Insights from a Multicenter Study on Adult H3 K27M-Mutated Glioma: Surgical Resection's Limited Influence on Overall Survival, ATRX as Molecular Prognosticator.

BACKGROUND: H3 K27M-mutated gliomas were first described as a new grade 4 entity in the 2016 WHO classification. Current studies have focused on its typical appearance in children and young adults, increasing the need to better understand the prognostic factors and impact of surgery on adults. Here, we report a multicentric study of this entity in adults. METHODS: We included molecularly confirmed H3 K27M-mutated glioma cases in patients >18 years diagnosed between 2016 and 2022. Clinical, radiological, and surgical features were analyzed. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Among 70 patients with a mean age of 36.1 years, the median overall survival (OS) was 13.6 + 14 months. Gross-total resection was achieved in 14.3% of patients, whereas 30% had a subtotal resection and 54.3% a biopsy.Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location in the mesencephalon/metencephalon showed a significantly longer OS (8.7 vs. 25.0 months, p=0.007). Preoperative Karnofsky Performance Score (KPS) < 80 showed a reduced OS (4.2 vs. 18 months, p=0.02). Furthermore, ATRX loss, found in 25.7%, was independently associated with an increased OS (31 vs. 8.3 months, p=0.0029). Notably, patients undergoing resection showed no survival benefit over biopsy (12 vs. 11 months, p=0.4006). CONCLUSION: The present study describes surgical features of H3 K27M-mutated glioma in adulthood in a large multicentric study. Our data reveal that ATRX status, location and KPS significantly impact OS in H3 K27M-mutated glioma. Importantly, our dataset indicates that resection does not offer a survival advantage over biopsy.

Chytrid infections exhibit historical spread and contemporary seasonality in a declining stream-breeding frog.

Species with extensive geographical ranges pose special challenges to assessing drivers of wildlife disease, necessitating collaborative and large-scale analyses. The imperilled foothill yellow-legged frog (Rana boylii) inhabits a wide geographical range and variable conditions in rivers of California and Oregon (USA), and is considered threatened by the pathogen Batrachochytrium dendrobatidis (Bd). To assess drivers of Bd infections over time and space, we compiled over 2000 datapoints from R. boylii museum specimens (collected 1897-2005) and field samples (2005-2021) spanning 9° of latitude. We observed a south-to-north spread of Bd detections beginning in the 1940s and increase in prevalence from the 1940s to 1970s, coinciding with extirpation from southern latitudes. We detected eight high-prevalence geographical clusters through time that span the species' geographical range. Field-sampled male R. boylii exhibited the highest prevalence, and juveniles sampled in autumn exhibited the highest loads. Bd infection risk was highest in lower elevation rain-dominated watersheds, and with cool temperatures and low stream-flow conditions at the end of the dry season. Through a holistic assessment of relationships between infection risk, geographical context and time, we identify the locations and time periods where Bd mitigation and monitoring will be critical for conservation of this imperilled species.

Mass producible, robust SERS substrates based on metal film on nanosphere (MFON) on an adhesive substrate for detection of surface-adsorbed molecules and their evaluation by helium ion microscopy.

We have developed a SERS stamp that can be pressed directly onto a solid surface for characterization of surface-adsorbed target molecules. The stamp was fabricated by transfer of a dense monolayer of SiO2 nanospheres from a glass surface onto a piece of adhesive tape and subsequent evaporation of silver. The performance of the resulting SERS stamps was evaluated by their exposure to methyl mercaptan vapor, and immersion in rhodamine 6G and ferbam solutions. It was found that beside the nanosphere diameter and metal deposition thickness, the extent of burial of the nanospheres into the adhesive tape, dictated by the pressure during the nanosphere transfer process, had a significant effect. We carried out FDTD calculations of the near field. Models are based on morphological information obtained from helium ion microscopy, which can provide high-resolution images of poor electrical conductors such as our SERS stamp. While one of our main eventual goals is detection of pesticides on agricultural produce, we have begun to take a careful step by testing our SERS stamp on better characterized surfaces such as a porous gel surface, having been immersed in fungicides such as ferbam. We also present our preliminary results with ferbam on oranges. It is expected that our well-characterized SERS stamp will play a role in shedding light on the poorly studied transfer process of target molecules onto a SERS surface as well as serving as a new SERS platform.

Experiences with a 3D4K Digital Exoscope System (ORBEYE) in a Wide Range of Neurosurgical Procedures.

