GammaTile® brachytherapy in the treatment of recurrent glioblastomas

Background GammaTile® (GT) is a recent U.S. Food and Drug Administration (FDA) cleared brachytherapy platform. Here, we report clinical outcomes for recurrent glioblastoma patients after GT treatment following maximal safe resection. Methods We prospectively followed twenty-two consecutive Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients (6 O6-Methylguanine-DNA methyltransferase methylated (MGMTm); sixteen MGMT unmethylated (MGMTu)) who underwent maximal safe resection of recurrent tumor followed by GT placement. Results The cohort consisted of 14 second and eight third recurrences. In terms of procedural safety, there was one 30-day re-admission (4.5%) for an incisional cerebrospinal fluid leak, which resolved with lumbar drainage. No other wound complications were observed. Six patients (27.2%) declined in Karnofsky Performance Score (KPS) after surgery due to worsening existing deficits. One patient suffered a new-onset seizure post-surgery (4.5%). There was one (4.5%) 30-day mortality from intracranial hemorrhage secondary to heparinization for an ischemic limb. The mean follow-up was 733 days (range 279-1775) from the time of initial diagnosis. Six-month local control (LC6) and twelve-month local control (LC12) were 86 and 81%, respectively. Median progression-free survival (PFS) was comparable for MGMTu and MGMTm patients (~8.0 months). Median overall survival (OS) was 20.0 months for the MGMTu patients and 37.4 months for MGMTm patients. These outcomes compared favorably to data in the published literature and an independent glioblastoma cohort of comparable patients without GT treatment. Conclusions This clinical experience supports GT brachytherapy as a treatment option in a multi-modality treatment strategy for recurrent glioblastomas.

Skull Base Meningiomas: Is Surgical Resection Enough? Outcome Evaluation and Prognostic Factors Analysis in a Single-Center Cohort

Background Surgical resection represents the mainstay of treatment in skull base meningiomas (SBMs). Considering the high recurrence rate reported, an adjuvant radiation therapy (RT) treatment should be considered. The aim of this study was to evaluate the progression-free survival (PFS), overall survival (OS), and prognostic factors conditioning outcome. Methods Patients receiving surgical resection for grade I SBMs were included. The extent of resection (EOR) was dichotomized as gross total resection (GTR) and subtotal resection (STR). RT was administered only in patients receiving STR. Clinical outcome was evaluated by brain magnetic resonance imaging (MRI) performed every 6 months for the first year and yearly thereafter. Results From January 2000 to December 2015, 123 patients were treated. The majority were females (70.7%), with a Karnofsky Performance Score (KPS) ≥80 (95%), and symptoms at diagnosis (91%). GTR was performed in 30% of cases and STR in 70%. RT was performed in 18 (20.9%) patients at diagnosis and in 29 (33.7%) patients at progression. Improvement or stability of neurologic status was obtained in 78.9% of patients. The median follow-up time was 91 months (range: 40–230 months). Local recurrence occurred in 34 (27.6%) patients at a median time of 45 months (range: 6–214 months). The median, 2-, 5-, and 10-year PFS were 193 months, 89.3, 81.8, and 72.5%, respectively. On univariate and multivariate analyses, factors impacting on PFS were EOR, tumor location, neurologic postoperative status, and adjuvant RT in STR. Conclusions A safe surgical resection followed by RT adjuvant treatment could represent the better choice to obtain local control maintaining neurologic integrity. Our data underlined the value of adjuvant RT in incompletely resected meningiomas.

Combined Application of Sodium Fluorescein and Neuronavigation Techniques in the Resection of Brain Gliomas

