bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSIG-26. TARGETING HYPOXIC CANCER CELLS IN MEDULLOBLASTOMA
Authors: Kuranaga Yuki , Van Meir Erwin 
Published: November 2023

Abstract
The goal of this study is to thoroughly assess the role of hypoxia-induced transcription factors (HIFs) in MB growth and examine HIF as a potential therapeutic target. We first examined patient MB tumor by IHC and identified scattered areas with expression of HIF1a and HIF2a. We then established orthotopic human MB xenografts in mice and found hypoxic areas throughout the tumors using pimonidazole detection and they expressed both HIF1a, and HIF2a. There are only few observations of hypoxic areas within experimental MB. To explore the impact of HIFs on MB growth, we exposed MB cell lines (ONS-76; Shh and D556; Group 3) to 1% hypoxia in cell culture. We observed a decrease in cell growth, an increase in HIF1a and HIF2a protein expression, activation of HIF targets (Glut-1, VEGF), and a hypoxia-response element-driven luciferase reporter assay. To further examine the role of individual HIF isoforms, we employed CRISPR/Cas9 to knockout (KO) the HIF1a and/or HIF2a genes in ONS76 MB cells. The HIF reporter activity was partially canceled with single HIF-KO and completely abrogated with double KO and double KO reduced cell growth, indicating that both HIF-1 and HIF-2 are having roles for activating transcription and cell growth. Treatment of MB cells with 64B, an arylsulfonamide HIF/p300 inhibitor abrogated reporter activity by both HIF-1 and HIF-2 and reduced expression of hypoxia-induced genes. To investigate the potential of targeting HIF in vivo, we injected mice brains with wild-type and HIF1a/2a-KO ONS-76 cells and monitored their growth and survival. Mice injected with double KO HIF cells exhibited prolonged survival compared to those with parental cells (n = 5, p&lt; 0.01). Further experiments to expand this approach with other MB cell line and test the anti-tumor effects of 64B in mice are ongoing. These findings support targeting HIFs as a novel therapeutic strategy in MB treatment.
CSIG-32. MYC DRIVEN CANCERS ARE DEPENDENT ON CONVERGENT ONCOGENIC PATHWAYS INDUCED BY GENOMIC REARRANGEMENTS AT PVT1
Authors: Bagchi Anindya 
Published: November 2023

Abstract
Plasmocytoma Variant Translocation 1 (PVT1) encodes a lncRNA that is co-amplified with MYC in multiple cancers. PVT1 is also a rearrangement hotspot in diverse human cancers with poor prognoses. However, the functional consequences of PVT1 rearrangement have remained obscure. Here we report that these genomic rearrangements often result in asymmetric enrichment of the proximal half of PVT1 (5’-PVT1) and loss of its distal half (3’-PVT1). Contrary to the general assumption of PVT1 being a non-coding RNA, we identified two distinct transcripts from the 5’-PVT1 and 3’-PVT1 that are capable of coding for functional peptides. A transcript from the retained 5’-PVT1 generates a circular RNA (CircPVT1) which codes for a previously unknown peptide, Firefox (FFX) with oncogenic properties. FFX can synergistically sensitize MYC and augment mTOR signaling in cancer cells. On the other hand, the 3’-PVT1 that is lost during the rearrangement, codes for a micropeptide, Honeybadger (HNB), with tumor-suppressive properties. Inhibition of HNB activates the RAS/MAPK signaling and enhances MYC stability by promoting phosphorylation of MYC Ser62. Molecular docking and biochemical analysis suggest that HNB can interfere with KRAS dimerization, implying its role as an allosteric modulator of RAS/MAPK signaling in cancer. We have previously revealed a strong selection and crucial cooperation between MYC and PVT1 in 8q24+ tumors. Moreover, breakpoints in PVT1 have led to PVT1 promoter-MYC fusions, found on ecDNA, resulting in promiscuous enhancer input to drive MYC transcription. Here we provide evidence that translocation events at the PVT1 locus can result into convergence of MYC, mTOR, and MAPK signaling. Taken together, our study nominates MYC/PVT1 amplification + PVT1 rearrangement as a major driver of cancer pathogenesis, and PVT1 as a critical node that coordinates MYC, mTOR, and MAPK activity in cancer, revealing new regulatory mechanisms that reshape the oncogenic landscape in tumors with genomic rearrangements at PVT1.
RADT-12. GENOMIC CHARACTERISTICS AND CLINICAL OUTCOMES OF STEREOTACTIC RADIOSURGERY FOR COLORECTAL CANCER BRAIN METASTASES
Authors: Gui Chengcheng , Walch Henry , Mueller Kirin , Eichholz Jordan , Khatri Ishaani , Del Balzo Luke , Kemeny Nancy , Imber Brandon , Schultz Nikolaus , Foote Michael , Yaeger Rona , Pike Luke 
Published: November 2023

