohort. Predictors of poor survival were cognitive disorder, motor dysfunction, sensory symptom, tumor hemorrhage, speech disorder and dizziness in the retrospective cohort and cognitive disorder, motor dysfunction, sensory symptom, and dizziness in the prospective cohort. Motor dysfunction served as an independent predictor of survival in a multivariate model (OR = 1.636). Conclusion: Primary and leading symptoms in diffuse gliomas are associated with prognoses in retrospective and prospective settings. Motor paresis was an independent prognostic factor for poor survival in multivariate analysis for grade 2-4 diffuse gliomas, especially in glioblastomas.

Novel composite implant in craniofacial bone reconstruction.

Bioactive glass (BAG) and polymethyl methacrylate (PMMA) have been used in clinical applications. Antimicrobial BAG has the ability to attach chemically to surrounding bone, but it is not possible to bend, drill or shape BAG during the operation. PMMA has advantages in terms of shaping during the operation, but it does not attach chemically to the bone and is an exothermic material. To increase the usefulness of BAG and PMMA in skull bone defect reconstructions, a new composite implant containing BAG and PMMA in craniofacial reconstructions is presented. Three patients had pre-existing large defects in the calvarial and one in the midface area. An additive manufacturing (AM) model was used preoperatively for treatment planning and custom-made implant production. The trunk of the PMMA implant was coated with BAG granules. Clinical and radiological follow-up was performed postoperatively at 1 week, and 3, 6 and 12 months, and thereafter annually up to 5 years. Computer tomography (CT) and positron emission tomography (PET-CT) were performed at 12 and 24 months postoperatively. Uneventful clinical recovery with good esthetic and functional outcome was seen. CT and PET-CT findings supported good clinical outcome. The BAG-PMMA implant seems to be a promising craniofacial reconstruction alternative. However, more clinical experience is needed.

Modelling aerosol-based exposure to SARS-CoV-2 by an agent based Monte Carlo method: Risk estimates in a shop and bar.

Present day risk assessment on the spreading of airborne viruses is often based on the classical Wells-Riley model assuming immediate mixing of the aerosol into the studied environment. Here, we improve on this approach and the underlying assumptions by modeling the space-time dependency of the aerosol concentration via a transport equation with a dynamic source term introduced by the infected individual(s). In the present agent-based methodology, we study the viral aerosol inhalation exposure risk in two scenarios including a low/high risk scenario of a "supermarket"/"bar". The model takes into account typical behavioral patterns for determining the rules of motion for the agents. We solve a diffusion model for aerosol concentration in the prescribed environments in order to account for local exposure to aerosol inhalation. We assess the infection risk using the Wells-Riley model formula using a space-time dependent aerosol concentration. The results are compared against the classical Wells-Riley model. The results indicate features that explain individual cases of high risk with repeated sampling of a heterogeneous environment occupied by non-equilibrium concentration clouds. An example is the relative frequency of cases that might be called superspreading events depending on the model parameters. A simple interpretation is that averages of infection risk are often misleading. They also point out and explain the qualitative and quantitative difference between the two cases-shopping is typically safer for a single individual person.

Modelling aerosol transport and virus exposure with numerical simulations in relation to SARS-CoV-2 transmission by inhalation indoors.

We provide research findings on the physics of aerosol and droplet dispersion relevant to the hypothesized aerosol transmission of SARS-CoV-2 during the current pandemic. We utilize physics-based modeling at different levels of complexity, along with previous literature on coronaviruses, to investigate the possibility of airborne transmission. The previous literature, our 0D-3D simulations by various physics-based models, and theoretical calculations, indicate that the typical size range of speech and cough originated droplets ( d ⩽ 20 µ m ) allows lingering in the air for O ( 1 h ) so that they could be inhaled. Consistent with the previous literature, numerical evidence on the rapid drying process of even large droplets, up to sizes O ( 100 µ m ) , into droplet nuclei/aerosols is provided. Based on the literature and the public media sources, we provide evidence that the individuals, who have been tested positive on COVID-19, could have been exposed to aerosols/droplet nuclei by inhaling them in significant numbers e.g. O ( 100 ) . By 3D scale-resolving computational fluid dynamics (CFD) simulations, we give various examples on the transport and dilution of aerosols ( d ⩽ 20 µ m ) over distances O ( 10 m ) in generic environments. We study susceptible and infected individuals in generic public places by Monte-Carlo modelling. The developed model takes into account the locally varying aerosol concentration levels which the susceptible accumulate via inhalation. The introduced concept, 'exposure time' to virus containing aerosols is proposed to complement the traditional 'safety distance' thinking. We show that the exposure time to inhale O ( 100 ) aerosols could range from O ( 1 s ) to O ( 1 min ) or even to O ( 1 h ) depending on the situation. The Monte-Carlo simulations, along with the theory, provide clear quantitative insight to the exposure time in different public indoor environments.

