bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSIG-31. T-TYPE CALCIUM CHANNEL BLOCKERS INDUCE METABOLIC ALTERATIONS AND APOPTOSIS IN MEDULLOBLASTOMA CELLS
Authors: Sedeeq Mohammed , Maklad Ahmed , Feng Zikai , Dutta Taush , Wilson Richard , Guven Nuri , Azimi Iman 
Published: November 2022

Abstract
Medulloblastoma (MB) is the most common malignant paediatric brain tumour. In our previous studies, in a screen of a panel of calcium channel modulators in our novel high-throughput 3D assay, we identified T-type (CaV3) channel inhibitors, mibefradil and NNC-55-0396 (NNC) as selective inhibitors of MB cell growth. Mibefradil was originally approved for the treatment of hypertension and angina pectoris, and recently successfully completed a Phase-I trial for recurrent high-grade glioma. NNC is an analogue of mibefradil with multiple advantages compared to mibefradil that makes it attractive for potential future clinical trials. T-type channels have a unique low voltage-dependent activation/inactivation, and many studies suggest that they have a direct regulatory role in controlling Ca2+ signalling in non-excitable tissues, including cancers. In this study, we characterized the effect of mibefradil and NNC on MB cells and elucidated their mechanism of action. This study demonstrates that the induction of toxicity in MB cells is selective to T-type but not to L-type Ca2+ channel inhibitors. Addition of CaV3 inhibitors to vincristine sensitised MB cells to this MB chemotherapeutic agent, suggesting an additive effect. Furthermore, CaV3 inhibitors induced cell death in MB cells via apoptosis. Supported by proteomics data and cellular assays, apoptotic cell death was associated with reduced mitochondrial membrane potential and reduced ATP levels, which suggests that both compounds alter the metabolism of MB cells. We also identified that CACNA1H (encoding the CaV3.2 protein) is significantly upregulated in aggressive Groups 3 and 4 MB patient samples, and its higher expression is associated with higher metastasis and lower patient survival rates. This study offers new insights into the action of mibefradil and NNC and will pave the way to test these molecules or their analogues in pre-clinical MB models alone and in combination with vincristine to assess their suitability as a potential MB therapy.
CSIG-35. TARGETING HYPOXIC CANCER CELLS IN MEDULLOBLASTOMA
Authors: Kuranaga Yuki , Van Meir Erwin 
Published: November 2022

Abstract
New treatment approaches are urgently needed for children with medulloblastoma (MB) to augment survival and reduce the long-term side effects from the treatment. Malignant tumors often display hypoxic regions where hypoxia-induced transcription factors (HIFs) increase the expression of genes that promote tumor growth (e.g., metabolic adaptation and invasion/metastasis). Based on the known roles of HIF in many solid tumors, we hypothesized that Hypoxia/HIFs contribute to MB cell growth and targeting HIF proteins is a viable strategy for treating MB. To test our hypothesis, first, we exposed MB cell lines (ONS-76; Shh and D556; Group 3) to 1% hypoxia in cell culture. We found increased expression of both HIF1a and HIF2a proteins and activation of a hypoxia-response element driven luciferase reporter assay. Treatment of the cells with 64B, an arylsulfonamide HIF inhibitor abrogated reporter activity and reduced expression of hypoxia-induced genes (GLUT-1, VEGF). Next, we used CRISPR/Cas9 to knockout singly or in combination HIF1a/HIF2a genes. The inhibition of HIF reporter activity by 64B was partially canceled in single HIF-KO cells and completely canceled in double HIFs-KO cells, showing both isoforms were active. Second, to investigate HIFs can be therapeutic targets, we established orthotopic human MB xenografts in mice. We first examined the tumor for the presence of hypoxic areas and used pimonidazole (Hypoxyprobe) injections followed by immunohistochemistry and found hypoxic areas throughout the tumors where tumor cells expressed HIF1a and/or HIF2a. Evaluation of human MB samples for HIF1/2 expression is also ongoing. Next, we plan on injecting mice with cells devoid of HIFs genes and examine their growth. We will also treat the mice with 64B to test whether it has anti-tumor effects and extends survival. In conclusion, these results indicate that HIF activation is part of the pathobiology of MB and HIF proteins may be a target for MB treatment.
CSIG-41. SENSITIZING CANCER CELLS TO TUMOR TREATING FIELDS (TTFIELDS) BY INHIBITION OF PI3K
Authors: Klein-Goldberg Anat , Voloshin Tali , Zemer-Tov Efrat , Paz Rom , Koren Lilach , Wainer-Katsir Kerem , Volodin Alexandra , Koltun Bella , Brant Boris , Barsheshet Yiftah , Kan Tal , Cohen Gadi , David Cfir , Khalil Tharwat Haj , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: November 2022

