"Let's put it this way: you can't really live without it" - digital technologies in routine palliative care delivery: an explorative qualitative study with patients and their family caregivers in Germany.

BACKGROUND: Despite ongoing efforts to integrate palliative care into the German healthcare system, challenges persist, particularly in areas where infrastructure does not fully support digital technologies (DT). The increasing importance of digital technology (DT) in palliative care delivery presents both opportunities and challenges. OBJECTIVE: This study aimed to explore the perspectives and preferences of palliative care patients and their family caregivers regarding the use of DT in care delivery. METHODS: An exploratory qualitative study was conducted using semi-structured interviews with palliative care patients and their family caregivers across various settings. Participants were selected through gatekeeper-supported purposive sampling. Interviews were analysed using structured qualitative content analysis. RESULTS: Nineteen interviews were conducted.Three themes emerged: (1) Application of DTs in palliative care; (2) Potential of DTs; (3) Barriers to the use of DTs. Key findings highlighted the preference for real-time communication using DTs that participants are familiar with. Participants reported limited perceived value for digital transformation in the presence of in-person care. The study identified requirements for DT development and use in palliative care, including the need for direct and immediate functionality, efficiency in healthcare professional (HCP) work, and continuous access to services. CONCLUSION: The findings highlight a demonstrate the importance of familiarity with DTs and real-time access for patients and their families. While DT can enhance palliative care efficiency and accessibility, its integration must complement, not replace, in-person interaction in palliative care. As DTs continue to grow in scope and use in palliative care, maintaining continued user engagement is essential to optimise their adoption and ensure they benefit patients and their caregivers.

Would they do it again? Final treatment decisions in malignant brain tumour patients-a caregiver's perspective.

PURPOSE: Overall survival of malignant brain tumour patients has significantly been increased over the last years. However, therapy remains palliative, and side effects should be balanced. Once terminal phase is entered, both patients and caregivers may find it hard to accept, and further therapies are demanded. But little is known about this highly sensitive period. Therefore, we analysed the last therapy decisions from the family caregiver's perspective. Would they support their beloved ones in the same way or would they now recommend a different therapy decision? METHODS: Caregivers of deceased malignant brain tumour patients, treated at our neurooncological centre between 2011 and 2017, were included. We designed a questionnaire to analyse the impact of the last therapy decision (resection, chemotherapy, radiotherapy), focusing on probable repeat of the choice taken and general therapy satisfaction. Independent variables, for example "satisfaction with therapy", were analysed using linear regression analysis, the coefficient of determination R2 and the standardized regression coefficient ß. The binary logistic regression analyses were taken to illustrate relationships with the dichotomously scaled outcome parameter "re-choice of therapy". Odds ratio analyses were used to determine the strength of a relationship between two characteristics. RESULTS: Data from 102 caregivers (life partners (70.6%)) were analysed retrospectively. Each 40% of patients died in a hospice or at home (20% in a hospital). In 67.6% the last therapy was chemotherapy followed by radiotherapy (16.7%) and surgery (15.7%). A positive evaluation of the last therapy was significantly correlated to re-choosing of respective therapy (chemo-/radiotherapy: p = 0.000) and satisfaction with informed consent (p = 0.000). Satisfaction regarding interpersonal contact was significantly correlated to satisfaction with resection (p = 0.000) and chemotherapy (p = 0.000 27 caregivers (28.7%) felt overburdened with this situation). CONCLUSION: This analysis demonstrates a significant correlation between a positive relation of patient/caregiver/physician and the subjective perception of the latest therapy. It underlines the central role of caregivers, who should be involved in therapy discussions. Neurooncologists should be specially trained in communication and psycho-oncology.

Determination of optimal time window for cortical mapping in awake craniotomy: assessment of intraoperative reaction speed.

