bluuebunny/crossref_metadata_2025_split huggingface dataset:
RADT-36. A SINGLE-CENTRE EXPERIENCE WITH HYPERARC FRACTIONATED STEREOTACTIC RADIOSURGERY [FSRS] FOR BENIGN BRAIN TUMOURS
Authors: Hicks Holly , Samuji Mohd , Barry Laura , Bennett Erica , Toomey Eoin , Kelly Paul 
Published: November 2023

Abstract

BACKGROUND
Treating benign brain tumours with fSRS may have radiobiologic and clinical advantages, such as lower rates of symptomatic oedema and radionecrosis[1]. HyperArc (HA, Varian Medical System) is an isocentric VMAT technique developed for non-coplanar, MLC-based stereotactic radiotherapy with automated optimizations and delivery. Here we report our initial clinical experience of HyperArc fSRS in treating benign brain tumours. MATERIALS AND

METHODS
We retrospectively reviewed 21 cases of benign brain tumours treated at the Bon Secours Radiotherapy Cork between May 2020-May 2023. Clinical and dosimetric parameters are reported.

RESULTS
A total of 21 patients were treated in a total of 105 SRS fractions, all using a 5-fraction regimen (5x5Gy, N = 20). The commonest tumour was meningioma (N = 9), followed by vestibular schwannoma (N = 7) and pituitary adenoma (N = 5). Median patient age was 59 years (range 26-86). Median PTV was 4.65 cc (IQR 1.9-14.6), median number of arcs was 4 (range 3-4), median PTV coverage was 99.6 % (IQR 98.0-99.9). Median prescription isodose was 79%. Median Paddick conformity index and gradient index was 0.86 (IQR 0.83-0.98) and 3.0 (IQR 2.9-3.2) respectively. Median follow-up was 7 months. No patient suffered from toxicity ≥ grade 2 (Common Toxicity Criteria, Version 5). Only 2/21 patients required steroid therapy during fSRS. No patient had a seizure.

CONCLUSION
HyperArc fSRS is a feasible option for benign brain tumours. Initial clinical experience in terms of plan quality and acute toxicity is encouraging. fSRS for benign brain tumours should be prospectively studied. REFERENCES: 1. Lehrer EJ et al IJROBP 2019 Mar1;103(3):610-630
RADT-47. MARGIN REDUCTION WITH THE INTRODUCTION OF INTRA-FRACTIONAL MONITORING USING IDENTIFY SGRT FOR FRAMELESS STEREOTACTIC CRANIAL RADIOSURGERY (SRS)
Authors: Tran Tai , Anderson Lee , Hu Yunfei , Gzelle Cecelia 
Published: November 2023

Abstract
The purpose of this study was to evaluate the potential for margin reduction in clinical treatment settings based on the accuracy of Varian Identify SGRT (Surface-Guided Radiation Therapy). The study considered various factors such as patient setup variations, intrafraction movement, and unique facial features. Identify version 2.3.1 was installed on a Truebeam v2.7 system and commissioned according to AAPM TG3021 test recommendations. Identify generated reports on patient offsets in all six degrees of freedom during motion monitoring. These offsets were retrospectively compared with radiographic images (CBCT and MV planar images) to determine the accuracy of patient positioning achieved using surface guidance. A retrospective analysis of 36 patients was performed for a total of 125 fractions. The characteristics of the patient cohort (age range from 39 – 92 years) consisted of a mixture of 8 benign, 28 malignant lesions, 11 single, 25 standard fully-fractionated treatments and anatomical sites such as parietal, frontal, ventricle, base of skull, pons and acoustic neuromas. RESULTS: show that for this clinical cohort, the variance between Identify and radiographic imaging ranges from -0.02 to 0.08 cm, -0.09 to 0.10 cm, -0.09 to 0.09 cm and -0.81 to 0.74 degrees for the vertical, longitudinal, lateral and rotation respectively. This average variance in the translational axes is 0.0cm ± 0.0014 cm, indicating no directional preference. The 3D vector of the displacement detected achievable by Identify is 1 mm within a 95% confidence interval (CI). Based on the findings, the researchers concluded that a minimum GTV-PTV (Gross Tumor Volume-Planning Target Volume) margin of 1 mm is appropriate for intrafraction monitoring with Identify SGRT on the TrueBeam system for stereotactic cranial treatments. This information can increase the radiation oncologist's confidence in patient positioning during treatment delivery and potentially lead to a decrease in the GTV-PTV margin.
CTIM-02. PHASE 2 TRIAL OF PEMBROLIZUMAB FOR PATIENTS WITH BRAIN METASTASES OF DIVERSE HISTOLOGIES
Authors: Brastianos Priscilla , Kim Albert , Giobbe-Hurder Anita , Lee Eudocia , Lin Nancy , Overmoyer Beth , Wen Patrick , Nayak Lakshmi , Cohen Justine , Dietrich Jorg , Eichler April , Heist Rebecca , Krop Ian , Lawrence Donald , Ligibel Jennifer , Tolaney Sara , Mayer Erica , Winer Eric , Bent Brittany , de Sauvage Magali , Ijad Nazanin , Larson Juliana , Marion Braxton , Nason Sally , Murthy Naina , Summers Elizabeth , Ratcliffe Sherry , Mahar Maura , Shih Helen , Oh Kevin , Cahill Daniel , Gerstner Elizabeth , Sullivan Ryan 
Published: November 2023