Abstract

PURPOSE
Brain metastases (BM) from colorectal cancer (CRC) portend a limited prognosis but are poorly understood, both clinically and biologically. This study defined the clinical outcomes and genomic features of CRC BM treated with stereotactic radiosurgery (SRS).

METHODS
Patients with newly diagnosed CRC BM treated with SRS at a single institution between 2009 and 2022 were included. Next-generation targeted sequencing using MSK-IMPACT of at least one intracranial or extracranial tumor was required. Overall survival (OS) was evaluated using Kaplan-Meier analysis. Intracranial progression (IP) and local recurrence (LR) were evaluated using competing risk analysis, accounting for death.

RESULTS
We identified 124 patients with 304 BM, of which, 66 BM received SRS postoperatively. The median prescription was 27 Gy in 3 fractions. Median OS after SRS was 7 months. Poorer KPS, progressive extracranial disease, and lung metastases independently predicted poorer OS. Twelve months after SRS, cumulative incidences of IP and LR were 37% per patient and 6.1% per lesion treated, respectively. Three or more BM at diagnosis independently predicted earlier IP. Biologically effective dose less than the median predicted LR, independent of tumor size. Genomic data were obtained from 68 primary tumors, 63 extracranial metastases, and 33 BM. BM demonstrated significantly greater fraction genome altered, chromosomal instability, and TP53 alterations compared to extracranial metastases and primary tumors. Among patients who had IP, compared to those who had no IP within 6 months, BM contained more frequent alterations in KRAS (56% vs. 43%), SMAD4 (44% vs. 0%), and APC (77% vs. 57%).

CONCLUSIONS
Among CRC BM treated with SRS, OS and IP were correlated with extracranial and intracranial disease burden, and LR was correlated with SRS dose. Genomic characteristics differed between BM and extracranial disease, and between patients who did and did not experience IP. Further investigation of these genomic differences is underway.
RADT-18. PROTON CRANIOSPINAL IRRADIATION WITH CHECKPOINT INHIBITOR THERAPY FOR PATIENTS WITH LEPTOMENINGEAL DISEASE FROM SOLID TUMORS – A SINGLE INSTITUTION CASE SERIES
Authors: Sener Ugur , Webb Mason , Breen William , Laack Nadia , Routman David , Brown Paul , Mahajan Anita , Frechette Kelsey , Leventakos Konstantinos , Dudek Arkadiusz , Markovic Svetomir , Kizilbash Sani H , Campian Jian 
Published: November 2023

Abstract

BACKGROUND
Leptomeningeal disease (LMD) is a devastating complication of cancer with median overall survival (OS) of 3-6 months following diagnosis. Proton craniospinal irradiation (pCSI) is a novel treatment option for LMD, permitting whole neuroaxis treatment with tolerable toxicity and improved efficacy compared to conventional photon whole brain radiation therapy and as needed focal spine radiotherapy. Despite this, patients experience progression and succumb to LMD. Addition of systemic therapy to pCSI may improve outcomes.

