Complement Components in Peripheral Blood from Adult Patients with IDH Wild-Type Glioblastoma.

BACKGROUND: The complement system seems to influence cancer pathophysiology. The primary aim of this study was to explore complement components associated with the classical pathway (CP) of the complement system in peripheral blood from patients with IDH-wild-type (IDH-wt) glioblastoma. METHODS: Patients undergoing primary surgery due to glioblastoma in the years 2019-2021 were prospectively included in the present study. Blood samples were collected prior to surgery, and analyzed with regard to CP complement components, as well as standard coagulation tests. RESULTS: In total, 40 patients with IDH-wt glioblastomas were included. C1q was reduced in 44% of the cases compared to the reference interval. C1r was reduced in 61% of the analyzed samples. Both C1q and C1r are parts of the initial steps of the classical complement activation pathway, which, however, was not correspondingly altered. Activated pro-thromboplastin time (APTT) was shorter in 82% of the analyzed samples compared to the reference interval. APTT was shorter in those with reduced C1q and C1r levels. C1q is an important link between the innate and acquired immunity, and C1q and C1r also interact with the coagulation system. Patients who displayed reduced levels of both C1q and C1r preoperatively had a significantly shorter overall survival compared with the rest of the cohort. CONCLUSIONS: Our findings demonstrate that there are alterations in C1q and C1r concentrations in peripheral blood from patients with IDH1-wt glioblastoma compared with the normal population. Patients who displayed reduced C1q and C1r levels had a significantly shorter survival.

[Neurosurgery still pivotal in the diagnostics and treatment of brain tumor patients]. / Neurokirurgin alltjämt kärnan i behandlingen av hjärntumörer.

Treatment of adult patients with brain tumors is a multi-disciplinary effort involving several medical disciplines: neurosurgery, oncology, neurology, neuropathology, neuroradiology, and rehabilitation medicine. While the brain tumor field has gone through vast diagnostical changes during the last decade, the hopes of similar achievements in the systemic treatment of these patients with new methods have so far not been fulfilled. As such, neurosurgery still has a pivotal role in the diagnostics and treatment of brain tumor patients. Improved preoperative evaluation of the tumor and adjacent anatomical and functional brain areas, together with advanced microsurgical techniques, intraoperative mapping and monitoring, as well as new minimally invasive techniques, makes brain tumor surgery safer. Indeed, it is now possible to safely operate patients previously considered to have too unfavorable risk-benefit ratio. This article aims at presenting an overview of current neurosurgical treatments of brain tumors.

Comparable Long-Term Tumor Control for Hypofractionated FLASH Versus Conventional Radiation Therapy in an Immunocompetent Rat Glioma Model.

Purpose: To ensure a clinical translation of FLASH radiation therapy (FLASH-RT) for a specific tumor type, studies on tumor control and toxicity within the same biological system are needed. In this study, our objective was to evaluate tumor control and toxicity for hypofractionated FLASH-RT and conventional radiation therapy (CONV-RT) in an immunocompetent rat glioma model. Methods and Materials: Fisher 344 rats (N = 68) were inoculated subcutaneously with NS1 glioma cells and randomized into groups (n = 9-10 per group). CONV-RT (∼8 Gy/min) or FLASH-RT (70-90 Gy/s) was administered in 3 fractions of either 8 Gy, 12.5 Gy, or 15 Gy using a 10-MeV electron beam. The maximum tumor diameter was measured weekly, and overall survival was determined until day 100. Long-term tumor control was defined as no evident tumor on day 100. Animals were evaluated for acute dermal side effects at 2 to 5 weeks after completed RT and for late dermal side effects at 3 months after initiation of treatment. Results: Survival was significantly increased in all irradiated groups compared with control animals (P < .001). In general, irradiated tumors started to shrink at 1 week post-completed RT. In 40% (23 of 58) of the irradiated animals, long-term tumor control was achieved. Radiation-induced skin toxic effects were mild and consisted of hair loss, erythema, and dry desquamation. No severe toxic effect was observed. There was no significant difference between FLASH-RT and CONV-RT in overall survival, acute side effects, or late side effects for any of the dose levels. Conclusions: This study shows that hypofractionated FLASH-RT results in long-term tumor control rates similar to those of CONV-RT for the treatment of large subcutaneous glioblastomas in immunocompetent rats. Neither treatment technique induced severe skin toxic effects. Consequently, no significant difference in toxicity could be resolved, suggesting that higher doses may be required to detect a FLASH sparing of skin.