Objectives: To explore the effectiveness and safety of the combined application of sodium fluorescein and neuronavigation techniques in the resection of brain gliomas in different locations and patients of different ages.Methods: Fifty clinical cases of brain gliomas treated at the Department of Neurosurgery of Beijing Tiantan Hospital were collected from March 2014 to March 2019. These cases were divided into a supratentorial group (24 cases) and a brainstem group (26 cases) based on location and an adult group (28 cases) and a pediatric group (22 cases) based on age. Fluorescein-guided surgery was performed: the adult group received 5 mg/kg sodium fluorescein before opening the dura, while the pediatric group received 2.5 mg/kg during resection. Tumor visualization was evaluated by the enhancement of yellow fluorescein and considered “satisfactory” if the illumination demarcated the tumor boundary. Additionally, the consistency between fluorescein and neuronavigation was analyzed. The Karnofsky performance score (KPS) of all patients was recorded and assessed at admission, discharge, and the 6-month follow-up.Results: In the 28 adult cases, 4 were unsatisfactory, while in the 22 pediatric cases, 2 were unsatisfactory; in 7 cases, there was an inconsistency between yellow fluorescein enhancement and neuronavigation, 6 were in the supratentorial group, and 1 was in the brainstem group. Statistical analysis showed no significant differences in the satisfactory rate between the adult and pediatric groups (P = 0.575), whereas there were significant differences inconsistency between the supratentorial group and brainstem group (P = 0.031). The mean KPS at admission was between 70 and 100, which was not significantly different from that at discharge (P = 0.839), but the KPS at the 6-month follow-up was significantly higher than that at admission (P = 0.041).Conclusions: The consistency between sodium fluorescein and the neuronavigation system was higher in the brainstem group than in the supratentorial group; a half dose of sodium fluorescein (2.5 mg/kg) was sufficient for pediatric patients. The combined utilization of sodium fluorescein and neuronavigation techniques may confer glioma patients the opportunity to obtain better clinical outcomes after surgery.

Reirradiation of Whole Brain for Recurrent Brain Metastases: A Case Report of Lung Cancer With 12-Year Survival

Whole brain radiotherapy (WBRT) for brain metastases (BMs) was considered to be dose limited. Reirradiation of WBRT for recurrent BM has always been challenged. Here, we report a patient with multiple BMs of non-small-cell lung cancer (NSCLC), who received two courses of WBRT at the interval of 5 years with the cumulative administration dose for whole brain as 70 Gy and a boost for the local site as 30 Gy. Furthermore, after experiencing relapse in the brain, he underwent extra gamma knife (GK) radiotherapy for local brain metastasis for the third time after 5 years. The overall survival was 12 years since he was initially diagnosed with NSCLC with multiple brain metastases. Meanwhile, each time of radiotherapy brought a good tumor response to brain metastasis. Outstandingly, during the whole survival, he had a good quality of life (QoL) with Karnofsky Performance Score (KPS) above 80. Even after the last GK was executed, he had just a mild neurocognitive defect. In conclusion, with the cautious evaluation of a patient, we suggest that reirradiation of WBRT could be a choice, and the cumulative radiation dose of the brain may be individually modified.

Higher Efficacy of TBI + Cyclophosphamide Than TBI + Fludarabine As Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia: An Analysis By the Acute Leukemia Working Party of the EBMT