Cranioplasty After Severe Traumatic Brain Injury: Effects of Trauma and Patient Recovery on Cranioplasty Outcome.

BACKGROUND: In patients with severe traumatic brain injury (sTBI) treated with decompressive craniectomy (DC), factors affecting the success of later cranioplasty are poorly known. OBJECTIVE: We sought to investigate if injury- and treatment-related factors, and state of recovery could predict the risk of major complications in cranioplasty requiring implant removal, and how these complications affect the outcome. METHODS: A retrospective cohort of 40 patients with DC following sTBI and subsequent cranioplasty was studied. Non-injury-related factors were compared with a reference population of 115 patients with DC due to other conditions. RESULTS: Outcome assessed 1 day before cranioplasty did not predict major complications leading to implant removal. Successful cranioplasty was associated with better outcome, whereas a major complication attenuates patient recovery: in patients with favorable outcome assessed 1 year after cranioplasty, major complication rate was 7%, while in patients with unfavorable outcome the rate was 42% (p = 0.003). Of patients with traumatic subarachnoid hemorrhage (tSAH) on admission imaging 30% developed a major complication, while none of patients without tSAH had a major complication (p = 0.014). Other imaging findings, age, admission Glasgow Coma Scale, extracranial injuries, length of stay at intensive care unit, cranioplasty materials, and timing of cranioplasty were not associated with major complications. CONCLUSION: A successful cranioplasty after sTBI and DC predicts favorable outcome 1 year after cranioplasty, while stage of recovery before cranioplasty does not predict cranioplasty success or failure. tSAH on admission imaging is a major risk factor for a major complication leading to implant removal.

Somatostatin receptor 2A in gliomas: Association with oligodendrogliomas and favourable outcome.

Somatostatin receptor subtype 2A (SSTR2A) is a potential therapeutic target in gliomas. Data on SSTR2A expression in different glioma entities, however, is particularly conflicting. Our objective was to characterize SSTR2A status and explore its impact on survival in gliomas classified according to the specific molecular signatures of the updated WHO classification. In total, 184 glioma samples were retrospectively analyzed for SSTR2A expression using immunohistochemistry with monoclonal antibody UMB-1. Double staining with CD68 was used to exclude microglia and macrophages from analyses. SSTR2A staining intensity and its localization in tumor cells was evaluated and correlated with glioma entities and survival. Diagnoses included 101 glioblastomas (93 isocitrate dehydrogenase (IDH) -wildtype, 3 IDH-mutant, 5 not otherwise specified (NOS)), 60 astrocytomas (22 IDH-wildtype, 37 IDH-mutant, 1 NOS), and 23 oligodendrogliomas (19 IDH-mutant and 1p/19q-codeleted, 4 NOS). SSTR2A expression significantly associated with oligodendrogliomas (79% SSTR2A positive) compared to IDH-mutant or IDH-wildtype astrocytomas (27% and 23% SSTR2A positive, respectively), and especially glioblastomas of which only 13% were SSTR2A positive (p < 0.001, Fisher's exact test). The staining pattern in glioblastomas was patchy whereas more homogeneous membranous and cytoplasmic staining was detected in oligodendrogliomas. Positive SSTR2A was related to longer overall survival in grade II and III gliomas (HR 2.7, CI 1.2-5.8, p = 0.013). In conclusion, SSTR2A expression is infrequent in astrocytomas and negative in the majority of glioblastomas where it is of no prognostic significance. In contrast, oligodendrogliomas show intense membranous and cytoplasmic SSTR2A expression, which carries potential diagnostic, prognostic, and therapeutic value.