BACKGROUND: Exoscopic 3D4K video systems (EX) have recently been introduced as an alternative to conventional operating microscopes (OM). However, experience in handling and setup remains scarce. This study evaluated the practicability of exoscopic surgery in a wide range of procedures. MATERIAL AND METHODS: All EX operations performed between August 2018 and May 2020 were evaluated and compared with procedures using OM. A standardized questionnaire was used to evaluate surgeons' comfort, image quality (including fluorescence modes), and handling. RESULTS: In all, 513 EX operations were performed during the investigated period. EX was generally rated as a valuable surgical tool. In particular, the digital 5-aminolevulinic acid (5-ALA) fluorescence and the comfort level of posture during surgery were stated to be superior to OM (100 and 83%, respectively). CONCLUSION: EX has been used for a significant number of neurosurgical procedures. While presuming that the technical methodology as such will not influence outcome of glioma surgery, proof of equipoise between different techniques expands the spectrum of surgical environments giving neurosurgeons a choice to work according to their preferred ergonomics.

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

Modulation of specific components of sleep disturbances by simultaneous subthalamic and nigral stimulation in Parkinson's disease.

OBJECTIVE: To compare the effect of simultaneous deep brain stimulation of the subthalamic nucleus and substantia nigra pars reticulata (STN+SNr-DBS) to conventional subthalamic stimulation (STN-DBS) on sleep quality in Parkinson's disease (PD) patients. METHODS: The study was a single-center, randomized, double-blind, cross-over clinical trial to compare the effect of STN-DBS vs. combined STN+SNr-DBS on subjective measures of sleep quality. Fifteen PD patients (2 female, age 62.5 ± 6.7 years) suffering from moderate idiopathic PD (disease duration: 12.0 ± 5.0 years, Hoehn & Yahr stage: 2.2 ± 0.4 in the MED-ON & STN-DBS-ON condition, Hoehn & Yahr stage: 2.6 ± 0.8 in the MED-OFF condition preoperatively) participated in the study. Sleep quality was evaluated in both stimulation conditions using the PDSS-2 score as a self-rating questionnaire covering several aspects of sleep disturbances. RESULTS: PD patients showed mild-moderate sleep disturbances (STN-DBS: PDSS-2 score 17.0 ± 11.0; STN+SNr-DBS: 14.7 ± 9.5) with slight but not significant differences between both stimulation conditions. Considering the different subitems of the PDSS-2, combined STN+SNr stimulation was superior to conventional STN stimulation in improving restless legs symptoms (RLS) at night (STN-DBS = 1.9 ± 2.7 STN+SNr-DBS = 1.0 ± 1.8; W = -2.06, p = 0.039) and immobility at night (STN-DBS = 1.5 ± 1.4 STN+SNr-DBS = 0.6 ± 0.8; W = -2.041, p = 0.041). CONCLUSION: This study demonstrates the safety of STN+SNr-DBS compared to conventional STN-DBS on sleep in general with potential beneficial input on RLS symptoms and akinesia at night.

Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients.

The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson's disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson's disease (1 female; age: 61.3 ± 7.3 years; disease duration: 12.3 ± 5.4 years; Hoehn and Yahr stage: 2.2 ± 0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and Parkinson's Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended.

Impact of dexamethasone in patients with aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: The role of corticosteroids in the treatment of patients with aneurysmal subarachnoid haemorrhage (SAH) has remained controversial for decades. Recent studies have suggested that the administration of corticosteroids in SAH patients is associated with favourable outcomes. Given their significant adverse effects, it is essential to identify those patients who will benefit from treatment with corticosteroids. METHODS: A retrospective analysis of a prospectively collected cohort (n = 306) with SAH who were treated by microsurgical clipping or endovascular intervention was performed. The role of dexamethasone administration was analysed with regard to clinical conditions and SAH-related complications. Outcome was assessed at discharge and during follow-up using the Glasgow Outcome Scale (GOS). RESULTS: Patients treated with dexamethasone presented with more episodes of hyperglycaemia (P < 0.001), more overall infections (P < 0.001) and more ventriculostomy-related infections (P = 0.004). Multivariate analysis demonstrated that treatment with dexamethasone was associated with an unfavourable outcome at discharge (GOS 1-3) [odds ratio (OR) 2.814, 95% confidence interval (CI) 1.440-5.497, P = 0.002]. In the subgroup of microsurgically treated patients, dexamethasone administration was associated with a favourable outcome at follow-up (OR 0.193, 95% CI 0.06-0.621, P = 0.006). A higher risk for unfavourable outcome (OR 3.382, 95% CI 1.67-6.849, P = 0.001) at discharge was observed in endovascularly treated patients who received dexamethasone but this had no impact on the outcome at follow-up. CONCLUSIONS: Treatment with dexamethasone seems to be associated with a risk reduction for an unfavourable outcome in those patients who underwent microsurgical clipping. Despite an increased frequency of adverse effects, glucocorticoids may have a potential benefit in this specific surgical subgroup compared to endovascularly treated SAH patients.