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) is a standard of care for adults with high-risk acute lymphoblastic leukemia (ALL) in first or subsequent complete remission (CR). Myeloablative total body irradiation (TBI) combined with cyclophosphamide (Cy) is the most frequently used conditioning regimen. In order to reduce toxicity Cy may be replaced by fludarabine (Flu). The goal of this registry-based, retrospective study was to compare outcomes of allo-HCT following TBI/Cy vs. TBI/Flu conditioning. PATIENTS AND METHODS: Included in the analysis were 2255 patients aged 18-65 years, treated with allo-HCT from either a matched sibling (43%) or unrelated (57%) donor in CR1 (83%) or CR2 (17%), between the years 2010-2020. Patients with Ph(-) B-ALL, Ph(+) B-ALL, and T-ALL were represented in equal proportions. TBI 12Gy + Cy was used in 2105 cases while TBI 12Gy + Flu was administered to 150 patients. Patients treated with TBI/Flu were significantly older (median 35 years vs. 33 years, p=0.006), with poorer Karnofsky performance score (<90, 27% vs. 20%, p=0.03), more frequently transplanted from unrelated donors (71% vs. 57%, p=0.0007) with less frequently use of bone marrow as a source of stem cells (5% vs. 21%, p<0.0001), and in more recent year (median 2018 vs. 2015, p<0.0001). RESULTS: Engraftment rate was 99% for both TBI/Cy and TBI/Flu patients. In a univariate analysis the use of TBI/Cy as compared to TBI/Flu was associated with a tendency to reduced incidence of relapse (24% vs. 29% at 2 years, p=0.1), increased incidence of grade 2-4 acute graft versus host disease (GVHD, 35.5% vs. 28%, p=0.08) and improved leukemia-free survival (LFS, 62% vs. 57%, p=0.18). The rates and causes of non-relapse mortality (NRM) did not differ significantly between the two conditioning groups. In a multivariate model adjusted for other prognostic factors, TBI/Cy conditioning was associated with reduced risk of relapse (HR=0.69, p=0.049) and increased risk of grade 2-4 acute GVHD (HR=1.57, p=0.03) without significant effect on other transplantation outcomes. An additional analysis was performed with TBI/Cy treated patients (n=132) matched strictly to those treated with TBI/Flu (n=132) in terms of disease subtype, disease status and donor type with the nearest neighbor for patient age, patient and donor sex, in vivo T-cell depletion, Karnofsky score and source of stem cells; the use of TBI/Cy as compared to TBI/Flu was associated with significantly reduced rate of relapse (18% vs. 30% at 2 years, p=0.015) and a tendency to an improved LFS (65% vs. 59%, p=0.07) and overall survival (OS, 73% vs. 68%, p=0.16) without effect on NRM and GVHD. CONCLUSIONS: The use of myeloablative TBI/CY as conditioning prior to allo-HCT for adult patients with ALL in CR1 or CR2 is associated with stronger anti-leukemic effect leading to significantly lower relapse rate compared to TBI/Flu and therefore should be likely considered a preferable regimen. Disclosures Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Labopin: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Forcade: Novartis: Consultancy, Other: Travel Support, Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support. Huynh: Jazz Pharmaceuticals: Honoraria. Spyridonidis: Menarini: Current Employment. Perić: therakos: Honoraria; servier: Honoraria; MSD: Honoraria; Astellas: Honoraria; NOVARTIS: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria. Mohty: Pfizer: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria.

Long-Term Outcome of Peripheral Blood Autologous Stem Cell Transplantation (AutoSCT) for De Novo Acute Myeloid Leukemia in Patients Achieving First Complete Remission after One Vs Two Induction Courses: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Achieving a first complete remission (CR1) is the primary goal in the treatment of AML and is an important prognostic factor for transplantation outcome in general and even more so for autologous transplantation (AutoSCT). However, there are no data for AutoSCT indicating whether the number of chemotherapy courses (1 vs 2) needed to achieve CR1 is of prognostic significance for transplantation outcome. Methods: Using the EBMT/ALWP registry, we compared transplantation outcomes of adult patients (pts) aged ≥18 years with de novo AML that underwent a peripheral blood AutoSCT in 2000-2019 in CR1 achieved following one vs two chemotherapy courses. The primary outcome was the Leukemia Free Survival (LFS). Multivariate analysis (MVA) adjusting for differences between the groups and knowns factors were performed using Cox's proportional- hazards regression model for outcomes. Results: 1825 pts were included: 1532 (84%) with one and 293 (16%) with two induction chemotherapies courses. Time from diagnosis to AutoSCT was 4.7 (3.9-5.8) vs 5.7 (4.7-7.1) months, respectively (p<0.001). Median follow-up was 7.9 (95% CI: 7.4-8.4) and 7.7 (95% CI: 7.0-8.6) years, respectively (p=0.8). Median year of transplant was 2005 (2002-2009) and 2004 (2002-2007), respectively (p<0.001). Median age was 49 (38-57) and 47 (36 -56) years (p=0.06); 54% and 57 % of both groups were male, (p=0.35). Cytogenetic risk as defined by the Medical Research Council (MRC) classification, differed significantly between the two induction groups (p<0.001). Patients with one induction had a higher percentage of favorable-risk than those with two inductions (18% vs 14%), and a lower percentage of adverse-risk cytogenetics (6% vs 13%), while 76% and 73%, respectively, had intermediate-risk cytogenetics (missing data-11percentage). Karnofsky performance score (KPS) > 90 was higher in pts receiving 1 vs 2 inductions, 71% and 58% of pts, respectively (p<0.001). The most frequent conditioning regimen for both groups was Busulfan (Bu) /Cytoxan (Cy) 50% vs 45% and Bu / Melphalan (Mel) 17% and 19%, respectively, for induction groups 1 and 2, respectively. Day 30 neutrophil engraftment incidence was 96% and 96.5%. Five -year non-relapse mortality (NRM) was 6.2% vs 6.0% for pts achieving CR1 with 2 vs 1 chemotherapy courses, respectively, and did not differ significantly (HR=1.31 (95% CI: 0.81-2.10), p=0.27). Five -year relapse incidence (RI) was higher :67.2% vs 52.3%, (HR=1.46 (95% CI: 1.25-1.72), p<0.001), while LFS and overall survival (OS) were lower for pts achieving CR1 with 2 vs 1 course of chemotherapy: 26.6% vs 41.7% (HR= 1.42 (95% CI: 1.22-1.66), p<0.001) and 36.2% vs 53.3%, (HR=1.48 (95% CI: 1.25-1.75), p<0.001), respectively (Figure). Other significant prognostic factors in MVA were adverse- compared to good risk cytogenetics and older age (per 10 years) for all AutoSCT outcome parameters including RI, NRM, LFS and OS; intermediate compared to good risk cytogenetics for RI, LFS and OS; female gender for RI and LFS ;and year of transplant for RI and OS. Conclusions: The five -year RI was higher and transplantation outcomes significantly inferior in pts with AML undergoing AutoSCT but who received two lines of chemotherapy to achieve CR1. Such pts may benefit from additional novel therapies in the conditioning or post-AutoSCT or be considered for allogeneic transplantation in an attempt to reduce their high RI and improve outcomes. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Huynh: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Gilead: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