Abstract
Tumor Treating Fields (TTFields) are alternating electric fields, which disrupt cellular process critical for cancer cell survival and tumor progression. TTFields therapy is approved for the treatment of glioblastoma (GBM) and unresectable malignant pleural mesothelioma, and is being tested in clinical studies for the treatment of other solid tumors, including ovarian cancer, non-small cell lung carcinoma (NSCLC), and hepatocellular carcinoma (HCC). The current study aimed to detect potential mechanisms that may reduce cellular sensitivity to TTFields, and target these pathways in order to re-sensitize the cells to TTFields. Cancer cells (Ovarian A2780, GBM U-87 MG, and NSCLC H1299) that display reduced sensitivity to TTFields were generated by continuous long-term TTFields application (7 or 13 days, depending on the cell line). A Luminex multiplex assay revealed activation of the PI3K/AKT/mTOR signaling pathway in these cells, with significant increases in phosphorylation levels of AKT and RPS6. This elevation was also observed by immunohistochemistry in tumor sections from N1S1 HCC tumor-bearing rats treated with TTFields relative to sham. Treatment of cells with PI3K inhibitors re-sensitized them to TTFields and downregulated the phosphorylation of AKT. Concomitant application of TTFields with the PI3K inhibitor alpelisib in mice orthotopically implanted with MOSE-L firefly luciferase (FFL) ovarian cancer cells resulted in enhanced efficacy, as determined by In Vivo Imaging System (IVIS) measurements of tumor volume. Overall, this study demonstrated that the PI3K/AKT/mTOR signaling pathway is involved in reduced cancer cell sensitivity to long-term application of TTFields, and that re-sensitization may be achieved with relevant inhibitors. The results provide a rationale for further examining the potential benefit of TTFields concomitant with PI3K inhibitors.
RADT-02. IMPACT OF SINGLE AND DUAL IMMUNE CHECKPOINT BLOCKADE ON RISK OF RADIATION NECROSIS AND LOCAL CONTROL AMONG PATIENTS WITH BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: Vaios Eugene , Shenker Rachel , Hendrickson Peter , D'Anna Rachel , Niedzwiecki Donna , Carpenter David , Floyd Warren , Winter Sebastian , Dietrich Jorg , Salama April , Clarke Jeffrey , Allen Karen , Mullikin Trey , Floyd Scott , Kirkpatrick John , Reitman Zachary 
Published: November 2022

Abstract

PURPOSE
Single and dual immune checkpoint inhibition (ICPI) are common treatment options for patients, particularly with melanoma and non-small cell lung cancer (NSCLC). While data suggest a cancer control benefit of combining stereotactic radiosurgery (SRS) and ICPI, we hypothesized that concurrent dual ICPI and SRS increases risk for radiation necrosis (RN).

METHODS
We retrospectively reviewed patients with metastatic melanoma or NSCLC treated with SRS for intact brain metastases from 2014-2020. Patients were stratified by receipt of dual ICPI, single ICPI, and SRS alone. Concurrent ICPI was defined as treatment within 30 days of SRS. RN and local control (LC) were biopsy confirmed or determined radiographically and longitudinally, in combination with clinical assessment and steroid use. Kaplan-Meier estimates were used to compare rates of RN and LC between cohorts.