Surgical management of pituitary metastases.

BACKGROUND: Pituitary metastases are rare and commonly described in case reports or small case series. Due to its rarity this entity is not subject to standardized treatment guidelines, there is debate about typical initial symptoms that may lead to finding the correct diagnosis and information about the clinical course is also sparse. METHODS: We have conducted a retrospective analysis of patients with pituitary metastases who were surgically treated via a transsphenoidal procedure at our institution between 2006 and 2014. Underlying primary disease, clinical and surgical course as well as adjuvant radiotherapy and follow-up data are presented. RESULTS: 14 patients met the inclusion criteria (8 female, 6 male). Mean age was 61.5 years. Most patients became symptomatic with visual symptoms--both visual deterioration and/or diplopia (n = 13)--and anterior lobe insufficiency (n = 8). Surprisingly diabetes insipidus was only seen in three patients. All patients underwent transsphenoidal surgery initially, four patients had to undergo surgery for residual tumor or recurrence, two of them via a transcranial route. Breast cancer was the most common entity (n = 6), followed by prostate cancer (n = 3), nsclc (n = 2) and melanoma, thyroid cancer and renal cancer in one case each. Postoperative MRI showed gross total resection in four cases and residual disease in eight cases (subtotal resection, partial resection and biopsy), two patients files were incomplete regarding MRI-results. All patients underwent adjuvant radiotherapy. Survival after the initial diagnosis of cancer was 36 and 16 months after diagnosis of pituitary metastases. CONCLUSION: Our results indicate that transsphenoidal surgery is a safe method to resect pituitary metastases and that the extend of resection does not have an influence on survival time. Our results also indicate that diabetes insipidus may not be the most common initial symptom of pituitary metastases and lack thereof should not lead to making a wrong diagnosis and delaying appropriate therapy.

Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus.

Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory-motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing.

Subthalamic deep brain stimulation improves auditory sensory gating deficit in Parkinson's disease.

OBJECTIVE: While motor effects of dopaminergic medication and subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients are well explored, their effects on sensory processing are less well understood. Here, we studied the impact of levodopa and STN-DBS on auditory processing. METHODS: Rhythmic auditory stimulation (RAS) was presented at frequencies between 1 and 6Hz in a passive listening paradigm. High-density EEG-recordings were obtained before (levodopa ON/OFF) and 5months following STN-surgery (ON/OFF STN-DBS). We compared auditory evoked potentials (AEPs) elicited by RAS in 12 PD patients to those in age-matched controls. Tempo-dependent amplitude suppression of the auditory P1/N1-complex was used as an indicator of auditory gating. RESULTS: Parkinsonian patients showed significantly larger AEP-amplitudes (P1, N1) and longer AEP-latencies (N1) compared to controls. Neither interruption of dopaminergic medication nor of STN-DBS had an immediate effect on these AEPs. However, chronic STN-DBS had a significant effect on abnormal auditory gating characteristics of parkinsonian patients and restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. CONCLUSIONS: This differential treatment effect suggests a divergent mode of action of levodopa and STN-DBS on auditory processing. SIGNIFICANCE: STN-DBS may improve early attentive filtering processes of redundant auditory stimuli, possibly at the level of the frontal cortex.

Long-term follow-up and quality of life in patients with intracranial germinoma.

Intracranial germinomas are fairly rare tumors occurring mostly in children or young adults with a comparatively good prognosis. Radiation is the preferred treatment of choice for this diagnosis. It has been thoroughly studied to what extent radiation doses and fields can be limited in order to avoid side effects in these young patients. The role of chemotherapy remains unclear, whereas surgery is limited to biopsy for proof of histology. Regarding the good overall survival rate, quality of life is a significant aspect to consider in these patients. We present a single institution analysis of patients with intracranial germinoma and analyze the long-term outcome with special regard to quality of life. Thirty-three patients with intracranial germinomas were analyzed by chart review, telephone interview, and neurological assessment. Additionally, a survey on quality of life was performed. The 10-year overall survival rate was 82.1 % at a mean follow-up of 141 (22-306) months. Three quarters (76 %) of the patients reached a favorable neurological outcome on the Modified Rankin Scale (mRS 0-2). However, the self-reported quality of life was significantly worse in germinoma patients compared with a healthy control group (p < 0.001). Surgical resection of the tumor led to no improvement regarding overall survival, neurological outcome, and quality of life. In terms of cognitive functioning, patients with tumor resection were significantly more impaired than biopsied patients (p = 0.04). Although germinomas are efficiently treatable tumors, the restrictions in quality of life in these often young patients are considerable, including financial difficulties. There seems no justification for tumor resection in newly diagnosed cases suspicious for germinoma as the cognitive outcome is worse than in biopsied patients, and there is no effect on overall survival.