IOTG-02. Glioma Supra Marginal Incision Trial (G-SUMIT): a phase II pilot randomized control trial to assess the feasibility of “supra-marginal” surgical resection of malignant glioma

High grade gliomas are the most common primary malignant brain tumor in adults having a median survival of only 13–16 months. This is despite the current standard of maximal safe surgical resection followed by fractionated radiotherapy and chemotherapy. Extending the tumor resection limit beyond the GAD-enhancing margin (i.e. supra-marginal resection) could in principle provide an added survival benefit as it has been shown that >80% of post-operative tumor recurrence is within a 2cm region surrounding the original GAD-enhancing margin. However, this must be weighed against the risk of potential damage to functional brain tissue. In this phase II pilot randomized control trial (RCT), we aim to assess the feasibility of “supra-marginal” resection extending 1cm beyond the enhancing tumor in adults with radiographic evidence of GAD-enhancing intra-axial tumour consistent with high grade glioma in a safe anatomical location and a Karnofsky Performance Score > 60. With six academic centres participating, we aim to enroll 72 patients over two years. Currently, four patients have already been enrolled in the first four months. Primary outcomes include evaluating the feasibility of performing a large-scale trial with regards to recruitment, allocation and outcome documentation as well as safety data. Secondary outcomes include determining if there is an increased survival benefit with supra-marginal resection and impact on quality of life. Our pilot RCT will test the feasibility of comparing standard gross total resection of GAD-enhancing tumour and supra-marginal resection to prepare for a larger definitive multicentre RCT.

INNV-09. SURGICAL STRATEGIES FOR OLDER PATIENTS WITH GLIOBLASTOMA

OBJECTIVE Though image-guided surgery with intraoperative magnetic resonance imaging (IoMRI) is associated with higher extent of resection, we aimed to determine the clinical outcome of its use, compared to other less time-consuming intraoperative ultrasound (IoUS), in this patient population. METHODS Clinical data of 221 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination of IoMRI + IoUS at Yale New Haven Hospital and Memorial Sloan Kettering Cancer Center were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed, including predictors of overall survival. RESULTS The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (HR=0.85, 95% CI 0.49-1.47; P= 0.56) or Karnofsky Performance Score (KPS) at 6 weeks postoperatively (OR=0.51, 95% CI 0.22-1.15; P= 0.102). On the contrary, the length of surgery (LOSx) was significantly longer (P< 0.0001) in the IoMRI group. Postoperative complications were significantly less in the IoUS-only group (OR=0.17, 95% CI 0.3-0.46; P=0.002) and in patients who had a preoperative KPS score of 70 or higher (OR=0.092, 95% CI 0.018-0.47; P=0.004). Patients with relatively lower preoperative KPS scores (< 70) showed significant clinical improvement at 6 weeks postoperatively (P=0.0002). Patients with postoperative complications were more likely to have lower KPS scores at 6 weeks postoperatively (OR=0.30, 95% CI 0.10-0.89; P= 0.031), while increased extent of resection was associated with improved KPS scores at 6 weeks postoperatively (OR=2.171, 95% CI 1.22-3.87; P= 0.009). CONCLUSION Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS scores. The use of IoMRI in this patient population does not appear to yield any survival benefit over IoUS but instead significantly prolongs the length of surgery, increasing the risk for potential postoperative complications.