Host-parasite models on graphs.

The behavior of two interacting populations "hosts" and "parasites" is investigated on Cayley trees and scale-free networks. In the former case analytical and numerical arguments elucidate a phase diagram for the susceptible-infected-susceptible model, whose most interesting feature is the absence of a tricritical point as a function of the two independent spreading parameters. For scale-free graphs, the parasite population can be described effectively by its dynamics in a host background. This is shown both by considering the appropriate dynamical equations and by numerical simulations on Barabási-Albert networks with the major implication that in the thermodynamic limit the critical parasite spreading parameter vanishes. Some implications and generalizations are discussed.

A glass fiber-reinforced composite - bioactive glass cranioplasty implant: A case study of an early development stage implant removed due to a late infection.

This case study describes the properties of an early development stage bioactive glass containing fiber-reinforced composite calvarial implant with histology that has been in function for two years and three months. The patient is a 33-year old woman with a history of substance abuse, who sustained a severe traumatic brain injury later unsuccessfully treated with an autologous bone flap and a custom-made porous polyethylene implant. She was thereafter treated with developmental stage glass fiber-reinforced composite - bioactive glass implant. After two years and three months, the implant was removed due to an implant site infection. The implant was analyzed histologically, mechanically, and in terms of chemistry and dissolution of bioactive glass. Mechanical integrity of the load bearing fiber-reinforced composite part of the implant was not affected by the in vivo period. Bioactive glass particles demonstrated surface layers of hydroxyapatite like mineral and dissolution, and related increase of pH was considerably less after two and three months period than that for fresh bioactive glass. There was a difference in the histology of the tissues inside the implant areas near to the margin of the implant that absorbed blood during implant installation surgery, showed fibrous tissue with blood vessels, osteoblasts, collagenous fibers with osteoid formation, and tiny clusters of more mature hard tissue. In the center of the implant, where there was less absorbed blood, only fibrous tissue was observed. This finding is in line with the combined positron emission tomography - computed tomography examination with (18F)-fluoride marker, which demonstrated activity of the mineralizing bone by osteoblasts especially at the area near to the margin of the implant 10 months after implantation. Based on these promising reactions found in the bioactive glass containing fiber-reinforced composite implant that has been implanted for two years and three months, calvarial reconstruction with the presented material appears to be a feasible method.

Somatostatin receptor subtype 2 in high-grade gliomas: PET/CT with (68)Ga-DOTA-peptides, correlation to prognostic markers, and implications for targeted radiotherapy.

BACKGROUND: High-grade gliomas (HGGs) express somatostatin receptors (SSTR), rendering them candidates for peptide receptor radionuclide therapy (PRRT). Our purpose was to evaluate the potential of (68)Ga-DOTA-1-Nal(3)-octreotide ((68)Ga-DOTANOC) or (68)Ga-DOTA-Tyr(3)-octreotide ((68)Ga-DOTATOC) to target SSTR subtype 2 (SSTR2) in HGGs, and to study the association between SSTR2 expression and established biomarkers. METHODS: Twenty-seven patients (mean age 52 years) with primary or recurrent HGG prospectively underwent (68)Ga-DOTA-peptide positron emission tomography/computed tomography (PET/CT) before resection. Maximum standardized uptake values (SUVmax) and receptor binding potential (BP) were calculated on PET/CT and disruption of blood-brain barrier (BBB) from contrast-enhanced T1-weighted magnetic resonance imaging (MRI-T1-Gad). Tumor volume concordance between PET and MRI-T1-Gad was assessed by Dice similarity coefficient (DC) and correlation by Spearman's rank. Immunohistochemically determined SSTR2 status was compared to receptor imaging findings, prognostic biomarkers, and survival with Kruskal-Wallis, Pearson chi-square, and multivariate Cox regression, respectively. RESULTS: All 19 HGGs with disrupted BBB demonstrated tracer uptake. Tumor SUVmax (2.25 ± 1.33) correlated with MRI-T1-Gad (r = 0.713, P = 0.001) although DC 0.41 ± 0.19 suggested limited concordance. SSTR2 immunohistochemistry was regarded as positive in nine HGGs (32%) but no correlation with SUVmax or BP was found. By contrast, SSTR2 expression was associated with IDH1 mutation (P = 0.007), oligodendroglioma component (P = 0.010), lower grade (P = 0.005), absence of EGFR amplification (P = 0.021), and longer progression-free survival (HR 0.161, CI 0.037 to 0.704, P = 0.015). CONCLUSIONS: In HGGs, uptake of (68)Ga-DOTA-peptides is associated with disrupted BBB and cannot be predicted by SSTR2 immunohistochemistry. Thus, PET/CT shows limited value to detect HGGs suitable for PRRT. However, high SSTR2 expression portends favorable outcome along with established biomarkers such as IDH1 mutation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01460706.