METHODS
In this single institution retrospective case series, we report feasibility of combination treatment with pCSI and immune checkpoint inhibitor (ICI) in patients with LMD from solid tumors.

RESULTS
Three patients were treated with pCSI (30 Gy in 10 fractions) and ICI. The first patient developed LMD related to large cell neuroendocrine carcinoma of lung primary, diagnosed by imaging and cytology, having previously undergone resection and stereotactic radiosurgery for brain metastases. Clinical and radiographic improvement was noted following pCSI, bevacizumab, and pembrolizumab therapy. Patient experienced disease progression and passed away only after ICI was held due to hypophysitis, with 6-month OS. The second patient developed LMD related to BRAF V600E mutant melanoma, diagnosed by imaging and cytology, having previously undergone ICI and BRAF-targeted therapy. Following pCSI, relatlimab, nivolumab, and BRAF-targeted therapy, the patient remains alive 7 months after LMD diagnosis despite radiographic progression treated with carboplatin, paclitaxel, intrathecal IL-2, ipilimumab, and bevacizumab. The third developed LMD related to BRAF-wildtype melanoma, diagnosed by imaging, having previously received ICI. Patient underwent pCSI followed by ipilimumab and nivolumab, progression-free 5 months after LMD diagnosis.

CONCLUSION
Addition of systemic therapy to pCSI is feasible for patients with LMD. Combination of ICI and pCSI may confer additional survival benefit, even among patients with prior exposure to ICI. These initial promising results warrant prospective evaluation.
RADT-25. IMPACT OF 18F-DOPA PET ON RADIATION TREATMENT PLANNING FROM PHASE II STUDY OF SHORT COURSE HYPOFRACTIONATED PROTON BEAM THERAPY FOR ELDERLY PATIENTS WITH GLIOBLASTOMA
Authors: Laughlin Brady , Pafundi Deanna , Buras Matthew , Ashman Jonathan , Bendok Bernard , Laack Nadia , Breen William , Ruff Michael , Mahajan Anita , Mrugala Maciej , Sio Terence , Uhm Joon , Yang Ming , Brinkmann Debra , Brown Paul , Hu Leland , Vora Sujay 
Published: November 2023

Abstract

PURPOSE
18F-DOPA is sensitive/specific for identifying areas of biologically aggressive disease for glioblastoma. We report the impact of 18F-DOPA on radiation treatment planning from a phase II study.

METHODS
Gross target volume (GTV) was defined by the boolean of high-risk PET (tumor/normal brain SUV &gt; 2.0) and MRI T1 contrast enhancement (MRI-CE) including surgical cavity. The clinical target volume (CTV) included the GTV with 1cm margin. Using proton beam therapy, GTV ≤ 65 cc was treated with 25 (CTV), 30 (MRI-CE), and 35 (PET) GyE over 5 fractions with a simultaneous integrated boost. GTV &gt; 65 cc received 30 (CTV), 35 (MRI-CE), and 40 (PET) GyE over 10 fractions. Radiation field design was compared to traditional 1.5cm CTV margin on MRI-CE.

RESULTS
Between May 2019 and October 2021, 39 patients were treated. The median MRI-CE tumor diameter was 5.2cm. The median PET volume was 7.9cc (range 0–64.9cc). The median MRI-CE volume was 35.1cc (range 8.6–114cc). High-risk PET was contained within: MRI-CE 18/39 (46%), MRI-CE + T2W FLAIR 13/39 (33%), MRI-CE + T2W FLAIR + outside GTV 4/39 (10%), outside GTV 2/39 (5%) and no uptake 2/39 (5%). Utilizing this planning technique, there was a 26% volume reduction in CTV to traditional 1.5 cm margin on MRI-CE. PET imaging in treatment planning allowed inclusion of high-risk disease that would have been excluded on traditional CTV in 23% of cases (range 1.6-33.8cc). PET was more predictive [HR 1.03 (95% CI 1.01, 1.05) p = 0.002] than MRI [HR 1.01 (95% CI 1.00, 1.03) p = 0.02] for death with each cc increasing risk of death by 3.1%.