Abstract

BACKGROUND
Patients with brain metastases have limited treatment options.The PD-L1/PD-1 pathway is an immune suppressive mechanism in brain metastases.

METHODS
This was a single-arm phase 2 clinical trial evaluating the intracranial efficacy of pembrolizumab, a PD-1 inhibitor, in patients with brain metastases. The target accrual was 58 patients to achieve at least 52 evaluable patients. The primary endpoint was intracranial benefit (complete response, partial response, or stable disease by modified RANO criteria). The study design compared a null intracranial benefit rate of 10% against an alternative of 24%. If at least 8 patients among 52 had intracranial benefit, the primary efficacy endpoint would be met and pembrolizumab would be considered worthy of further study (type-I error of 10%, power of 89%).

RESULTS
In 57 evaluable patients, median age was 53 (range 28-80). Tumor histologies included breast (n = 35), NSCLC (n = 7), melanoma (n = 2), small-cell lung cancer (n = 2), sarcoma (n = 2), and other (n = 9). For patients with breast cancer, 16 patients had HER-2 positive, 17 had hormone-receptor positive and 11 patients had triple-negative disease. The study met its primary endpoint and achieved an intracranial benefit rate of 42.1% (90% confidence interval [CI]: 31-54%). Thirty-seven percent of breast cancer patients (90% CI: 24–52%) and 43% of NSCLC patients (90% CI: 13–77%) had intracranial benefit. All four breast cancer subtypes derived efficacy from pembrolizumab. Seven patients, who had either breast cancer, melanoma or sarcoma, had overall survival &gt;2 years. The extracranial benefit rate in patients with evaluable extracranial disease based on RECIST 1.1 criteria was 45% (90% CI: 31-59%). Median overall survival was 8.0 months (90% CI: 5.5-8.7 months). Grade 4 toxicities at least possibly related to treatment were observed in 2 patients: cerebral edema.

CONCLUSIONS
Our study of pembrolizumab met overall primary endpoint for intracranial benefit in patients with brain metastases across diverse histologies.
CTIM-07. PHASE IIB RANDOMIZED, BLINDED, CONTROLLED TRIAL EVALUATING NEOADJUVANT PD-1 BLOCKADE COMBINED WITH A2B5+ GLIOMA STEM-LIKE CELL LYSATE-LOADED DCV IN RECURRENT GLIOBLASTOMA (IDH1/2 -)- TRAIL IN PROGRESS
Authors: Yao Yu , Huang Xiaoming , Chen Di , Hu Lang , Zhou Bingyi , Li Chenwei , Chen Lingchao , Zhou Nan , Ji Chunxia , Wang Yuan , Zhou Liangfu 
Published: November 2023