Outcomes of cranioplasty with synthetic materials and autologous bone grafts.

OBJECTIVE: Using current surgical methods, cranioplasty is associated with a high complication rate. We analyzed if there are preexisting medical conditions associated with complications and compared the effect of different implant materials on the degree of complications. METHODS: A retrospective review of the medical records of all patients who underwent cranioplasty for cranial bone defects during the period 2002-2012 was conducted, and 100 consecutive cranioplasty procedures that met eligibility criteria were identified. Patients were analyzed in 4 groups, which were created based on the cranioplasty material: autograft (n = 20), bioactive fiber-reinforced composite (n = 20), hydroxyapatite (n = 31), and other synthetic materials (n = 29). Survival estimates were constructed with Kaplan-Meier curves, and the differences between categorical variable levels were determined using a log-rank test. Multiple comparisons were adjusted using a Sidák correction. RESULTS: During a median follow-up time of 14 months (interquartile range 3-39 months), 32 of 100 patients (32.0%) developed at least 1 complication. A minor complication occurred in 13 patients (13.0%), whereas 19 patients (19.0%) developed a major complication, which required reoperation or removal of the implant. In the autograft subgroup, 40.0% of patients required removal of the cranioplasty. The 3-year survival of the autograft subgroup was lower compared with other subgroups of synthetic materials. In hydroxyapatite and bioactive fiber-reinforced composite groups, fewer complications were observed compared with the autograft group. CONCLUSIONS: Based on these results, synthetic materials for cranial bone defect reconstruction exhibit more promising outcomes compared with autograft. There were differences in survival rates among synthetic materials.

Uptake of 4-borono-2-[18F]fluoro-L-phenylalanine in sporadic and neurofibromatosis 2-related schwannoma and meningioma studied with PET.

PURPOSE: Meningiomas and schwannomas associated with neurofibromatosis 2 (NF2) are difficult to control by microsurgery and stereotactic radiotherapy alone. Boron neutron capture therapy (BNCT) is a chemically targeted form of radiotherapy requiring increased concentration of boron-10 in tumour tissue. PET with the boron carrier 4-borono-2-[(18)F]fluoro-L-phenylalanine ([(18)F]FBPA) allows investigation of whether 4-borono-L-phenylalanine (BPA) concentrates in NF2 tumours, which would make BNCT feasible. METHODS: We studied dynamic uptake of [(18)F]FBPA in intracranial meningiomas (n=4) and schwannomas (n=6) of five sporadic and five NF2 patients. Tracer input function and cerebral blood volume were measured. [(18)F]FBPA uptake in tumour and brain was assessed with a three-compartmental model and graphical analysis. These, together with standardised uptake values (SUVs), were used to define tumour-to-brain [(18)F]FBPA tissue activity gradients. RESULTS: Model fits with three parameters K (1) (transport), k (2) (reverse transport) and k (3) (intracellular metabolism) were found to best illustrate [(18)F]FBPA uptake kinetics. Maximum SUV was two- to fourfold higher in tumour as compared with normal brain and independent of NF2 status. The increased uptake was due to higher transport of [(18)F]FBPA in tumour. In multiple-time graphical analysis (MTGA, Gjedde-Patlak plot) the tumour-to-brain [(18)F]FBPA influx constant (K (i) -MTGA) ratios varied between 1.8 and 5.4 in NF2-associated tumours while in sporadic tumours the ratio was 1-1.4. CONCLUSION: [(18)F]FBPA PET offers a viable means to evaluate BPA uptake in meningiomas and schwannomas in NF2. Based on our results on tumour uptake of [(18)F]FBPA, some of these benign neoplasms may be amenable to BNCT.