Currently, there is no known time frame when the patients are the most responsive during awake craniotomy. The aim of this work is therefore to determine when the patient has the shortest reaction time and so to extrapolate the optimal time window for cortical mapping. In this analytic observational study, our group has recorded the reaction times of 35 patients undergoing an awake craniotomy and compared them with the preoperative baseline. The operations were performed according to a "sleep-awake-awake" protocol. Data collection was performed in parallel with standard methods for evaluation of language and cognitive functions. The preoperative reaction times of our patient cohort (average ± SD = 510 ± 124 ms) were significantly shorter than those measured during the operation 786 ± 280 ms, p < .001. A one-factor ANOVA within subjects showed a significant increase in reaction times; p < .001. Post hoc comparisons on a Bonferroni-corrected α-error level of .05 showed significant differences between the reaction speed during the 0-10 min time frame and the preoperative baseline, as well as the intraoperative reaction times during the 20-30 min, 30-40 min, and the t > 40 min time frames. In conclusion, measurement of intraoperative reaction speed seems to be a technically feasible method that is well tolerated by the patients. The intraoperative reaction speed performance was shown to be significantly slower than on the day before the operation. The patients seem to be the slowest directly after extubation and gradually wake up during the awake phase. The poorest wakefulness is demonstrated during the first 20 min after extubation.

[Vagus Nerve Stimulation for Affective Disorders]. / Vagusnervstimulation bei affektiven Störungen.

Vagus nerve stimulation (VNS) is a minimally invasive neurostimulation method and was approved for drug-resistant epilepsy in children and adults in Europe in 1994. The observation that depression -the most common comorbidity in epilepsy - improved with VNS prompted trials of VNS in treatment-resistant depression (TRD) leading to European approval of VNS for TRD in 2001. Use of VNS for TRD patients in Germany is currently limited to a few highly specialized tertiary centers and the method is largely unknown in psychiatric clinical practice. We therefore systematically review the most recent publications on VNS in TRD as well as recommendations in guidelines and discuss the use of VNS in clinical practice. In the past 5 years, 5 level-2 studies and 4 level-3 studies were published on the effect of VNS in TRD patients. Clinical studies have failed to demonstrate short-term efficacy of VNS in TRD patients. Long-term efficacy of VNS in TRD patients is documented by multiple studies: the recently published largest ever investigation on the subject confirms favorable outcomes in TRD patients receiving adjunctive VNS in addition to treatment-as-usual compared to patients receiving treatment-as-usual-only over a 5-year period. Long-term efficacy of VNS is documented by level-2 evidence; however, it is not known which TRD patients have a higher probability of responding to VNS, which may complicate patient selection in clinical practice. Additionally, the unclear and variable definition of TRD may hinder or postpone adequate use of neurostimulation treatments.

Outcome following surgical treatment of chronic subdural hematoma in the oldest-old population.

As a result of the demographic shift in western societies, the mean age at presentation of patients suffering from chronic subdural hematomas (cSDH) is increasing. Therapeutic strategies, surgical and non-surgical, need to be reevaluated and adapted accordingly. Age is considered to be a positive risk factor for a higher perioperative morbidity and mortality. The purpose of this study is to determine if old age (≥85 years) should be seen as a contraindication for surgical treatment. Two groups (56 patients each) with cSDH over and below 85 years of age from a single neurosurgical department with well-defined surgical treatment guidelines were retrospectively analyzed. Clinical characteristics of the patients, localization, treatment, prior medication, and complications were compared. Outcome was measured by clinical improvement postoperatively and by the Glasgow Outcome Scale (GOS) at 1 month after surgery. Age ≥85 years was associated with higher GOS 1 month after surgery (p = 0.038). 51.8% (58) of all patients had a complete neurological recovery postoperatively, and 74% (43) of these patients were ≥85 years. Elderly patients suffered from a significantly higher complication rate (p < 0.001) with odds of having a complication 18.3 times higher (p < 0.001) compared to patients <85 years. Both groups had a comparable mean hospitalization time (9.8 days for patients ≥85 years and 9.5 days for patients <85 years). Old age has no negative impact on overall outcome after surgical therapy of cSDH. Despite significantly higher complication rate in elderly patients, the outcome assessed by the GOS at 1 month after surgery was significantly better in comparison to patients younger than 85 years. Old age does therefore not seem to be a contraindication for surgical treatment of cSDH.

Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial.

PURPOSE: Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma. METHODS: This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary end point was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of preoperative and postoperative MRI with 1-mm slices. Secondary end points included progression-free survival (PFS) and overall survival (OS), patient-reported quality of life, and clinical parameters. RESULTS: We recruited 314 patients with newly diagnosed glioblastomas at 11 German centers. A total of 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as-treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm (P = .79). Incision-suture times (P < .001) were significantly longer in the iMRI arm (316 v 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0 cm³) was a significant favorable prognostic factor for PFS (P < .001) and OS (P = .048), especially in methylguanine-DNA-methyltransferase unmethylated tumors (P = .006). CONCLUSION: We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.

Secretory meningiomas: systematic analysis of epidemiological, clinical, and radiological features.

BACKGROUND: Secretory meningiomas are known as a rare histological subtype within the meningioma family. In contrast to benign intracranial meningiomas, they are dreaded for causing an extensive perifocal cerebral tumor edema and life-threatening complications. The objective of the present study is a systematic, retrospective analysis of epidemiological, clinical, and radiological features of secretory meningiomas to predict potential patterns prior to surgery to reduce associated morbidity. MATERIAL AND METHODS: A systematic database search of PubMed with review of the literature was performed to identify clinical studies analyzing epidemiological, clinical, and radiological features of secretory meningiomas. Additionally, we supplemented our series of 17 patients with secretory meningiomas. Studies with available information for each patient were statistically metaanalyzed. RESULTS: In summary, seven large series with a total number of 120 patients were identified, containing detailed information about epidemiological, clinical, and radiological features of secretory meningiomas. Epidemiologically, female predominance was a characteristic. Peritumoral brain edema occurred in about 70% of patients and holohemispheric in more than 50% of patients. Life-threatening complications and severe neurological deficits frequently occur potentially due to extensive peritumoral brain edema. At last, frontal location and age older than 66 years significantly correlated with the development of peritumoral brain edema. CONCLUSION: Secretory meningiomas are histologically benign tumors and are therefore associated with an excellent prognosis. Nevertheless, frequently life-threatening complications due to the development of an extensive peritumoral brain edema are documented. Predictive risk factors are frontal tumor location, increasing age, and visible pial tumor vessel supply. A careful preoperative evaluation, identification of risk factors, and a specific therapy might reduce perioperative morbidity.

Direct Cortical Stimulation in Neurosurgical Emergencies: Single-Center Experience in 2 Patients.

BACKGROUND: Intraoperative neuromonitoring (IONM) is widely used for elective resection of eloquently located brain tumors to increase safety and extent of resection. Owing to the need for specially trained personnel for IONM and the sophisticated, time-consuming technical setup, standard IONM is usually not suitable for emergency situations. We report the use of a device that can be operated by the neurosurgeon autonomously for monopolar brain mapping in 2 emergency cases. METHODS: Both patients were initially scheduled for elective neurosurgery under IONM. Acute neurological deterioration in both cases led to emergency surgery. For monopolar cortical/subcortical stimulation, a standard monopolar probe was connected to a new device enabling electromyography real-time tracking of 8 muscles. Preoperative application of subdermal electromyography needles and intraoperative handling of the device were performed by the neurosurgeons independently. RESULTS: Cortical mapping of the motor cortex was performed in both patients with a threshold of 4 mA in case 1 and 14 mA in case 2. Gross total resection with residual tumor volume of <2 mL in case 1 and subtotal resection with residual tumor volume of 4.2 mL in case 2 were achieved under use of the new device without any new neurological deficit. Grade IV glioblastoma was diagnosed in both patients. CONCLUSIONS: We demonstrate the feasibility of monopolar stimulation in 2 patients undergoing emergency neurosurgery using a device autonomously operated by the surgeon. Owing to fast setup and nondemanding handling, monopolar stimulation could be used during emergency neurosurgery to extend resection with preservation of neurological function in both cases.

Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs).

Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.

Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide.

Glioblastoma (GBM) is a lethal disease with limited clinical treatment options available. Recently, a new inhibitor targeting the prominent cancer signaling pathway mTOR was discovered (Rapalink-1), but its therapeutic potential on stem cell populations of GBM is unknown. We applied a collection of physiological relevant organoid-like stem cell models of GBM and studied the effect of RL1 exposure on various cellular features as well as on the expression of mTOR signaling targets and stem cell molecules. We also undertook combination treatments with this agent and clinical GBM treatments tumor treating fields (TTFields) and the standard-of-care drug temozolomide, TMZ. Low nanomolar (nM) RL1 treatment significantly reduced cell growth, proliferation, migration, and clonogenic potential of our stem cell models. It acted synergistically to reduce cell growth when applied in combination with TMZ and TTFields. We performed an in silico analysis from the molecular data of diverse patient samples to probe for a relationship between the expression of mTOR genes, and mesenchymal markers in different GBM cohorts. We supported the in silico results with correlative protein data retrieved from tumor specimens. Our study further validates mTOR signaling as a druggable target in GBM and supports RL1, representing a promising therapeutic target in brain oncology.

Robot technology identifies a Parkinsonian therapeutics repurpose to target stem cells of glioblastoma.

Aim: Glioblastoma is a heterogeneous lethal disease, regulated by a stem-cell hierarchy and the neurotransmitter microenvironment. The identification of chemotherapies targeting individual cancer stem cells is a clinical need. Methodology: A robotic workstation was programmed to perform a drug concentration to cell-growth analysis on an in vitro model of glioblastoma stem cells (GSCs). Mode-of-action analysis of the selected top substance was performed with manual repetition assays and acquisition of further parameters. Results: We identified 22 therapeutic potential substances. Three suggested a repurpose potential of neurotransmitter signal-modulating agents to target GSCs, out of which the Parkinson's therapeutic trihexyphenidyl was most effective. Manual repetition assays and initial mode of action characterization revealed suppression of cell proliferation, cell cycle and survival. Conclusion: Anti-neurotransmitter signaling directed therapy has potential to target GSCs. We established a drug testing facility that is able to define a mid-scale chemo responsome of in vitro cancer models, possibly also suitable for other cell systems.

A computational guided, functional validation of a novel therapeutic antibody proposes Notch signaling as a clinical relevant and druggable target in glioma.