Abstract
Our previous phase II randomized trials have determined that A2B5+ glioma stem-like cell lysate-loaded DC vaccine (GSC-DCV) demonstrates favorable safety and significantly extends the survival of glioblastoma (GBM) (NCT01567202). This study aims to investigate the clinical feasibility and efficacy of the GSC-DCV combined with aPD-1 mAbs neoadjuvant therapy in recurrent GBM (NCT04888611). GBM (IDH1/2 -) patients who had received radiotherapy and TMZ chemotherapy were enrolled in the study after pathologically confirmed recurrence. All patients received aPD-1 mAbs treatment (3mg/kg, up to 200mg) 14±5 days before surgery. Following surgery, eligible patients were randomized in a 1:1 ratio to receive either a combination treatment of aPD-1 mAbs with GSC-DCV or aPD-1 mAbs with placebo. The above-mentioned postoperative therapy was given every three weeks until disease progression or unacceptable toxicity. Besides evaluating treatment response using the iRANO criteria, MRI scans were conducted before each treatment and after surgery (in 72h) to evaluate tumor size/volume to analyze the relationship between tumor burden and prognosis. The primary endpoint of the study was overall survival, while the secondary endpoints included the evaluation of treatment-related adverse events (trAEs) and the measurement of indicators related to the immune response. From October 2021 through May 2023, a total of 22 patients were enrolled and successfully randomized. At the latest follow-up, the two groups were generally balanced with respect to baseline characteristics, encompassing age, gender, KPS, steroid use, MGMTp status, TERTp status, and tumor volume at registration. Notably, differences in survival were observed between the two groups, with respective follow-up periods ranging from 1.3 to 19.9 months and 1.0 to 12.1 months. The incidence of trAEs in all patients was 22.7%, with no grade 3 or higher trAEs observed thus far, and the main adverse event was reactive cutaneous capillary endothelial proliferation (RCCEP).
CTIM-15. T CELL RESPONSE DYNAMICS IN PHASE 3 GLIOBLASTOMA PATIENTS IMMUNIZED WITH AUTOLOGOUS DENDRITIC CELLS PULSED WITH AUTOLOGOUS TUMOR CELL LYSATE
Authors: Bosch Marnix , Liau Linda , Ashkan Keyoumars 
Published: November 2023

Abstract

BACKGROUND
331 glioblastoma patients were immunized with autologous dendritic cells (DCs) pulsed with autologous tumor cell lysate or placebo in a Phase 3 clinical trial. Immunization with the pulsed DCs was associated with extended overall survival in both newly diagnosed and recurrent disease. Objective: To characterize T cell responses and T cell response dynamics in patients immunized with autologous dendritic cells pulsed with autologous tumor cell lysate.

METHODS
we performed T cell receptor sequencing on peripheral blood mononuclear cells from both newly diagnosed and recurrent glioblastoma patients that were treated with the pulsed DCs. Timepoints from both before and after immunization were compared to understand T cell response dynamics.

RESULTS
Expansion of several hundred new T cell clones as well as more than 700 previously detected T cell clones was detected over time in both newly diagnosed and recurrent GBM patients who were treated with the pulsed DCs. Investigation of the dynamics of the response demonstrated that further expansion was triggered by ongoing immunizations. Correlations between T cell response data and clinical outcomes are ongoing.

CONCLUSION
Immunization with autologous DCs pulsed with autologous tumor cell lysate induces broad spectrum immune responses in patients with glioblastoma.
CTIM-25. EO2401 PEPTIDE IMMUNOTHERAPY + NIVOLUMAB +/- BEVACIZUMAB IN FIRST RECURRENT GLIOBLASTOMA: THE PHASE 1/2 EOGBM1-18/ROSALIE STUDY (NCT04116658)
Authors: Reardon David , Idbaih Ahmed , Vieito Maria , Ghiringhelli François , Stradella Agostina , Tabatabai Ghazaleh , Burger Michael C , Mildenberger Iris , Herrlinger Ulrich , Wen Patrick , Touat Mehdi , Wick Antje , González Macarena , Hervieu Alice , GilMartin Marta , Renovanz Mirjam , Gouttefangeas Cécile , Maia Ana , Bonny Christophe , Paillarse Jean-Michel , Chêne Laurent , Fagerberg Jan , Wick Wolfgang 
Published: November 2023