CONCLUSIONS
The incorporation of 18F-DOPA in treatment planning yields a more targeted approach with reductions in both normal brain treated and risk of geographic miss compared to traditional CTV margins.
RADT-29. TARGETING ANDROGEN RECEPTOR FOR GLIOBLASTOMA: A NOVEL RADIOSENSITIZING THERAPY THROUGH TGF-Β/LIF/STAT3 PATHWAY AND IMMUNOMODULATION
Authors: Khan Rubayat , Zhao Nan , Zhang Chi 
Published: November 2023

Abstract
In the search for more effective treatments for glioblastoma (GBM), a primary brain malignancy, we explored the synergistic effects of androgen receptor antagonists (ARAs) and radiotherapy (RT). Prior research indicated that ARA treatment alone improved survival in GBM mouse models, primarily through the suppression of glioma cancer stem cells. Our recent investigations aimed to ascertain the radiosensitizing effects of ARAs when combined with RT. Initial in vitro experiments, using proliferation assays on cultured GBM cells, showed only mild radiosensitizing effects. ARAs, however, induced apoptosis, enriched the G2/M phase in cell cycling, and decreased expression in numerous DNA repair genes, which were confirmed through RNA sequencing and TCGA database analyses. Additionally, Western blotting revealed that ARAs modulated SMAD2/3 phosphorylations differentially in c-terminal and linker domains in the TGF-β pathway and suppressed LIF-STAT3 signaling. This intricate mechanism involving the alteration of key cellular signaling pathways led us to hypothesize that ARAs may potentiate RT in vivo. To validate this hypothesis, we conducted in vivo studies using an orthotopic GBM mouse model. Substantial synergy was observed between ARAs and brain RT, with combined ARA and RT treatment achieving 100% long-term survival and establishing immune memory, a significant increase compared to &lt;50% survival for the ARA only group and 0% for the RT only group. Notably, we identified significant immunostimulating effects within the tumor microenvironment and systemically, as determined by immunohistochemistry and flow cytometry on peripheral blood and spleen, respectively. Our findings demonstrate that although ARAs show mild radiosensitizing effects on GBM cells in vitro, they significantly synergize with RT in vivo, via alterations in TGF-β/LIF/STAT3 signaling pathways which have been known to influence immunomodulation. The local and systemic immunomodulatory effects demonstrated in our studies by ARA treatment warrant further study combining ARA with immunotherapeutics.
RADT-34. CLINICAL OUTCOMES OF LOCALISED AND METASTATIC CENTRAL NERVOUS SYSTEM HAEMANGIOPERICYTOMAS/SOLITARY FIBROUS TUMOURS – A SINGLE INSTITUTION EXPERIENCE
Authors: Venkatasai Jeyaanth , Manik Vishal , Chia Kazumi , Swampillai Angela , Al-Salihi Omar , Brazil Lucy 
Published: November 2023

Abstract

BACKGROUND/OBJECTIVE
Central nervous system (CNS) haemangiopericytomas (HPC) or solitary fibrous tumours (SFT) are rare aggressive tumours. Surgery is the primary modality of treatment, however, often followed by postoperative radiotherapy due to high tendency for local recurrence. Although rare, extracranial metastases to several sites have been described. We aim to report our institutional experience in managing these rare tumours.

METHODS
Patients with central nervous system HPC/SFT who underwent surgical resection from 2012 to 2022 were included in the study. Data collected included patient demographics, tumour characteristics, treatment details (including primary surgery, radiotherapy and treatment for relapse) and clinical outcomes.