The Notch signaling network determines stemness in various tissues and targeting signaling activity in malignant brain cancers by gamma-secretase inhibitors (GSI) has shown promising preclinical success. However, the clinical translation remains challenging due to severe toxicity side effects and emergence of therapy resistance. Better anti-Notch directed therapies, specifically directed against the tumor promoting Notch receptor 1 signaling framework, and biomarkers predicting response to such therapy are of highest clinical need. We assessed multiple patient datasets to probe the clinical relevance Notch1 activation and possible differential distribution amongst molecular subtypes in brain cancers. We functionally assessed the biological effects of the first-in-human tested blocking antibody against Notch1 receptor (brontictuzumab, BRON) in a collection of glioma stem-like cell (GSC) models and compared its effects to genetic Notch1 inhibition as well as classical pharmacological Notch inhibitor treatment using gamma-secretase inhibitor MRK003. We also assess effects on Wingless (WNT) stem cell signaling activation, which includes the interrogation of genetic WNT inhibition models. Our computed transcriptional Notch pathway activation score is upregulated in neural stem cells, as compared to astrocytes; as well as in GSCs, as compared to differentiated glioblastoma cells. Moreover, the Notch signature is clinical predictive in our glioblastoma patient discovery and validation cohort. Notch signature is significantly increased in tumors with mutant IDH1 genome and tumors without 1p and 19q co-deletion. In GSCs with elevated Notch1 expression, BRON treatment blocks transcription of Notch pathway target genes Hes1/Hey1, significantly reduced the amount of cleaved Notch1 receptor protein and caused significantly impairment of cellular invasion. Benchmarking this phenotype to those observed with genetic Notch1 inhibition in corresponding cell models did result in higher reduction of cell invasion under chemotherapy. BRON treatment caused signs of upregulation of Wingless (WNT) stem cell signaling activity, and vice versa, blockage of WNT signaling caused induction of Notch target gene expression in our models. We extend the list of evidences that elevated Notch signal expression is a biomarker signature declaring stem cell prevalence and useful for predicting negative clinical course in glioblastoma. By using functional assays, we validated a first in man tested Notch1 receptor specific antibody as a promising drug candidate in the context of neuro oncology and propose biomarker panel to predict resistance and therapy success of this treatment option. We note that the observed phenotype seems only in part due to Notch1 blockage and the drug candidate leads to activation of off target signals. Further studies addressing a possible emergence of therapy resistance due to WNT activation need to be conducted. We further validated our 3D disease modeling technology to be of benefit for drug development projects.

30 years of vagus nerve stimulation trials in epilepsy: Do we need neuromodulation-specific trial designs?

Neuromodulation therapies represent an important treatment arm for patients with drug-resistant epilepsy (DRE) who are not candidates for resective surgery. Vagus nerve stimulation (VNS) - the neurostimulation modality in focus in this review - was the first available neuromodulatory therapy for DRE and was followed by anterior thalamic deep brain stimulation (ANT-DBS) and responsive neurostimulation (RNS). Although no comparative trials of these treatments have been performed, published data and clinical experience suggest comparable effectiveness. In VNS, DBS and RNS seizure reduction is delayed and increases over time raising the question of anti-epileptogenic mechanisms of neuromodulation. Considering the long-term effectiveness assumed for neuromodulatory treatments and the chronic nature of drug-resistant epilepsy, study designs allowing for long-term comparative observations would be of great value, but are hindered by the inherent nature of a long-term [surgical] control group and the bias associated with open-label trials. New trial designs using objective endpoints are needed, and may be aided by novel biomarkers of risk and disease severity for specific epilepsy populations.

Can the combination of hyperthermia, seizures and ion channel dysfunction cause fatal post-ictal cerebral edema in patients with SCN1A mutations?

A 21-year-old male with an SCN1A mutation died of cerebral herniation 3 h after a seizure occurring during physical activity. Cases of fatal cerebral edema in patients with SCN1A mutations after fever and status epilepticus have been recently reported raising the question whether sodium channel dysfunction may contribute to cerebral edema and thereby contribute to the increased premature mortality in Dravet Syndrome. We report on our patient and discuss whether the combination of hyperthermia and ion channel dysfunction may not only trigger seizures but also a fatal pathophysiological cascade of cerebral edema and herniation leading to cardiorespiratory collapse.

Efficacy of adjunctive vagus nerve stimulation in patients with Dravet syndrome: A meta-analysis of 68 patients.