RESULTS
673 brain lesions from 93 patients met inclusion criteria [median (Q1, Q3): 5.0 (2.0-10.0) lesions per patient]. Median follow-up was 8.1 months (95% CI: 7.3-8.7). Histologies included melanoma (53.5%), adenocarcinoma NSCLC (27.3%), squamous cell NSCLC (6.1%), and NSCLC NOS (6.1%). 88 lesions from 25 patients (27%) developed RN and 11 (13%) were biopsy-proven. ICPI use was enriched among lesions that developed RN (85.2%) versus those that did not (19.8%). RN was associated with concurrent ICPI (p&lt; 0.001). Freedom from RN at 6 months was 80% for dual ICPI, 82% for single ICPI, and 97% for SRS alone; 12-month rates were 78% in each ICPI cohort and 95% with SRS alone (p=0.0002). LC differed among dual (97.5%), single (88.7%), and no ICPI (79.7%, p &lt; 0.001). There was a trend toward improved LC with RN (96.6% vs 91.8%; p=0.087).

CONCLUSIONS
In a large cohort of brain metastases, we observed increased risk of RN and improved LC with SRS plus concurrent dual or single ICPI. Awareness of these associations is critical for patient management.
RADT-09. PREOPERATIVE STEREOTACTIC RADIOSURGERY FOR LARGE CEREBRAL METASTASES – A PROSPECTIVE CLINICAL TRIAL SHOWING EFFICACY AND DECREASED TIME TO RESUMPTION OF IMMUNOTHERAPY
Authors: Mallela Arka , Iheagwara Uzoma , Fogg David , Anthony Austin Walker , Zhang Xiaoran , Gersey Zachary , Abou-Al-Shaar Hussam , Xu Emily , Zinn Pascal , Burton Steve , Quinn Annette , Clump David , Siddiqui Zaid , Amankulor Nduka 
Published: November 2022

Abstract

INTRODUCTION
Preoperative stereotactic radiosurgery (SRS) is an emerging therapeutic strategy for treatment of brain metastasis requiring surgical resection. Prior reports have been highly-controlled, excluding very large brain metastases. Here, we report a prospectively-collected preoperative series reflective of a real-world neurosurgical patient cohort, with a particular focus on resumption of immunotherapy.

METHODS
Our series included Nf27 prospective preoperative compared to concurrently collected Nf37 postoperative patients. Demographic, SRS volumes/dose, pre/postoperative immunotherapy, and clinical outcomes were collected. Subsequent univariate comparisons between groups were performed.

RESULTS
Pre/postoperative tumor volumes (19.1 [range: 2.4-65.1] vs. 12.5 [3.6-80.3]cc, p=0.20); local tumor control at 1 year (77.6% vs. 71.4%, p=0.616); overall survival (1.0 [0.8-2.2] vs. 1.3 [0.7-NR] years, p=0.8) were comparable between groups. Rates of LMD (3.7% vs. 8.0%, p=0.39) and subsequent WBRT (8.0% vs. 16.2%, p=0.46) were not statistically different. OR time (168 vs. 173 min, p=0.64), estimated blood loss (133 vs. 180 mL, p=0.31), and wound infections (1 vs. 1, p=1.00) were not significantly different.An ostensible advantage to preoperative SRS is that steroids may be weaned more quickly to allow resumption of immunotherapy. Median steroid taper length was significantly shorter (8 vs. 21.5 days, p=0.007), and median daily Dexamethasone dose at 1 week post-op was significantly lower in the preoperative group (1 vs. 7mg d, p=0.007). All preoperative patients eligible for resumption of immunotherapy (Nf5) resumed treatment within 6 weeks. Conversely, only 2/6 in postoperative patients resumed treatment within 6 weeks, (p=0.07), while 4 failed to resume immunotherapy altogether. In patients initiating immunotherapy after OR/SRS, time to initiation was non-significantly lower in the preoperative group (52[38-84] vs.163[108-208] days, p=0.06).