PATH-12. CLINICAL AND PATHOLOGICAL ANALYSIS OF 43 PATIENTS WITH EPITHELIOID GLIOBLASTOMA

BACKGROUND AND PURPOSE Epithelioid glioblastoma (eGBM) is a rare and aggressive subtype of glioblastoma. The clinical characteristics, pathological features and radiological findingsare still not well characterized. METHODS The clinical data of 43 patients with eGBM confirmed pathologically after surgery in Guangdong Sanjiu Brain Hospital from June 2015 to January 2021 were reviewed, and to investigate the clinical, pathological and imaging characteristics of the eGBM. RESULTS The range of patients' age was from 5 to 70 years (median 39 years). There were 24 males and 19 females. The median karnofsky performance score (KPS）at diagnosis was 70 (40-90). The most common symptom were headache (81.4%), and other common symptoms included nausea or vomiting (44.1%), limb weakness (30.2%), disturbance of consciousness (20.9%) and seizures (9.3%). Most of the tumors (97.6%) were located in the cerebral hemisphere ,except for one case located in the cerebellum,and with an average diameter of 5.3 cm (2.5-9.4 cm). There were 2 cases of intracranial metastasis and 7 cases of spinal cord metastasis in MRI. In pathologic examination, immunohistochemistry showed all the patients were IDH1 wild-type (43/43) and H3K27M wild-type(34/34). 25 (58.1%) of cases harbored BRAF mutation and 19 (44.2%) cases of MGMT positive. Most of patients were positive for GFAP, P53, Olig-2 and ATRX. CONCLUSION Epithelioid glioblastoma is more common in adults, most of which are located on the supratentorial, intracranial and spinal cord dissemination may occur. Half of patients showed BRFA mutation and maybe benefit from targeted therapy.These findings may help clinicians understand and treat epithelioid glioblastoma better.

Granulocyte Colony-Stimulating Factor for Treatment of Patients with Chronic Traumatic Brain Injury: A Preliminary Pre-Post Study

Chronic traumatic brain injury (TBI) can cause permanent disability and thereby negatively affect patients, families, and society. Currently, there is no effective treatment for patients with chronic TBI. One possible option is granulocyte colony-stimulating factor (G-CSF), which has potential neuroregenerative and neuroprotective effects through its ability to mobilize hematopoietic stem cells and increase neurogenic growth factor levels. Previous studies have shown that G-CSF administration is safe for patients with neurological diseases such as stroke and dementia. The present study aimed to explore the safety and efficacy of G-CSF use in patients with chronic TBI. Methods: 38 patients with chronic TBI were administered 3-day rounds of G-CSF (10 μg/kg per day) once a month for 6 months. These patients were clinically evaluated using the modified Rankin scale (mRS) and Karnofsky Performance Score (KPS). Laboratory measures of the leucocyte counts and differential count percentage were also assessed. Results: At the 6-month follow-up, further assessment showed that patients tolerated the treatment well with only mild and transient side effects being observed. Further clinical evaluation showed significant improvements in mRS and KPS after G-CSF treatment. Laboratory results also confirmed the action of the medication, with increased leukocytosis and band forms. Conclusions: The results suggest that 6-month chronic G-CSF treatment is safe for patients with chronic TBI and may provide clinical benefits and neurological improvements. The adverse effects of the treatment, however, are transient and usually tolerable. Thus, these preliminary findings suggest that future clinical trials of G-CSF use in patients with chronic TBI are warranted.