RESULTS
Five patients were included in this study. All were women and their mean age at diagnosis was 43 years. Four patients presented with intracranial disease and one with cervico-thoracic spine disease. All patients had undergone primary surgery and gross total resection was achieved in two patients. Two patients had grade 1, one with grade 2 and two with grade 3 HPC. Four patients received radiotherapy (median dose 60Gy) and one was on imaging surveillance after surgery. Three patients had relapsed – one with locoregional relapse only, one with distant (liver and bone) relapse and other with locoregional and distant (lung and bone). Time to relapse were 192, 39 and 120 months respectively. Stereotactic radiotherapy was used to treat local relapse in posterior fossa and dura of cervical spine, and metastatic relapse in lung with a stable radiological response. One patient with a painful destructive bone metastases was treated with palliative radiotherapy with good pain control. Four patients were alive at the time of the study, and one was lost to follow up.

CONCLUSION
We present our institutional experience in management of localised and metastatic HPC/SFT. Stereotactic radiotherapy could be considered an effective treatment modality for small volume relapse of HPC.
RADT-40. FINAL RESULTS OF THE PROSPECTIVE PHASE 2 MARCIE TRIAL: EFFICACY AND TOXICITY OF POSTOPERATIVE BIMODAL RADIOTHERAPY WITH C12-BOOST IN PATIENTS WITH ATYPICAL MENINGIOMAS FOLLOWING SUBTOTAL RESECTION
Authors: Deng Maximilian , Hinz Felix , Karger Christian , Sievers Philipp , Eichkorn Tanja , Meixner Eva , Hörner-Rieber Juliane , Lischalk Jonathan , Seidensaal Katharina , Jungk Christine , Unterberg Andreas , Wick Antje , Wick Wolfgang , von Deimling Andreas , Sahm Felix , Bernhardt Denise , Combs Stephanie , Herfarth Klaus , Debus Jürgen , König Laila 
Published: November 2023

Abstract
Radiotherapy is recommended by current EANO guidelines for patients with atypical meningiomas (WHO grade 2) following subtotal resection. While meningiomas are generally considered radioresistant, novel radiotherapeutic modalities using carbon ions present an increased relative biological effectiveness (RBE) compared to photons, while reducing the radiation exposure for adjacent organs at risk by exploiting the Bragg peak. Our prospective phase 2 trial investigated bimodal radiotherapy using a carbon-ion boost in patients with atypical meningiomas following subtotal resection. A total of 33 patients were enrolled from 07/2012 until 07/2020. The study was prematurely terminated in 07/2020 after recruiting 33 of the initially planned 40 patients due to one grade 5 toxicity. Study treatment comprised a carbon ion boost (18 Gy [RBE] in 6 fractions) targeted to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was progression-free survival, and secondary endpoints included overall survival, safety and toxicities. With a median follow-up of 42 months, the 3-year estimates of progression-free survival (PFS), local PFS and overall survival were 80.3%, 86.7% and 89.8%, respectively. Radiation-induced contrast enhancements (RICE) was encountered in 45%, particularly in cases of periventricularly-located meningiomas. Patients exhibiting (transient) RICE were either asymptomatic (40%) or presented immediate improvement (47%) after the administration of corticosteroids or/and bevacizumab. Treatment-associated complications were encountered in 2 patients with radiation necrosis: 1 patient died due to postoperative complications in an external center after resection of radiation necrosis, and the other received an aggregated 21 cycles of bevacizumab. As a result, the study was prematurely terminated. Post-hoc integrated molecular-morphologic scoring identified patients at risk of tumor progression. Study treatment may be considered for selected patients with molecular high-risk meningiomas to achieve high tumor control rates. Patients’ risk to develop radiation-induced side effects depends on the location of the treatment volume.
RADT-44. LONG-TERM OUTCOMES WITH REDUCED-DOSE WHOLE BRAIN RADIOTHERAPY AND A STEREOTACTIC RADIOSURGERY BOOST FOR PRIMARY CNS LYMPHOMA
Authors: Foreman Bronwen , Mullikin Trey , Floyd Scott , Kelsey Chris , Patel Mallika , Peters Katherine , Kirkpatrick John , Reitman Zachary , Vaios Eugene 
Published: November 2023