Abstract
EO2401 expands existing memory T cells recognizing protein sequences from gut bacteria, which cross-react with tumor associated antigens (TAAs). EO2401 contains three CD8 HLA-A2 epitopes with mimicry to glioblastoma-TAAs (IL13Rα2, BIRC5, and FOXM1) and the CD4 epitope UCP2. Patients received EO2401 (300μg/peptide, q2weeks x4, then every 4weeks) with nivolumab (3mg/kg, q2weeks) in cohorts: C1a (n = 21, Ex2→EN; option for symptom directed low-dose bevacizumab [sLDB; 5mg/kg, q2weeks] as anti-edema treatment); C2a/1 (n = 23, EN); C2a/2 (n = 15, EN+sLDB); C2b (n = 6, adjuvant EN+sLDB); C2c (n = 9, neoadjuvant ENx2→surgery→adjuvant EN+sLDB); C3 (n = 26, EN+bevacizumab, q2weeks, 10mg/kg). EO2401/nivolumab+/-bevacizumab safety profile consistent with profile of nivolumab, and when applicable bevacizumab, except the addition of local administration site reactions which occurred in 39% of patients; 96% of events Grade 1/2 and 4% Grade 3. Immune monitoring (peripheral blood, ELISPOT, tetramer assessments) demonstrated expanded mimic specific CD8 T cells with cross-reactivity against the targeted human TAAs. In C2a/1 (83% tested) and in C3 (81% tested), 89% and 95% of tested patients showed expansion. Expansions were early (week 2 after starting EO2401), durable (up to 23 months), and robust (approximately 30% of all peripheral CD8 T cells were mimic specific in 3 clinical responders). In C2c, surgery specimens after two EO2401/nivolumab doses showed increased tumor T cell infiltration versus pre-treatment tumor in 5 of 6 patients. Addition of sLDB to EO2401/nivolumab prolonged treatment duration vs EO2401/nivolumab alone by reducing edema likely worsened by study therapy induced immune cell infiltration. Integration of bevacizumab with EO2401/nivolumab in C3 further increased efficacy in C3. C2a/1vsC2a/2vsC3: median treatment duration 1.4vs3.2vs4.8 months, disease control rate 22%vs40%vs88%, median PFS 1.6vs3.6vs5.5 months; median survival 9.0vs12.6vstoo early (C3 median FU 8.3 mo, survival ongoing up to 2 years). Further follow-up will be presented.
CTIM-28. FIRST-IN-HUMAN TRANSGENE DETECTION 17 MONTHS POST-ADENOVIRAL THERAPY
Authors: Varela Maria , West Molly , Faisal Syed M , Comba Andrea , Castro Maria , Lowenstein Pedro 
Published: November 2023

Abstract
Gene therapy was developed as a promising approach to treat high-grade glioma (HGG). One of the main strategies is suicide gene therapy. This method introduces the expression of an enzyme that converts a non-toxic prodrug to an active toxic compound, thereby causing the death of transduced cells. Specifically, herpes simplex virus thymidine kinase (HSV1-TK) converts the pro-drug valacyclovir into phosphorylated valacyclovir. When cells initiate DNA replication, phosphorylated valacyclovir is incorporated into de novo DNA strands, causing DNA replication to arrest, followed by apoptosis. This approach is lethal only for replicating cells, (i.e., tumor cells), without harming non-dividing brain cells. An infected cell, expressing HSV1-TK, requires two further simultaneous events to induce cell death: (1) to be exposed to valacyclovir and (2) enter into cell division. Without either of these events, the cell will remain alive and will still express HSV1-TK. Previous work from our lab in murine models demonstrated the long-term expression of transgenes β-galactosidase and HSV1-TK up to 12 months after viral therapy administration (Zermansky et al 2001; Barcia et al 2007). We recently completed and published our Phase I clinical trial (NCT01811992), where dual vector viral therapy, Ad-TK/Ad-Flt3L, and valacyclovir was administered to patients suffering from HGG (Umemura et al, 2023). In paraffin embedded tumor samples from recurrent tumors to our surprise we detected HSV1-TK immunoreactivity up to 17 months after initial treatment. HSV1-TK immunoreactive cells were found in five out of eight patients’ samples. We analyzed HSV1-TK expression to further characterize HSV1-TK positive cells using combination immunohistochemistry, allowing us to identify them as tumor cells, neurons, or astrocytes. The presence of HSV-TK positive cells in the recurrent tumors strongly supports the administration of further cycles of pro drug (valacyclovir), following Ad-TK administration.
CTIM-29. FINAL EFFICACY AND CORRELATIVE ANALYSES OF 2-THE-TOP: A PILOT STUDY OF TTFIELDS (OPTUNE) PLUS PEMBROLIZUMAB PLUS MAINTENANCE TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: Tran David , Chen Dongjiang , Le Son , Ghiaseddin Ashley 
Published: November 2023