NDRG1 prognosticates the natural course of disease in WHO grade II glioma.

There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.

Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy.

BACKGROUND: This prospective multicenter study assessed the prognostic influence of the extent of resection when compared with biopsy only in a contemporary patient population with newly diagnosed glioblastoma. PATIENTS AND METHODS: Histology, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and clinical data were centrally analyzed. Survival analyses were carried out with the Kaplan-Meier method. Prognostic factors were assessed with proportional hazard models. RESULTS: Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31). CONCLUSIONS: The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy.

MGMT promoter methylation status and prognosis of patients with primary or recurrent glioblastoma treated with carmustine wafers.

The prognostic role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma patients treated with carmustine (BCNU) wafer implantation is unclear. Here, we report on a retrospective study of 47 patients with either newly diagnosed (30 patients) or recurrent (17 patients) glioblastoma (WHO grade IV) treated with BCNU (bis-chloroethylnitrosourea) wafers. Thirteen of the newly diagnosed patients received local BCNU and irradiation only (first-line BCNU), while 17 patients additionally received concomitant and adjuvant temozolomide (TMZ) radiochemotherapy (first-line BCNU + TMZ). Of the 17 patients treated for recurrent glioblastoma (second-line BCNU), 16 had received radiotherapy with concomitant and adjuvant TMZ as an initial treatment. Median overall survival (OS) did not significantly differ between 19 patients with MGMT promoter methylated tumors when compared to 28 patients with unmethylated tumors (18.9 vs 15.0 months; p = 0.1054). In the first-line BCNU + TMZ group, MGMT promoter methylation was associated with longer OS (21.0 vs 11.1 months, p = 0.0127), while no significant survival differences were detected in the other two subgroups. Progression-free survival did not significantly differ between patients with and without MGMT promoter methylated tumors in the entire patient cohort or any of the three subgroups. The first-line BCNU + TMZ group showed no significant difference in OS when compared to the first-line BCNU group (18.9 vs 14.7 months), but tended to have more therapy-related adverse effects (53% vs 24%, p = 0.105). In summary, MGMT promoter methylation showed a non-significant trend toward longer survival in our patient cohort. The combination of TMZ radiochemotherapy with local delivery of BCNU did not provide a significant survival benefit compared to local BCNU alone, but was associated with a higher rate of adverse effects. Owing to the small number of patients investigated, however, these findings would need to be corroborated in larger patient cohorts.

The combination of carmustine wafers and temozolomide for the treatment of malignant gliomas. A comprehensive review of the rationale and clinical experience.

Current treatment strategies in patients with newly-diagnosed glioblastoma include surgical resection with post-operative radiotherapy and concomitant/adjuvant temozolomide (the "Stupp protocol") or resection with implantation of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafers in the surgical cavity followed by radiotherapy. In clinical practice, patients with malignant glioma treated with BCNU wafer often also receive adjuvant temozolomide. However, current treatment guidelines are unclear on whether and how these treatment practices can be combined, and no prospective phase 3 study has assessed the safety and efficacy of combining BCNU wafers with temozolomide and radiation in high-grade malignant glioma. The rationale for multimodal therapy comprising surgical resection with adjunct local BCNU wafers followed by radiotherapy and temozolomide is based on complementary and synergistic mechanisms of action between BCNU and temozolomide in preclinical studies; a shared primary resistance pathway, methylguanine-DNA methyltransferase (MGMT); and the opportunity to overcome resistance through MGMT depletion to boost cytotoxic activity. A comprehensive review of the literature identified 19 retrospective and prospective studies investigating the use of this multimodal strategy. Median overall survival in 14 studies of newly-diagnosed patients suggested a modest improvement versus resection followed by Stupp protocol or resection with BCNU wafers, with an acceptable and manageable safety profile.