Risk factors for need of reoperation in bilateral chronic subdural haematomas.

BACKGROUND: Chronic subdural haematoma (CSDH) is one of the most common neurosurgical diseases. A subtype of CSDH is bilateral chronic subdural haematoma (bCSDH) which represents 20-25% of patients with CSDH and has a higher recurrence rate. There is no clear consensus on how bCSDH should be treated regarding upfront unilateral- or bilateral evacuation of both haematomas. The purpose of this study was to identify risk factors associated with reoperation of bCSDH. METHODS: A total of 326 patients with radiological evidence of bCSDH were included in this retrospective cohort study where 133 (40.8%) patients underwent primary bilateral evacuation and 193 (59.2%) primary unilateral evacuation. The two centres operated using different surgical approaches. Analyses were performed to identify risk factors associated with reoperation of bCSDH. Reoperation rate was defined as reoperation of CSDH on either side of the hemisphere within 3 months after primary evacuation. RESULTS: The cohort had a total reoperation rate of 26.4%. Patients which underwent unilateral evacuation had a reoperation rate of 32.1%, and the bilateral group had a reoperation rate of 18.0% (p=0.005). Multivariable logistic regression identified unilateral evacuation (OR 1.91, p=0.022) and complications according to Ibanez (OR 2.20, p=0.032) to be associated with the need of reoperation of bCSDH. One-burr hole craniostomy with active subgaleal drain was primarily performed in bilateral approach (69.4%) whereas patients operated with minicraniotomy with passive subdural drain were primarily operated by unilateral evacuation of the larger symptomatic side (92.8%). CONCLUSIONS: Unilateral evacuation of bCSDH was associated with a higher risk for reoperation than upfront bilateral evacuations in this study. There is a need to further discuss the criteria for uni- or bilateral evacuation since patients are treated differently at different centres.

Extreme intracranial pressure elevation > 90 mmHg in an awake patient with primary CNS lymphoma-case report.

We describe a patient with primary CNS lymphomas, awake despite an extreme ICP elevation. A 48-year-old woman presented with headache since 1 month, and bilateral papillary edema was observed. Magnetic resonance imaging revealed diffuse infiltration around the petrous bone. Following external ventricular drainage (EVD) placement, ICP levels of > 90 mmHg were recorded while the patient was fully awake. Cytology revealed an aggressive primary CNS lymphoma. Cerebrospinal fluid (CSF) drainage at high opening pressure levels was required. We conclude that extreme ICP elevations, treatable by CSF drainage, can be observed without a reduced level of consciousness.

Does time from diagnostic CT until surgical evacuation affect outcome in patients with chronic subdural hematoma?