RATIONALE: Dravet Syndrome (DS) is a severe epileptic encephalopathy of childhood involving intractable seizures, recurrent status epilepticus and cognitive decline. Because DS is a rare disease, available data is limited and evidence-based treatment guidelines are lacking. Vagus nerve stimulation (VNS) is an established neurostimulation treatment for intractable epilepsy, however little evidence is published on its efficacy in patients with DS. METHODS: We performed a meta-analysis of all peer-reviewed English language studies reporting seizure outcomes of patients with DS treated with adjunctive vagus nerve stimulation. The primary and secondary outcome measures were ≥50% reduction of seizures or of the most-debilitating seizure type and seizure reduction per patient. RESULTS: 13 studies comprising 68 patients met the inclusion criteria of which 11 were single-center retrospective case series, one was a multi-center retrospective analysis and one was a case report. 52.9% of patients experienced a ≥50% reduction of seizures and the average seizure reduction, which could only be assessed in n=28 patients was 50.8%. 7 out of 13 studies reported additional benefits of VNS, however this could not be assessed systematically. CONCLUSION: Vagus nerve stimulation appears to reduce seizure frequency in patients with DS. Based on this preliminary analysis, controlled trials of VNS in this rare condition using patient-centric outcome measures are indicated.

5-Aminolevulinic acid-based photodynamic therapy of chordoma: In vitro experiments on a human tumor cell line.

BACKGROUND: Chordomas are very rare tumors of the skull base and the sacrum. They show infiltrating and destructive growth and are known to be chemo- and radio-resistant. After surgical resection, the recurrence rate is high and overall survival limited. As current adjuvant treatments are ineffective, new treatment concepts are urgently needed. 5-aminolevulinic acid-based photodynamic therapy (5-ALA based PDT) showed promising results for malignant gliomas. However, it is unknown so far, whether chordomas accumulate protoporphyrin IX (PPIX) after application of 5-ALA and whether they are sensitive to subsequent 5-ALA based PDT. METHODS: The immortalized human chordoma cells U-CH2 were used as in vitro model. After incubation for 4h or 6h with different 5-ALA concentrations, PPIX accumulation was determined by flow cytometry. To assess sensitivity to PDT, chordoma cells were incubated at 30.000cells/well (high cell density) or 15.000cells/well (low cell density) with graded doses of 5-ALA (0-50µg/ml) in 96-well plates and subsequently exposed to laser light of 635nm wavelength (18.75J/cm2). Cell survival was measured 24h after exposure to laser light using the WST-1 assay. RESULTS: U-CH2 cells dose-dependently accumulated PPIX (ANOVA; p<0.0001). PPIX fluorescence was significantly higher, when cells were incubated with 5-ALA for 6h compared to 4h at higher 5-ALA concentrations (ANOVA/Bonferroni; p≤0.05 for≥30µg/ml 5-ALA). For both cell densities, a 5-ALA dose-dependent decline in viability was observed (ANOVA; p<0.0001). Viability was significantly lower at higher 5-ALA concentrations, when 30.000 cells/wells were treated compared to 15.000cells/well (ANOVA/Bonferroni; p≤0.001 for≥30µg/ml 5-ALA). LD50 was 30.25µg/ml 5-ALA. CONCLUSION: The human UCH-2 cell line was a very useful in vitro model to study different effects of 5-ALA based PDT. For the first time, it could be shown that human chordoma cells may be destroyed by 5-ALA/PDT.

Efficacy of 5-aminolevulinic acid based photodynamic therapy in pituitary adenomas-experimental study on rat and human cell cultures.