The effect of combined neurolytic blocking agent 5% phenol-glycerol in rat sciatic nerve.

Combined 5% phenol-glycerol has been used to treat cancer pain or spasticity and as sympathetic blocks. The major clinical problems have been the unpredictable effects on pain and on the duration of the blocks. Previously we have shown that intraneurally injected phenol induces haemorrhagic necrosis as well as dissolving of the nerve fibres. Glycerol, on the other hand, induces dispersion of nerve fibre debris into the endoneurium. We have now studied the effects of a combination of these two chemically different agents. The endoneurial and epineurial responses of rat peripheral nerve were followed after intraneural and perineural injections. Samples for electron microscopic and immunohistochemical studies were taken at 1-26 weeks after the injection. The intraneural phenol-glycerol injection resulted in gross endoneurial damage with partly or totally dissolved nerve fibres. Totally dissolved nerve fibres showed empty, collapsed basal lamina tubes and partly dissolved nerve fibres showed breaching of remaining degenerative debris into the endoneurial space. Axonal regeneration was delayed and was observed first after 2 weeks and it took 4 months before most of the nerve fibres were myelinated. The perineural injections resulted in partial subperineurial damage of the endoneurium morphologically similar to the results caused by the intraneural injection. An initial high accumulation of epineurial macrophages was noted at 1 and 2 weeks. An invasion of macrophages into the endoneurium occurred within 1 week after the intraneural and perineural injections and the number of endoneurial macrophages remained high for up to 6 months. The present study shows that glycerol added to phenol diminishes the necrotizing effect of phenol after an intraneural injection. Combined phenol-glycerol-induced nerve injury is reversible and the axons regenerate but residual morphological changes can be observed even after 6 months.

The perineurium modifies the effects of phenol and glycerol in rat sciatic nerve.

Endoneurial cell response and type of nerve fibre damage were studied after perineural injections of 7% phenol-aqua and pure glycerol. Our previous studies have shown that phenol and glycerol induce different types of nerve fibre degeneration after intraneural injections: phenol dissolves axons and Schwann cells inside the basal lamina tubes but glycerol breaks them down into cellular flakes. The current study investigated whether the difference in type of endoneurial damage also appears after perineural application and how the perineurium affects the effect of these neurolytic agents. Rat sciatic nerves were treated with perineural injections of 7% phenol-aqua or pure glycerol and were followed up to 6 months. The results support the previous findings that perineural phenol injection induces damage that covers almost the whole endoneurium, but glycerol injection results in minor subperineurial damage. An ultrastructural study showed that the endoneurial effects are much milder after perineural injection than after intraneural injections. Phenol-induced nerve fibre dissolving was only rarely seen and the nerve fibre damage appeared similar to that after regular Wallerian degeneration in both groups. Axonal regeneration began within 2 weeks of the injections. Endoneurial macrophages were numerous in the damaged area in many individual nerves even at 3-6 months in both groups, which may indicate impaired phagocytotic activity. Regenerating axonal sprouts were seen first at 1 week post injection and Schwann cells proliferated within 2 weeks in both groups. However, the number of axonal sprouts was higher (P=0.002) and the size of the sprouts appeared larger after glycerol injection at 4 weeks post injection. The present study shows that the effects of extraneurally applied neurolytic agents phenol and glycerol are modified by the perineurium. Phenol readily penetrates the perineurium, but glycerol causes only subperineurial damage. The type of damage is rather similar to regular Wallerian degeneration in both groups and the endoneurial effects differ from those seen after intraneural injections.