BACKGROUND: Chronic subdural hematoma (CSDH) is one of the most common neurosurgical conditions. Patients diagnosed with CSDH's are often planned for subacute surgery. This means that time from diagnostic CT scan until actual surgery might often be prolonged. There are no previous studies that highlight the effect of delayed intervention in this population. METHOD: Patients that underwent surgical evacuation for a CSDH at Skåne University Hospital between 1 January 2015 and 31 December 2016 were included in this retrospective cohort study (n = 179). The primary aim was to determine if time from initial diagnosis by head-CT until surgical evacuation had a significant effect on outcome. The following was assessed by mortality, re-operation, number of days spent in hospital, discharge to home/institution, and functional outcome assessed by GOS. Secondary aims were to evaluate the effect of NOAC, vitamin K antagonists, and antiplatelet drugs on time from CT to surgery and re-operation frequency. RESULTS: Mean time from diagnostic CT scan until surgery was 76 h. No significant relationship was found between time from CT to surgical evacuation and number of days spent in hospital, discharge to own home/institution, 1-year mortality, or outcome assessed by GOS at discharge from hospital. The clear majority (95.5%) of the patients were GCS ≥ 13 pre-operatively. No correlation could be seen between use of NOAC, vitamin K antagonists, or antiplatelet drugs regarding the risk for reoperation within 6 months, and no correlation between the use of these agents and time from CT to surgery. The 30-day mortality was too low to draw any statistically significant conclusions (n = 4). CONCLUSION: In this retrospective cohort study, we could conclude that a delay from initial diagnosis confirming a CSDH to surgical evacuation had no negative effect on outcome when surgery was performed within the time frames and on patients with pre-operatively favorable GCS scores (≥ 13) outlined in our study.

Mathematical modelling of the synergistic combination of radiotherapy and indoleamine-2,3-dioxygenase (IDO) inhibitory immunotherapy against glioblastoma.

OBJECTIVE: Recent research has shown that combining radiotherapy and immunotherapy can counteract the ability of cancer to evade and suppress the native immune system. To optimise the synergy of the combined therapies, factors such as radiation dose and fractionation must be considered, alongside numerous parameters resulting from the complexity of cancer-immune system interactions. It is instructive to use mathematical models to tackle this problem. METHODS: In this work, we adapted a model primarily to describe the synergistic effect between single-fraction radiotherapy and immunotherapy (1-methyl tryptophan) observed in previous experiments with glioblastoma-carrying rats. We also showed how the model can be used to generate hypotheses on the outcome of other treatment fractionation schemes. RESULTS: The model successfully reproduced the results of the experiments. Moreover, it provided support for the hypothesis that, for a given biologically effective dose, the efficacy of the combination therapy and the synergy between the two therapies are favoured by the administration of radiotherapy in a hypofractionated regime. Furthermore, for a double-fraction irradiation regimen, the synergy is favoured by a short time interval between the treatment fractions. CONCLUSION: It was concluded that the model could be fitted to reproduce the experimental data well within its uncertainties. It was also demonstrated that the fitted model can be used to form hypotheses to be validated by further pre-clinical experiments. Advances in knowledge: The results of this work support the hypothesis that the synergetic action of combined radiotherapy and immunotherapy is favoured by using a hypofractionated radiation treatment regimen, given over a short time interval.

C1-inactivator is upregulated in glioblastoma.

BACKGROUND: Glioblastoma is the most common and aggressive type of primary brain tumor in adults. A key problem is the capacity of glioma cells to inactivate the body's immune response. The complement system acts as a functional bridge between the innate and adaptive immune response. Still, the role of the complement system has almost been forgotten in glioma research. In our present study, we hypothesize that C1 inactivator (C1-IA) is upregulated in astrocytoma grade IV, and that its inhibition of the complement system has beneficial effects upon survival. METHODS AND RESULTS: We have explored this hypothesis both on gene and protein levels and found an upregulation of C1-IA in human glioblastoma cells using data from a publicly available database and our own mRNA material from glioblastoma patients. Furthermore, we demonstrated the presence of C1-IA by using immunohistochemistry on glioma cells from both humans and rats in vitro. Finally, we could demonstrate a significantly increased survival in vivo in animals inoculated intracerebrally with glioma cells pre-coated with C1-IA antibodies as compared to control animals. CONCLUSIONS: Our findings indicate that overexpression of C1-IA is present in glioblastomas. This could be demonstrated both at the gene level from patients with glioblastoma, on mRNA level and with immunohistochemistry. Treatment with antibodies against C1-IA had beneficial effects on survival when tested in vivo.