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BackgroundPreclinical studies suggest that skull remodeling surgery (SR-surgery) increases the dose of tumor treating fields (TTFields) in glioblastoma (GBM) and prevents wasteful current shunting through the skin. SR-surgery introduces minor skull defects to focus the cancer-inhibiting currents towards the tumor and increase the treatment dose. This study aimed to test the safety and feasibility of this concept in a phase 1 setting.Methods15 adult patients with first recurrence of GBM were treated with personalized SR-surgery, TTFields and physician’s choice oncological therapy. The primary endpoint was toxicity and secondary endpoints included standard efficacy outcomes.ResultsSR-surgery resulted in a mean skull defect area of 10.6 cm 2 producing a median TTFields enhancement of 32% (range 25-59%). The median TTFields treatment duration was 6.8 months and the median compliance rate 90%. Patients received either bevacizumab, bevacizumab/irinotecan, or temozolomide rechallenge. We observed 71 adverse events (AEs) of grades 1 (52%), 2 (35%), and 3 (13%). There were no grade 4 or 5 AEs or intervention-related serious AEs. Six patients experienced minor TTFields-induced skin rash. The median progression-free survival (PFS) was 4.6 months and the PFS rate at 6 months was 36%. The median overall survival (OS) was 15.5 months and the OS rate at 12 months was 55%.ConclusionsTTFields therapy combined with SR-surgery and medical oncological treatment is safe and non-toxic and holds potential to improve the outcome for GBM patients through focal dose enhancement in the tumor.

We present a clinical open label, phase-1 trial (OptimalTTF-1, NCT02893137), which aims to test a novel treatment for first recurrence glioblastoma (rGBM). The aim of the treatment is to optimize the electric field generated by Tumor Treating Fields (TTFields) with targeted and individualized skull-remodeling surgery (SR-surgery). Selectively placed burrholes reduces the electric resistance created by the bone and thus improves the electric field focally. Preclinical research has indicated this conclusion. The final analysis examined the toxicity and efficacy of this combined intervention in addition to best practice chemotherapy.

Introduction The clinical outcome of spinal cord stimulation (SCS) shows very large individual variation: Some patients experience almost complete pain relief, while others have no beneficial effect at all and ultimately undergo explantation of the SCS device. Therefore, the implanter needs to rely on different assessment tools when evaluating SCS candidates. One such tool is the Pain Catastrophizing Scale (PCS) being a 13-item psychological evaluation instrument used to measure the level of catastrophic thinking in relation to pain. The scale yields a score from 0-52; 0 = no catastrophic thinking, 52 = highest possible level of catastrophic thinking. Previous studies investigating the use of PCS scores as a predictor of SCS outcomes showed conflicting results. The aim of this cohort study was to investigate whether baseline PCS scores in SCS patients could predict: 1) Latest rating on Patients’ Global Impression of Change Scale5 (PGIC) and 2) Risk of undergoing permanent explantation of the SCS device. MethodsWe used data from the Neurizon Neuromodulation Database containing detailed records of patients implanted with a SCS device at either Aarhus, Odense, or Aalborg University Hospitals, Denmark. Patient follow-up was performed approximately every six months and included the PGIC rating, explantations of SCS devices were continuously being registered in the database. Patients were included if they had a baseline PCS score (obtained prior to implantation) and a minimum follow-up of six months. Included patients were grouped by latest PGIC-rating and subsequently by current treatment status (active stimulation /permanently explanted). A one-way ANOVA was used to evaluate the association between baseline PCS scores and latest PGIC rating, while the relation between baseline PCS scores and current treatment status was assessed using an exact T-test. Results A total of 249 patients we included: 212 had a follow-up PGIC rating, 41 underwent permanent explantation of their SCS device. Mean baseline PCS score of included patients was 30.4, [29.0, 31.7]. No difference in mean baseline PCS score was found between PGIC groups (p-value = 0.15). Mean baseline PCS scores between groups of treatment status did not differ (Diff = -0.3, [-3.9, 3.3], p-value = 0.87). Follow-up ranged from 0.5 - 8 years (median = 3.0 years) and was not associated with treatment outcomes. Conclusion Baseline PCS scores failed to predict both latest PGIC rating and risk of undergoing permanent explantation of the SCS device. Our findings do not provide any support for withholding SCS therapy in patients with a high level of pain catastrophizing.