Abstract

INTRODUCTION
TTFields induce anti-tumor immunity via the STING and AIM2 inflammasomes. Thus, TTFields-treated GBM cells may provide a complete in situ vaccination platform and synergize with immune checkpoint inhibitors to prolong survival in GBM patients.

METHODS
We enrolled 26 ndGBM patients in a pilot study combining TTFields, pembrolizumab and maintenance temozolomide (TMZ). To distinguish immune effects of TTFields from pembrolizumab, TTFields starts at cycle 1 of TMZ while pembrolizumab (200mg Q3Wks) at cycle 2. The primary endpoint is PFS versus a case-matched cohort of 56 patients from the EF-14 study. Secondary endpoints include OS, toxicity, and mechanism of response by multiomics of PBMCs and tumors.

RESULTS
The median age was 60.5 years. Fourteen (54%) had biopsy only or partial resection. Nineteen (73%) had unmethylated MGMT and 3 (11.5%) had an IDH mutation. Median PFS was 12.0 months versus 5.8 months in controls (HR = 0.377; 95CI: 0.217-0.653; P = 0.0026). Median OS was 24.8 months versus 14.6 months in controls (HR = 0.522; 95CI: 0.301-0.905; P = 0.047). Importantly, residual tumor size positively correlated with the objective response and survival. Six of 15 (40%) patients with measurable disease achieved partial to complete response. The most common SAEs were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (7.7%) patients, respectively. Molecular analyses confirmed robust T cell activation by TTFields via T1IFN-dependent plasmacytoid dendritic cells (Spearman coefficient = -0.8; P = 0.014). Successful clonal replacement of the most expanded T cell clones after pembrolizumab strongly predicted objective responses to the triple combination in a Cox HR fit model (concordance rate = 0.876; P = 0.031).

CONCLUSIONS
The triple combination was well tolerated and demonstrated promising efficacy in ndGBM. Bulky residual disease was associated with better outcomes, consistent with the in-situ immunizing properties of TTFields, which synergize with pembrolizumab. Additional molecular analysis will be updated
CTIM-31. CLINICAL IMPACT OF ADDING PEMBROLIZUMAB TO STANDARD OF CARE CHEMORADIATION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Ambady Prakash , Barajas Ramon , Fu Rochelle , Szidonya Laszlo , Huddleston Amy , Popp Lauren , Moussalli Dana , Turchan Maria , Diaz Claire , Edward Neuwelt 
Published: November 2023

Abstract

BACKGROUND
Standard of care (SOC) for newly diagnosed glioblastoma includes radiotherapy plus temozolomide followed by 6 adjuvant cycles monthly temozolomide per the Stupp protocol. We report the secondary objectives of a single arm phase 2 study evaluating the clinical impact of the addition of immune check point inhibitor pembrolizumab to this standard therapy.

