Autophagy Inhibition Reduces Irradiation-Induced Subcortical White Matter Injury Not by Reducing Inflammation, but by Increasing Mitochondrial Fusion and Inhibiting Mitochondrial Fission

Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if genetic inhibition of autophagy has an impact on subcortical white matter development in the juvenile mouse brain after irradiation. Ten-day-old selective neural Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6-Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and Atg7 deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the differentially expressed genes between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 (P-DRP1) were dramatically decreased in KO mice under physiological conditions. The protein levels of OPA1and P-DRP1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased levels in the KO mice after irradiation. These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.

ML-17 Clinical usefulness of Tirabrutinib in recurrent PCNSL: single institute experience

Background: Primary central nervous system lymphoma (PCNSL) is a lymphoma whose primary lesion is localized in the brain and spinal cord. Treatment is a combination of high-dose methotrexate-based chemotherapy and whole-brain irradiation, often leading to recurrence. Pathologically, non-GCB type diffuse large B-cell lymphoma (DLBCL) predominates. In DLBCL, constitutive activation of B cell receptor signal (BCR) is the tumor mechanism of tumor development and growth. Tirabrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) located downstream of BCR. In a phase I / II study, an overall response rate was 64%. Currently, Tirabrutinib is used to treat relapsed or refractory PCNSL. Purpose: Tirabrutinib is a drug that has just been approved, and there are few reports of its use in clinical practice. We report on our experience with Tirabrutinib with a review of the literature. Methods: We retrospectively examined the clinical course of 11 recurrent PCNSL patients treated with Tirabrutinib at our institution. Results: The average age of the subjects was 68.7 years, and 7 cases were male. Tirabrutinib 480 mg was administered in all cases. The response rate was 60% (6/10 cases). The median progression-free survival was 4.3 months. The adverse events were Grade 3 neutropenia in 1 patient and Grade 2 skin disorder in 4 patients. Treatment was discontinued in 5 of the 11 patients due to the progression of the disease. Due to the eruption, Tirabrutinib was reduced to 320 mg in 1 patient and discontinued in 1 patient. Treatment was discontinued at the request of the patient in 1 case, and four patients are still on medication. Summary: According to the results we obtained, the response rate was the same as that in the phase I / II study, and the progression-free survival was slightly longer.

MET-4 Clinical investigation of the cases recurred as dissemination after postoperative local irradiation for metastatic brain tumors

Last year, the authors examined the outcome of the patients with metastatic brain tumor (MBT)treated by whole-brain irradiation (WBRT)or local irradiation (LRT)after surgery. As a result, it was shown that the overall survival (OS) was same but the recurrence pattern was different. Furthermore, it was shown that there were some cases with disseminated recurrence in the LRT group. One year has passed, cases showing disseminated recurrence after LRT were examined. The subjects were 28 patients for whom LRT was selected as post-surgical irradiation since December 2017, with an average age of 66.2 years and a male-female ratio of 19: 9. Non-small cell lung cancer was the most in 17 cases. During the observation period, recurrence was observed in 12 cases, new outbreaks at other sites in 8 cases, disseminated recurrence in 4 cases, and no local recurrence. There was no clear difference in kinds of carcinoma and removal fashion between disseminated recurrence cases and other cases. Disseminated recurrence occurred between 3–10 months after surgery, 2 presented with headache, 1 with convulsions, 1 confirmed during follow-up of images, and all underwent WBRT. The lesions shrank after irradiation, but they were easy to re-grow, and the prognosis was poor. On the other hand, 10 cases died in 24 cases other than disseminated recurrence, but all cases died of primary cancer. Although LRT after surgery is non-inferior to WBRT in terms of OS and has the advantage of maintaining cognitive function, this study shows that there is a considerable risk of disseminated recurrence regardless of the removal fashion or kinds of carcinoma. It was also shown that prognosis after disseminated recurrence was poor. It is desirable to select postoperative irradiation after explaining the recurrence pattern, and when LRT is adopted, it is necessary to consider setting a short observation interval immediately after irradiation.

SURG-03. The effect of surgery on radiation necrosis in irradiated brain metastases: extent of resection and long-term clinical and radiographic outcomes

Objective Radiation therapy is a cornerstone of brain metastasis (BrM) management but carries the risk of radiation necrosis (RN), which can require resection for palliation or diagnosis. We sought to determine the relationship between extent of resection (EOR) of pathologically-confirmed RN and postoperative radiographic and symptomatic outcomes. Methods A single-center retrospective review was performed at an NCI-designated Comprehensive Cancer Center to identify all surgically-resected, previously-irradiated necrotic BrM without admixed recurrent malignancy from 2003–2018. Clinical, pathologic and radiographic parameters were collected. Volumetric analysis determined EOR and longitudinally evaluated perilesional T2-FLAIR signal preoperatively, postoperatively, and at 3-, 6-, 12-, and 24-months postoperatively when available. Rates of time to 50% T2-FLAIR reduction was calculated using cumulative incidence in the competing risks setting with last follow-up and death as competing events. The Spearman method was used to calculate correlation coefficients, and continuous variables for T2-FLAIR signal change, including EOR, were compared across groups. Results Forty-six patients were included. Most underwent prior stereotactic radiosurgery with or without whole-brain irradiation (n=42, 91%). Twenty-seven operations resulted in gross-total resection (59%; GTR). For the full cohort, T2-FLAIR edema decreased by a mean of 78% by 6 months postoperatively that was durable to last follow-up (p<0.05). EOR correlated with edema reduction at last follow-up, with significantly greater T2-FLAIR reduction with GTR versus subtotal resection (p<0.05). There was a trend towards decreased steroid use, from 8mg daily dexamethasone-equivalent (range 2–36) preoperatively to 3mg 12-months postoperatively (range 1–8; p=0.063). Conclusions RN resection conferred both durable T2-FLAIR reduction, which correlated with EOR, and reduced steroid dependency.

Individual 3D-printed fixation masks for radiotherapy: first clinical experiences

Purpose To show the feasibility of 3D-printed fixation masks for whole brain radiation therapy in a clinical setting and perform a first comparison to an established thermoplastic mask system. Methods Six patients were irradiated with whole brain radiotherapy using individually 3D-printed masks. Daily image guidance and position correction were performed prior to each irradiation fraction. The vectors of the daily position correction were compared to two collectives of patients, who were irradiated using the standard thermoplastic mask system (one cohort with head masks; one cohort with head and neck masks). Results The mean systematic errors in the experimental cohort ranged between 0.59 and 2.10 mm which is in a comparable range to the control groups (0.18 mm–0.68 mm and 0.34 mm–2.96 mm, respectively). The 3D-printed masks seem to be an alternative to the established thermoplastic mask systems. Nevertheless, further investigation will need to be performed. Conclusion The prevailing study showed a reliable and reproducible interfractional positioning accuracy using individually 3D-printed masks for whole brain irradiation in a clinical routine. Further investigations, especially concerning smaller target volumes or other areas of the body, need to be performed before using the system on a larger basis.