CONCLUSIONS
Preoperative SRS is safe and provides comparable local tumor control rate even in large tumors ( &gt;20cc). In patients requiring resumption of immunotherapy, preoperative SRS may provide a faster pathway towards resumption of systemic therapy.
RADT-15. 18F-DOPA PET/CT SURVEILLANCE FOR GLIOBLASTOMA: A RADIOMIC MODEL FROM A PROSPECTIVE PHASE II CLINICAL TRIAL PREDICTING SURVIVAL IN IDH-WILDTYPE, MGMT-UNMETHYLATED PATIENTS
Authors: Qian Jing , Pafundi Deanna , Breen William , Brown Paul , Hunt Christopher , Jacobson Mark , Johnson Derek , Kaufmann Timothy , Kemp Bradley , Kizilbash Sani , Lowe Val , Ruff Michael , Sarkaria Jann , Uhm Joon , Chan Tseung Hok Seum Wan , Yan Elizabeth , Zhang Yan , Laack Nadia , Brinkmann Debra 
Published: November 2022

Abstract

BACKGROUND
Interpretation of serial magnetic resonance imaging (MRI) for glioblastoma following radiation therapy (RT) is complicated by difficulty differentiating tumor from treatment-related changes, even using updated RANO criteria. The incorporation of novel imaging such as 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET/CT to post-treatment serial imaging may improve prognostication and better facilitate future treatment decisions.

METHODS
The secondary analysis of a recent phase II prospective clinical trial of 18F-DOPA PET/CT-directed dose-escalated RT included patients with IDH-wildtype, MGMT-unmethylated glioblastoma who underwent post-treatment serial 18F-DOPA PET/CT surveillance. Quantitative features were extracted from pre-RT and post-RT serial PET/CT images, and robust prognostic features were selected using an in-house workflow. Both an automated machine learning (ML) algorithm and an interpretable ML algorithm were utilized to correlate surveillance PET image features with subsequent survival of greater than 12 months versus less than 12 months from the surveillance timepoint. Changes from pre-RT to post-RT PET/CT (delta model) were also assessed for association with post-RT survival and validated with a separate cohort.

RESULTS
Thirty-five patients with IDH-wildtype, MGMT-unmethylated glioblastoma who had at least one available (range: 1-14) post-treatment 18F-DOPA PET/CT were included. Twenty-four were used for model training, while 11 were used for validation. Ultimately, a five-feature post-RT model utilizing two shape, two texture, and one first-order radiomic feature was selected. For the delta model, five texture, two shape, and one first order radiomic feature were selected. The models show 90% accuracy in predicting survival &lt; 12 months post-surveillance on the training set, and 68%-73% accuracy (AUC 0.64-0.73) for the validation cohort. Delta features were significantly associated with overall survival (p &lt; 0.05).

CONCLUSIONS
Post-RT serial 18F-DOPA PET/CT imaging can help distinguish true tumor progression in patients with glioblastoma using a radiomics model. Tumor response evaluated for changes from pre-RT to post-RT 18F-DOPA PET/CT also predicted subsequent overall survival.
RADT-16. CLINICAL OUTCOMES FOR HIGH RISK WHO GRADE II GLIOMA PATIENTS TREATED WITH UPFRONT TMZ-BASED CHEMORADIOTHERAPY
Authors: Zarabi Hosniya , Wicks Robert , Russel Gregory , Banderage Dineth , Strowd Roy , Mott Ryan , Laxton Adrian , Tatter Stephen , White Jaclyn , Lo Hui-Wen , Debinski Waldemar , Chan Michael , Lesser Glenn , Cramer Christina 
Published: November 2022

Abstract

OBJECTIVE
RTOG 9802 demonstrated improved survival using chemoradiotherapy (CRT) over radiotherapy (RT) alone for WHO Grade II gliomas (LGG) using PCV with RT. We analyze our retrospective dataset of predominantly temozolomide (TMZ)-based CRT in LGG patients who would have been eligible for RTOG 9802.

METHODS
Retrospective review of LGG patients (2000–2017) treated at a single institution (67 patients). Histologies included oligodendroglioma(OD), astrocytoma(AC) or astrocytoma (OA). Those who received upfront RT +/- chemotherapy were included. The CRT cohort (n=40) consisted primarily of TMZ (n=36) administered concurrently with RT. 27 patients received RT alone. RT for both cohorts consisted of a median dose of 54 Gy (range 50.4 - 54 Gy). 65/67 patients had “high risk” LGG as defined by RTOG 9802 criteria. Kaplan Meier analysis was used to assess overall survival (OS) and progression free survival (PFS).