METHODS
Patients with histopathology proven glioblastoma (WHO 4) eligible to receive SOC were prospectively enrolled to received pembrolizumab 200 mg iv every 3 weeks for up to 35 doses, progression, development of dose limiting toxicity or withdrawal of consent. Patients also receive ferumoxytol steady state MRI scans at baseline, 4 weeks after the last day of standard of care stereotactic radiosurgery or chemoradiotherapy, every 9 weeks thereafter until suspected radiographic progression, and then within 4 weeks from suspected radiographic progression. Primary endpoints of the study were to test the sensitivity and specificity of ferumoxytol steady state imaging for response assessment in this cohort. Secondary objective includes Progression free (PFS) and Overall survival (OS) and toxicity. PFS and OS were analyzed using Kaplan-Meier method.

RESULTS
A total of 52 patients (19 F, 33 M; 43 IHD wt and 9 IDH mu; 25 MGMT gene methylated, 27 unmethylated) were enrolled and included. At a median Follow up of 14.3 months, median PFS was 10.7 m (95% CI:8.1-12.6) and median OS was 14.4 m (95%CI: 12.5-16.9). Two grade 3 or higher toxicities (bullous dermatitis and Steven-Johnson syndrome) were attributed to pembrolizumab.

CONCLUSIONS
Although, the addition of pembrolizumab to SOC was well tolerated in most patients, this study did not see any meaning clinical benefit in PFS or OS with the addition of pembrolizumab in patients with newly diagnosed glioblastoma. Analysis for the primary imaging endpoint is ongoing.
CTIM-32. A PARALLEL COHORT PHASE 2 STUDY OF REGORAFENIB PLUS NIVOLUMAB FOR RECURRENT OR METASTATIC SOLID TUMORS: RESULTS IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (GBM) OR ANAPLASTIC ASTROCYTOMA (AA)
Authors: Simonelli Matteo , Caccese Mario , Larrieu-Ciron Delphine , Franceschi Enrico , Kim Tae Min , Fayette Jerome , Freres Pierre , Robert Marie , Eoli Marica , Luce Sylvie , Portnow Jana , Hirata Yuki , Enya Kengo , Waxman Ian , Jin Lixian , Shah Dipam , Drews Uta , Berre Marie-Aude Le , Lombardi Giuseppe 
Published: November 2023

Abstract

INTRODUCTION
The multikinase inhibitor regorafenib improved overall survival (OS) versus lomustine in relapsed GBM in the randomized phase 2 REGOMA study. The aim of this study was to evaluate the efficacy of regorafenib combined with nivolumab in this setting (NCT04704154).

METHODS
Patients aged ≥ 18 years with recurrent GBM/AA (WHO 2016 classification) after radiotherapy plus temozolomide, and an ECOG performance status (PS) of 0/1, received oral regorafenib 90 mg/day on days 1–21 and intravenous nivolumab 480 mg on day 1 of each 28-day cycle. If tolerated, the regorafenib dose could be escalated to 120 mg/day from cycle 2. Prior regorafenib treatment or immunotherapy was not allowed. The primary endpoint was objective response rate (ORR) using RANO criteria. Secondary endpoints included progression-free survival (PFS), OS, and safety (MedDRA; CTCAE v5.0).

RESULTS
Of the 36 patients enrolled, 30 were treated and were eligible for analysis. Median age was 60 years, 63% had an ECOG PS of 1, and 90% had GBM (10% AA). All patients discontinued treatment as of the primary analysis (March 9, 2023). One patient had a best-overall partial response (ORR; 3%) and nine (30%) had stable disease. Median number of cycles of regorafenib and nivolumab infusions was three. Median PFS (RANO) was 2.7 months (80% CI 1.8, 7.3) and 6-month PFS was 31.5%. Median OS was 8.0 months (80% CI 4.6, 12.4) and 12-month OS was 33.7%. Thirteen patients (43%) had grade 3/4 treatment-emergent adverse events (TEAEs), which were drug-related in 12 patients (40%). The most common drug-related grade 3/4 TEAEs were AST increase (13%), ALT increase (10%), and hypertension (10%). There were no immune-mediated serious TEAEs or drug-related grade 5 TEAEs.

CONCLUSION
The efficacy results of this study do not support further evaluation of regorafenib combined with nivolumab in GBM/AA. The safety profile was acceptable and manageable.