BACKGROUND: Incomplete resection of pituitary adenomas may result in recurrence. As adjuvant irradiation is not riskless, alternative treatment options should be investigated. 5-aminolevulinic acid based photodynamic therapy (5-ALA based PDT) showed promising results for malignant gliomas. The present study examined the efficacy of 5-ALA PDT in vitro on benign pituitary adenoma cell cultures. METHODS: In group I experiments were performed on immortalized rat pituitary adenoma cells (GH3). The cultured cells were treated with different 5-ALA concentrations ranging from 7.5-16.5µg/ml. In Group II human pituitary adenoma cell cultures were obtained from surgically resected adenoma tissue (n=15). These were incubated with 5-ALA concentrations from 12.5-100µg/ml. The concentration ranges had been determined in preliminary dose-finding tests. For both groups incubation time was four hours and PDT was performed by exposition to laser light (635nm, 625s, 18.75J/cm(2)). Cell viability was examined by WST-1 assay. RESULTS: In both groups PDT showed a 5-ALA concentration-dependent effect on cell death. In group I lower 5-ALA concentrations were necessary to destroy all cells as compared to group II. Moreover, in group II, the different subtypes of human adenomas showed different sensitivities to 5-ALA-based PDT (secreting vs. non-secreting). Especially corticotroph adenomas were highly sensitive to 5-ALA PDT. CONCLUSIONS: The GH3 cell line was an useful in vitro model to optimize different PDT parameters. Human pituitary adenoma cells could also be killed by 5-ALA PDT, however this required higher 5-ALA concentrations. Furthermore, the results suggested different 5-ALA sensitivities between different human adenoma cell types. More experiments are necessary to confirm these preliminary results.

The influence of decompressive craniectomy for major stroke on early cerebral perfusion.

OBJECT: Multiple trials have shown improved survival and functional outcome in patients treated with decompressive craniectomy (DC) for brain swelling following major stroke. It has been assumed that decompression induces an improvement in cerebral perfusion. This observational study directly measured cerebral perfusion before and after decompression. METHODS: Sixteen patients were prospectively examined with perfusion CT within 6 hours prior to surgery and 12 hours after surgery. Preoperative and postoperative perfusion measurements were compared and correlated. RESULTS: Following DC there was a significant increase in cerebral blood flow in all measured territories and additionally an increase in cerebral blood volume in the penumbra (p = 0.03). These changes spread as far as the contralateral hemisphere. No significant changes in mean transit time or Tmax (time-to-peak residue function) were observed. CONCLUSIONS: The presurgical perfusion abnormalities likely reflected local pressure-induced hypoperfusion with impaired autoregulation. The improvement in perfusion after decompression implied an increase in perfusion pressure, likely linked to partial restoration of autoregulation. The increase in perfusion that was observed might partially be responsible for improved clinical outcome following decompressive surgery for major stroke. The predictive value of perfusion CT on outcome needs to be evaluated in larger trials.

Cerebral perfusion changes in chronic subdural hematoma.

Abstract Chronic subdural hematoma is a frequent disorder in the elderly. Although intensively investigated, numerous aspects, including the pathophysiology of clinical symptoms, remain unclear. Perfusion deficits are likely to induce the transient neurologic symptoms seen in chronic subdural hematoma (cSDH). The aim of the present study was to quantify cerebral perfusion impairment in cSDH. Before surgery, 34 patients were examined neurologically using the National Institutes of Health Stroke Scale (NIHSS) score and investigated by CT perfusion imaging. Hematoma volume, localization, and hematoma configuration were recorded. Clinical and radiological data were correlated. Mean hematoma volume was 91.8 cm(3) (16.2-241.6 cm(3), standard deviation [SD] 49.5). Whole brain mean transit time (MTT) was slightly elevated (mean 36.6 sec, SD 5.8). Hematoma volume and cerebral blood volume (CBV) in the underlying hemisphere correlated marginally but not significantly (p=0.067). Perfusion parameters determined in the area below the hematoma (ABH) and the corresponding contralateral cortex (MAC) were highly significantly different regarding cerebral blood flow (CBF) (mean 88.8 vs. 70.4, p<0.01) and CBV (mean 29.4 vs. 22.5, p<0.01). On the other hand, MTT and Tmax were almost equal between these areas (MTT means 35.0 vs. 34.8, (p)=0.914; tMax means 16.0 vs. 15.4, p=0.587). We conclude that local brain perfusion autoregulation is active in the cortical area below cSDH. CBV and CBF are significantly upregulated in the cortical area below cSDH indicating the effect of autoregulation in tissue at risk of ischemia. Cerebral autoregulation is intact in cSDH. Neurologic deficits are likely induced by borderline perfusion.