RESULTS
5-year PFS for patients receiving CRT was 64% vs. 44% in those receiving RT alone (log rank p=0.009). Difference in PFS due to chemotherapy was driven by AC histology (57% vs. 21% PFS at 5 years, log rank p=0.002) while OD/OA PFS was not statistically altered (79% vs. 72% PFS at 5 years, p=0.21). 5-year OS for patients receiving CRT was 76% vs. 69% in those receiving RT alone (p=0.11). Cox Proportional Hazards analysis showed that use of upfront CRT (HR=0.4, p=0.009) was the only factor that decreased the risk of earlier progression.

CONCLUSION
Use of upfront, predominantly TMZ-based CRT, has a PFS benefit over RT alone in a population of WHO grade II gliomas. This benefit appears to be driven by AC histology and also appears to extend beyond the “very high risk” cohort from RTOG 0424 to include the “high risk” group from RTOG 9802.
RADT-18. PARTICLE BEAM RADIATION THERAPY PLUS TUMOR TREATING FIELDS IN THE TREATMENT OF NEWLY DIAGNOSED WHO GRADE 4 GLIOMAS: AN EARLY RESULT OF PHASE 2 SINGLE-ARM TRIAL
Authors: Qiu Xianxin , Gao Jing , Yang Jing , Hu Jiyi , Hu Weixu , Huang Qingting , Zhang Haojiong , Kong Lin , Lu Jiade 
Published: November 2022

Abstract

OBJECTIVES
Tumor Treating Fields (TTFields) is increasingly provided to patients with WHO grade 4 gliomas following radiotherapy. Particle beam radiotherapy (PBRT) represents a novel promising radiation approach with improved therapeutic ratio. This study was aimed to report an early result of TTFields in combination with PBRT for treating WHO grade 4 gliomas based on a prospective phase 2 trial from Shanghai Proton and Heavy Ion Center.

METHODS
This phase 2 trial was designed as a single-arm study to test the outcome of PBRT plus TTFields. Six patients with newly diagnosed WHO grade 4 gliomas receiving surgery, PBRT, temozolomide, and TTFields, from August 2021 to May 2022, were enrolled and analyzed. Tumor histologies based on the WHO CNS5 classification system were IDH-wild glioblastoma (n=4), IDH-mutant astrocytoma (n=1), and H3G34-mutant diffuse hemispheric glioma (n=1). For PBRT, all patients were irradiated with a baseline standard dose of 60GyE/30 utilizing proton. Carbon-ion boost of 15GyE/3 for tumor residual was performed for one patient prior to proton radiation. TTFields treatment was recommended to start soon after PBRT.

RESULTS
With a median follow-up of 5.5 months, all patients were alive at the time of this analysis; one patient with left thalamic glioblastoma had tumor progression of distant failure outside the radiation field at 4 months after partial tumor resection. The median interval between PBRT and TTFields was 2 days (range 1-22 days). No patient had dermatitis during PBRT. No severe TTField-related skin toxicity (Grade 3 or above) was observed. Five patients (83.3%, 5/6) developed mild skin toxicities (Grade 1) during TTField treatments.

CONCLUSIONS
Starting TTField early following PBRT is feasible for treating WHO grade 4 gliomas, the overall side effects are mild. Prospective studies with further follow-up are warranted to identify the outcomes of PBRT in combination with TTField in terms of survival and side effects.
RADT-21. PATTERNS OF CARE AND OUTCOMES IN PEDIATRIC HIGH-GRADE GLIOMA PATIENTS ENROLLED IN THE PEDIATRIC PROTON/PHOTON CONSORTIUM REGISTRY
Authors: Schramski Anna , Yock Torunn I , Hill-Kayser Christine , Indelicato Daniel J , Paulino Arnold C , Hartsell William , Ermoian Ralph , Mangona Victor , Kwok Young , MacEwan Iain , Wolden Suzanne , DeNunzio Nicholas , Shin Brion , Goyal Subir , Eaton Bree 
Published: November 2022

Abstract

BACKGROUND
Proton therapy (PRT) is increasingly utilized for pediatric brain tumors to reduce radiation associated treatment effects, but there is a lack of data evaluating PRT in pediatric high-grade glioma (pHGG). The purpose of this analysis is to report patterns of care and clinical outcomes for pHGG patients treated with PRT and enrolled in the prospective Pediatric Proton/Photon Consortium Registry (PPCR).