Skeletal spread of an anaplastic astrocytoma (WHO grade III) and preservation of histopathological properties within metastases.

BACKGROUND: The incidence of extraneural metastases of glioma is low. Metastases occur at different sites and, infrequently, as diffuse bone marrow infiltration. Direct contact of a glioma with extrameningeal tissues might be a reason for extraneural metastases. However, the role of haematogenous spread remains unclear. METHODS: We report on a young patient who suffered from a left frontal anaplastic WHO grade III astrocytoma, which was treated with gross total resection and irradiation (60 Gy). No local relapse occurred during the following course, but a diffuse infiltration of the bone marrow was diagnosed 12 months after the initial diagnosis. The patient died 6 months later, as a result of hypercalcaemia and pancytopenia. The histopathological properties of the tumour and its bone metastases were analysed, as well as the mutations of the isocitrate dehydrogenase 1 gene (IDH1). To study the route of tumour dissemination, the peripheral blood of the patient was analysed for circulating tumour cells (CTCs). RESULTS: This study describes a rare case of an extraneurally metastasised WHO grade III anaplastic astrocytoma. The occurrence of bone marrow infiltration coinciding with the finding of a stable intracranial tumour is a notably unusual situation. The properties of the primary tumour were maintained within the metastases in our patient. No CTCs were found in the peripheral blood at one random time point after the diagnosis of bone metastases. CONCLUSIONS: Despite young patient age, a stable intracranial course with a single location and mutations in the IDH1 gene, the patient's overall survival was short at 18 months after diagnosis. This finding illustrates the therapeutic dilemma in patients with bone marrow involvement complicating the use of alkylating agents, such as temozolomide. Repeated and systematic blood sampling in a large cohort of patients is needed for the detection of CTCs in glioma patients with systemic tumour spread. Future studies investigating how intrinsic factors in glioma cell biology cause rare metastases in these tumours are needed.

Efficacy and safety of 10% HES 130/0.4 versus 10% HES 200/0.5 for plasma volume expansion in cardiac surgery patients.

AIM: Hydroxyethyl starch (HES) solutions are frequently used for perioperative volume replacement. Whereas older HES specimen tended to accumulate in the plasma and to cause negative effects on hemostasis, more recent products, e.g., HES 130/0.4, are characterised by improved pharmacological properties. The present study was designed to compare the efficacy and safety of 10% HES 130/0.4 and 10% HES 200/0.5. METHODS: In this post-hoc analysis of a prospective, randomised, double-blind, multi-center therapeutic equivalence trial, 76 patients undergoing elective on-pump cardiac surgery received perioperative volume replacement using either 10% HES 130/0.4 (N.=37) or 10% HES 200/0.5 (N.=39) up to a maximum dose of 20 mL kg-1. RESULTS: Equivalent volumes of investigational medication were infused until 24 hours after the first administration (1577 vs. 1540 mL; treatment difference 37 [-150; 223] mL; P<0.0001 for equivalence). Whereas standard laboratory tests of coagulation were comparable between groups, von Willebrand factor activity on the first postoperative morning tended to be higher following treatment with 10% HES 130/0.4 as compared to 10% HES 200/0.5 (P=0.025) with this difference being statistically significant only in the per-protocol analysis (P=0.02). Treatment groups were comparable concerning other safety parameters and the incidence of adverse drug reactions. In particular, renal function was well preserved in both groups. CONCLUSION: Ten percent HES 130/0.4 was equally effective and safe as compared to 10% HES 200/0.5 for volume therapy in patients undergoing cardiovascular surgery. Postoperative coagulation and renal function, as measured by standard laboratory tests, were similar among groups.

A hematogenous spread brain abscess invading the right damaged temporomandibular joint.

We report a rare case of a brain abscess which drained spontaneously in a temporomandibular joint damaged by osteoarthritis. The female patient presented to our hospital with a severe headache and pain in the temporomandibular joint. She showed elevated inflammatory parameters with unknown cause. Magnetic resonance imaging of her whole body revealed a large temporal brain abscess extending into the glenoid fossa of the temporomandibular joint. The brain abscess was incised and drained by neurosurgeons in our hospital and in the same operation we resected the articular disc and the affected part of the right temporomandibular joint. Histological examination confirmed a chronic arthrosis in the resected bone of the temporomandibular joint and an inflammatory abscess in the resected brain tissue. The patient recovered well and the inflammation resolved as seen in postoperative investigations. Magnetic resonance imaging a month later confirmed local consolidation in the brain with no sign of residual inflammation.