Tumor treating fields (TTFields) is a new non-invasive approach to cancer treatment. TTFields is low-intensity (1-5 V/m), intermediate frequency (150-200 kHz) alternating electric fields delivered locally to the tumour to selectively kill dividing cells and disrupt cancer growth. TTFields has proven safe and effective for newly diagnosed glioblastoma and is currently being tried for multiple other tumours. This review presents an introduction to TTFields, covering the main indications, the application method, the mechanism of action, the clinical results and the perspectives for implementation in Danish cancer treatment.

Introduction: Stereotactic radiosurgery (SRS) has proven an effective tool for treatment of tumors, arterio-venous malformation, acoustic neuroma, and functional conditions, in which cell death is the desired treatment outcome. However, radiation-induced therapeutic effect in the remaining living cells in functional SRS is also suggested. Modulation of the neuronal activity without causing death requires knowledge of radiation dose tolerance at very small tissue volume. The aim of the presented study was to document the thresholds for late-onset cell death when high doses of radiation are delivered to small brain volumes. Methods: Six female Gottingen minipigs were used. At baseline, the MRI was acquired. Five animals received focal stereotactic radiosurgery in the left primary motor cortex and to the right cortical white matter, and one animal remained as unirradiated control. Follow-up MRI and PET scans were done at three weeks, three and six months after the irradiation, followed by analysis of the histological changes at 6 months post-radiation after euthanization and fixation.Results: We observed a dose dependent gradient of cellular reaction to the radiation and spreading inflammatory changes along the neural tracts in white matter. Necrotic changes in both MRI and histology were seen at 6 months post-radiation. The threshold of radio-destructive lesions was 100 Gy in cortical gray matter, and 60 Gy in white matter.Conclusion: The threshold for radiation doses causing necrotic changes were defined in this study. Radiosurgery have both direct dose-dependent effect, and possibly indirect neuromodulatory effects; mediated by endogenous immunoreactive agents. Neuromodulative responses to radiation may be mediated by both vascular changes, as well as neuronal cell changes and glial cell remodeling.