METHODS
Fifty-five pHGG participants treated with PRT were enrolled in the PPCR between Jan 2013 and Aug 2020. Progression free (PFS) and overall survival (OS) rates were calculated according to the Kaplan-Meier method. Univariate analyses were performed using Cox proportional hazards model with Firth’s penalization.

RESULTS
Among 49 patients with complete data, the median age was 12, the majority of patients were male (29), white (35), and non-Hispanic/Latino (41). Histology was grade IV (37), grade III (10) or HGG not specified (8). Resection was gross-total (24), near-total (4), or sub-total/biopsy (17). Six patients received prior RT. The median RT dose was 57.6 Gy (RBE) starting a median of 33.5 days after surgery. 39 patients received chemotherapy. The most common acute treatment toxicities were alopecia (36), fatigue (34), radiation dermatitis (22), nausea/vomiting (19), and headache (19). Median follow-up was 3.14 years (95% CI 1.62-3.97). At 3 years, PFS (95% CI) was 35.5% (20.8-50.6%) and OS was 55.6% (38-70%). Median PFS and OS are 1.6 (1.2-3.1) and 3.6 (1.6-NA) years, respectively. Higher radiation dose was associated with greater PFS (HR 0.97 (0.94-1.01), p=0.059) and OS (HR 0.95 (0.93-0.99), p=0.006). Patients ≤ 3 years at diagnosis (n=8) had 3-year PFS/OS of 72.9%/87.5% vs. 27.8%/49.4% for older patients (p=0.068/0.089, respectively).

CONCLUSION
These are the first published data with PRT for pHGG. Clinical outcomes are comparable to historical data with photon therapy. Additional analysis of treatment associated toxicity and patient quality-of-life are warranted.
RADT-27. FRACTIONATED RADIOTHERAPY AS FIRST-LINE TREATMENT FOR INTRACRANIAL MENINGIOMAS
Authors: Wang Justin , Landry Alexander , Nassiri Farshad , Lee Grace , Rogers Lauren , Zuccato Jeffrey , Voisin Mathew , Munoz David , Tsang Derek , Laperriere Normand , Zadeh Gelareh 
Published: November 2022

Abstract

BACKGROUND
Meningiomas are the most common primary brain tumour, and patients requiring intervention typically undergo surgical resection as first-line therapy. However, fractionated radiotherapy (fRT) as primary treatment remains an option for patients with larger tumours and surgical contraindications, although outcome prediction in this group remains uncertain. We aimed to assess the clinical factors that contribute to treatment failure in a cohort of meningiomas treated with fRT as first-line therapy.

METHODS
Patients treated with primary fRT for intracranial meningiomas at our institution from November 1, 1998 to December 30, 2017 were reviewed. Those who received upfront surgical resection, radiosurgery, or had less than 6 months of clinical follow up were excluded. We applied logistic regression and Cox regression analysis to ascertain key predictors of treatment failure, progression-free survival (PFS), and adverse events following radiotherapy.

RESULTS
Our cohort included 147 tumours, of which 25 progressed after fRT (median PFS of 3.45 years). Tumours that progressed following RT had a larger median gross tumour volume (GTV) than those that did not (32.3cm3 vs 20.2cm3,p = 0.03768). Pre-RT GTV greater than 11.27cm3 was independently predictive of treatment failure. Larger pre-RT GTV was also associated with significant (grade 3/4) adverse events following fRT. Finally, cerebellopontine angle meningiomas were more prevalent in the group that progressed (20% vs 3.3%, p = 0.0046), whereas cavernous sinus and optic nerve sheath meningiomas had longer PFS (p = 0.0067).

CONCLUSION
We present the largest known cohort of meningiomas treated with fRT as first line therapy and find pre-RT tumour GTV and location to be the critical predictors of outcome, adding to the discussion of treatment considerations in this heterogeneous disease.