Abstract

BACKGROUND
Primary central nervous system lymphoma (PCNSL) is an aggressive diffuse large B-cell lymphoma. Treatment approaches are historically associated with neurotoxicity, particularly with high-dose whole-brain radiotherapy (WBRT). We hypothesized that reduced dose-WBRT (rd-WBRT) followed by a stereotactic radiosurgery (SRS) boost could provide durable disease control without significant adverse effects.

METHODS
We retrospectively reviewed PCNSL patients treated with rd-WBRT plus an SRS boost at Duke University between 2008 and 2021. Progression-free survival (PFS) and overall survival (OS) were estimated using competing risk and Kaplan Meier methods.

RESULTS
We identified 23 patients with pathologically confirmed PCNSL. Median age at diagnosis was 69 years (Q1Q3:52–74) and median KPS was 80 (Q1Q3:70–80). Median follow-up was 21 months. Median doses for rd-WBRT and SRS were 23.4Gy (Q1Q3:23.4–23.4) and 12Gy (Q1Q3:12–12.5), respectively. The cumulative incidence of intracranial progression at two years was 23% (95%CI:8-42). Six patients (26%) developed distant radiographic progression while two patients (9%) developed both distant and local progression. Ten patients (44%) were alive without progression at last follow-up. By Kaplan Meier estimate, the two-year overall survival was 69% (95%CI:46-84). There were no reported grade 3+ radiation-induced toxicities.

CONCLUSIONS
The combination of rd-WBRT with an SRS boost appears well-tolerated with durable intracranial control. This approach represents a treatment option for select patients, such as those with progressive or refractory disease. Further prospective studies are needed to validate these findings and determine whether this approach could be incorporated into consolidation strategies.
RADT-48. RADIATION MYELOPATHY AFTER STANDARD DOSE RADIATION: POTENTIAL RADIATION SENSITIZING EFFECTS OF SYSTEMIC THERAPY
Authors: Hazy Allison , Grills Inga , Ogaily Mohammed , Stender Michael , Rogers Lisa R 
Published: November 2023

Abstract
Radiation myelopathy is an uncommon adverse effect of spinal irradiation. It is especially rare following conventional palliative fractionation regimens for vertebral metastasis. We present two cases of delayed thoracic radiation myelopathy in patients with breast cancer. In both cases, palliative radiation of 30 Gy in ten fractions was administered to thoracic spinal metastases. Neither patient received concurrent systemic therapy. One began trastuzumab emtansine nine days after finishing radiation and the other started palbociclib three months afterwards, which was switched to capecitabine at disease progression. Each patient developed progressive leg weakness and numbness, ten months following radiation and eleven months following radiation (four weeks following capecitabine), respectively. MRI showed edema and focal contrast enhancement within the radiation field in each. Both were treated with high-dose corticosteroid, vitamin E, and pentoxifylline. Neither patient returned to their neurologic baseline and remain with significant deficits, requiring assistance with ambulation. Serial MRIs revealed eventual reduction in cord enhancement and edema, followed by cord atrophy in one case. The cumulative radiation dose of 30 Gy is typically within the safety tolerance of the spinal cord, so it is speculative if post-radiation systemic therapy played a role in the development of myelopathy. The timing is particularly convincing in the patient who developed symptoms within four weeks of starting capecitabine. These cases are similar to recently reported instances of radiation myelopathy after standard dose spinal radiation followed by chemotherapy or immunotherapy. Recognition of the potential radiation sensitizing effects of systemic therapy should lead clinicians to consider radiation myelopathy early if spinal cord symptoms develop and to consider the timing of initiation of potential sensitizing drugs when spinal radiation has been given.