Introduction:It is well documented that opioid usage leads to increased mortality and morbidity and that certain patients may develop opioid addiction. At the same time, the clinical outcome of spinal cord stimulation (SCS) shows very large individual variation: Some patients experience almost complete pain relief, while others have no beneficial effect at all and may end up being explanted. Recently published data shows opioid consumption prior to initiation of SCS may be associated with an unfavorable treatment outcome. We investigated whether opioid usage prior to initiation of SCS was associated with: 1) Risk of permanent explantation as a proxy of treatment failure. 2) Latest rating on Patients’ Global Impression of Change (PGIC) scale.Methods:We used data from the Neurizon Neuromodulation Database containing detailed records of patients implanted with a device for SCS at Aarhus, Odense or Aalborg University Hospital, Denmark. From the database records we identified patients with a preimplantation medicine registration and subsequently their current treatment status (active stimulation/permanently explanted) and latest PGIC rating.Patients were grouped according to preimplantation opioid use (Y/N) and oral morphine equivalent values (OME) were calculated for opioid users.The relationships between preimplantation opioid use, current treatment status and latest PGIC rating were evaluated with chi^2-tests. Associations between preimplantation OME values, current treatment status and latest PGIC rating were assessed by a t-test and a one-way ANOVA of log transformed data, respectively.Results:A total of 248 patients had a preimplantation medicine registration – all of these had a registration of currents treatment status and 190 patients had a PGIC rating. The presence of opioid usage (Y/N) prior to initiation of SCS was not associated with current treatment status (p-value =0.58) or latest PGIC rating (p-value = 0.39). Among opioid users median preimplantation OME values did not differ between groups of current treatment status (p-value = 0.20) or PGIC rating (p-value = 0.48).Conclusion:The presence of opioid usage (Y/N) prior to implantation with a device for SCS was not associated with risk of permanent explantation or latest PGIC rating. Among patients using opioids prior to implantation, the dosage of opioids expressed in terms of OME values was not associated with risk of being permanently explanted or latest PGIC rating. Introduction:It is well documented that opioid usage leads to increased mortality and morbidity and that certain patients may develop opioid addiction. At the same time, the clinical outcome of spinal cord stimulation (SCS) shows very large individual variation: Some patients experience almost complete pain relief, while others have no beneficial effect at all and may end up being explanted. Recently published data shows opioid consumption prior to initiation of SCS may be associated with an unfavorable treatment outcome. We investigated whether opioid usage prior to initiation of SCS was associated with: 1)Risk of permanent explantation as a proxy of treatment failure. 2)Latest rating on Patients’ Global Impression of Change (PGIC) scale.Methods:We used data from the Neurizon Neuromodulation Database containing detailed records of patients implanted with a device for SCS at Aarhus, Odense or Aalborg University Hospital, Denmark. From the database records we identified patients with a preimplantation medicine registration and subsequently their current treatment status (active stimulation/permanently explanted) and latest PGIC rating.Patients were grouped according to preimplantation opioid use (Y/N) and oral morphine equivalent values (OME) were calculated for opioid users.The relationships between preimplantation opioid use, current treatment status and latest PGIC rating were evaluated with chi^2-tests. Associations between preimplantation OME values, current treatment status and latest PGIC rating were assessed by a t-test and a one-way ANOVA of log transformed data, respectively.Results:A total of 248 patients had a preimplantation medicine registration – all of these had a registration of currents treatment status and 190 patients had a PGIC rating. The presence of opioid usage (Y/N) prior to initiation of SCS was not associated with current treatment status (p-value =0.58) or latest PGIC rating (p-value = 0.39). Among opioid users median preimplantation OME values did not differ between groups of current treatment status (p-value = 0.20) or PGIC rating (p-value = 0.48).Conclusion:The presence of opioid usage (Y/N) prior to implantation with a device for SCS was not associated with risk of permanent explantation or latest PGIC rating. Among patients using opioids prior to implantation, the dosage of opioids expressed in terms of OME values was not associated with risk of being permanently explanted or latest PGIC rating.

Aim and clinical rationale for the study: Spontaneous intracerebral haemorrhage (sICH) is an acute life-threatening injury and constitutes 10–15% of first-ever stroke cases. The Surgical Trials in Intracerebral Haematoma studies (STICH and STICH II) represent the two foremost studies in the field, however, with arguable shortcomings. To find more accurate criteria, we aimed to correlate the preoperative neurological and neuroimaging findings with the clinical outcome of operated patients. Materials and methods: In this retrospective study, sICH patients were recruited from the Central Denmark Region from 2010 to 2016. We evaluated the patients' medical records regarding preoperative Glasgow Coma Scale (GCS) 6 months and one year after surgery, focal neurological defects, thrombolytic treatment, pupil status, and haemorrhage localization visualized by neuroimaging. The patients' clinical outcome was assessed using the Glasgow Outcome Scale (GOS). Results: Based on logistic multiple linear analysis, age, basal ganglia haemorrhage and mass effect had significant effect on the mortality rate. Besides, age, basal ganglia haemorrhage, intra ventricular haemorrhage and pupil difference had significant correlation with good outcome (GOS > 3). Conclusions and clinical implications: Neurosurgical treatment of the sICH patients is indicated only if age and potentially improved morbidity is carefully evaluated considering the STICH and this study; otherwise, we will just increase the health care burden with a number of extremely care-dependent patients.