Combined anti-C1-INH and radiotherapy against glioblastoma.

BACKGROUND: A more effective immune response against glioblastoma is needed in order to achieve better tumor control. Radiotherapy can induce anti-tumor mediated immune reactions, in addition to its dose response effects. The complement system can function as a bridge between innate and adaptive immune responses. Combining radiotherapy and complement activating therapy is theoretically interesting. METHODS: Radiotherapy at 8 Gy × 2 was combined with treatment against C1-inhibitor (C1-INH), a potent inhibitor of activation of the classical pathway of the complement system. Anti-C1-INH was delivered as intratumoral injections. Fully immunocompetent Fischer 344 rats with NS1 glioblastoma tumors were treated. Survival was monitored as primary outcome. Models with either intracranial or subcutaneous tumors were evaluated separately. RESULTS: In the intracranial setting, irradiation could prolong survival, but there was no additional survival gain as a result of anti-C1-INH treatment. In animals with subcutaneous tumors, combined radio-immunotherapy with anti-C1-INH and irradiation at 8 Gy × 2 significantly prolonged survival compared to control animals, whereas irradiation or anti-C1-INH treatment as single therapies did not lead to significantly increased survival compared to control animals. CONCLUSIONS: Anti-C1-INH treatment could improve the efficacy of irradiation delivered at sub-therapeutic doses and delay tumor growth in the subcutaneous tumor microenvironment. In the intracranial setting, the doses of anti-C1-INH were not enough to achieve any survival effect in the present setting.

Comparable survival in rats with intracranial glioblastoma irradiated with single-fraction conventional radiotherapy or FLASH radiotherapy.

Background: Radiotherapy increases survival in patients with glioblastoma. However, the prescribed dose is limited by unwanted side effects on normal tissue. Previous experimental studies have shown that FLASH radiotherapy (FLASH-RT) can reduce these side effects. Still, it is important to establish an equal anti-tumor efficacy comparing FLASH-RT to conventional radiotherapy (CONV-RT). Methods: Fully immunocompetent Fischer 344 rats with the GFP-positive NS1 intracranial glioblastoma model were irradiated with CONV-RT or FLASH-RT in one fraction of 20 Gy, 25 Gy or 30 Gy. Animals were monitored for survival and acute dermal side effects. The brains were harvested upon euthanasia and tumors were examined post mortem. Results: Survival was significantly increased in animals irradiated with CONV-RT and FLASH-RT at 20 Gy and 25 Gy compared to control animals. The longest survival was reached in animals irradiated with FLASH-RT and CONV-RT at 25 Gy. Irradiation at 30 Gy did not lead to increased survival, despite smaller tumors. Tumor size correlated inversely with irradiation dose, both in animals treated with CONV-RT and FLASH-RT. Acute dermal side effects were mild, but only a small proportion of the animals were alive for evaluation of those side effects. Conclusion: The dose response was similar for CONV-RT and FLASH-RT in the present model. Tumor size upon the time of euthanasia correlated inversely with the irradiation dose.

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.

Long-term anti-tumor effects following both conventional radiotherapy and FLASH in fully immunocompetent animals with glioblastoma.

Radiotherapy can induce an immunological response. One limiting factor is side effects on normal tissue. Using FLASH radiotherapy, side effects could possibly be reduced. The efficacy of FLASH in relation to conventional radiotherapy (CONV-RT) has not been extensively explored in fully immunocompetent animals. Fully immunocompetent Fischer 344 rats were inoculated with NS1 glioblastoma cells subcutaneously or intracranially. Radiotherapy was delivered with FLASH or CONV-RT at 8 Gy × 2 (subcutaneous tumors) and 12.5 Gy × 2 (intracranial tumors). Cured animals were re-challenged in order to explore long-term anti-tumor immunity. Serum analytes and gene expression were explored. The majority of animals with subcutaneous tumors were cured when treated with FLASH or CONV-RT at 8 Gy × 2. Cured animals could reject tumor re-challenge. TIMP-1 in serum was reduced in animals treated with FLASH 8 Gy × 2 compared to control animals. Animals with intracranial tumors survived longer when treated with FLASH or CONV-RT at 12.5 Gy × 2, but cure was not reached. CONV-RT and FLASH were equally effective in fully immunocompetent animals with glioblastoma. Radiotherapy was highly efficient in the subcutaneous setting, leading to cure and long-term immunity in the majority of the animals.

Identifying Unmet Rehabilitation Needs in Patients After Stroke With a Graphic Rehab-CompassTM.

BACKGROUND: Unmet rehabilitation needs are common among stroke survivors. We aimed to evaluate whether a comprehensive graphic "Rehab-Compass," a novel combination of structured patient-reported outcome measures, was feasible and useful in facilitating a capture of patients' rehabilitation needs in clinical practice. METHODS: A new graphic overview of broad unmet rehabilitation needs covers deficits in functioning, daily activity, participation, and quality of life. It was constructed by using 5 patient-oriented, well-validated, and reliable existing instruments with converted data into a 0 (worst outcome) to 100 (best outcome) scale but unchanged in terms of variable properties. Satisfaction of the Rehab-CompassTM was studied by a qualitative interview of 9 patients with stroke and 3 clinicians. Practical feasibility and capacity of the instrument were evaluated in a cross-sectionalstudy with 48 patients at 5-month follow-ups after subarachnoid hemorrhage. RESULTS: The Rehab-CompassTM identified and graphically visualized a panoramic view of the multidimensional needs over time which was completed before clinical consultation. The Rehab-CompassTM appeared to be feasible and time-efficientin clinical use. The interviews of both patients and clinicians showed high satisfaction when using the Rehab-CompassTM graph. In the studied stroke patients, the Rehab-CompassTM identified memory and processing information, fatigue, mood, and pain after subarachnoid hemorrhage as the most common problems. CONCLUSIONS: The graphic Rehab-CompassTM seems to be a feasible, useful, and time-saving tool for identification of unmet rehabilitation needs among stroke survivors in clinical practice. Further research is needed to make the Rehab-CompassTM more concise and evaluate the instrument among different stroke subgroups.