bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-11. TUMOR-CELL INTRINSIC CALCIUM OSCILLATIONS DRIVE BRAIN METASTASIS
Authors: Hebach Nils R , Olshausen Niels , Schlag Joana S , Bang Severin , Kraft Theresa , Mayer Chanté , Linke Zoe , Westphal Dana , Seifert Michael , Timmer Jens , Wick Wolfgang , Winkler Frank , Karreman Matthia A
Published: November 2024

Calcium is a ubiquitous secondary messenger which regulates many cellular processes. Recently, we have shown that a subpopulation of glioblastoma cells can intrinsically generate calcium oscillations which drive proliferative signalling. Here, we set out to investigate whether such cancer cell autonomous oscillations are also present in secondary brain tumours. Employing longitudinal intravital two-photon microscopy in awake mice, we demonstrate that brain metastases of melanoma and lung cancer exhibit spontaneous calcium oscillations in vivo along the metastatic cascade. These oscillations are already observed during intravascular arrest and in in vitro monocultures, suggesting a tumour-cell intrinsic origin. We developed a fully automatic image analysis pipeline to accurately quantify calcium oscillations both in vivo and in vitro. Mathematical modelling of cytosolic and ER calcium stores can predict stable calcium oscillations with similar frequency and peak characteristics as those experimentally observed. We discovered that these oscillations are tightly regulated by an interplay of calcium-induced calcium release and store-operated calcium entry (SOCE). Similarly, SOCE-related ion channels are enriched in tissue from human melanoma brain metastases compared to healthy brain controls and calcium activity can also be observed ex vivo in patient-derived brain metastasis resections. Finally, by correlating calcium activity and EdU incorporation we discovered that the presence of calcium oscillations predicts their proliferative potential in vitro. Importantly, by intravital two-photon microscopy we show that calcium activity correlates with metastasis size in preclinical models, suggesting a potential new therapeutic angle from which to target brain metastases.
CSIG-20. LIPOCALIN-2 DRIVES CELL-INTRINSIC FUNCTIONS IN GLIOBLASTOMA
Authors: Wang Sabrina , Timken J , Bishop Christopher , Deleyrolle Loic , Lathia Justin
Published: November 2024

Glioblastoma (GBM) continues to persist despite aggressive therapies, many of which are cytotoxic, and therapeutic failure is driven, in part, by the tumor cell’s ability to evade multiple forms of cell death, including ferroptosis. Lipocalin-2 (LCN2) functions to sequester iron and is considered an inflammatory marker through its function of limiting iron for bacterial usage; it has also been described to have pro and anti-tumorigenic effects depending on environmental iron status. In previously published studies in brain metastases, LCN2 promotes tumor cell proliferation by sequestering iron for cancer cells growth and survival, but the mechanisms of how LCN2 contributes to GBM progression is unknown. LCN2 expression in patient data revealed that high LCN2 expression is associated with reduced survival in GBM patients. A survey of mouse glioma models demonstrated a range of LCN2 secretion across models with KR158 and CPA being high and medium LCN2 secretors. LCN2 short hairpin knockdown of KR158 and CPA and decreased tumor cell viability and proliferation. Furthermore, when both KR158 and CPA control versus LCN2 knockdown cells were orthotopically implanted into mice, survival was increased. To understand if LCN2 impacted cell death dynamics, we investigated various cell death mechanisms and found that LCN2 knockdown increases tumor susceptibility to ferroptotic death by sensitizing cells to lipid peroxidation as well as reducing key anti-ferroptotic proteins GPX4 and xCT. To elucidate downstream mechanisms, we performed a phosphorylation array and discovered that phosphorylation of AXL, which has recently been linked to ferroptosis, is decreased with LCN2 knockdown. Moreover, AXL phosphorylation was localized to the nucleus, indicating that LCN2 knockdown attenuates AXL processing and downstream signaling. Overall, these findings indicate that LCN2 in GBM promotes tumor cell growth through AXL signaling and evasion of ferroptotic death, ultimately revealing a novel signaling network that can be leveraged for future therapeutic development.
CSIG-28. DISSECTING THE FUNCTIONAL IMPAIRMENT OF WILD-TYPE P53 IN HUMAN GLIOBLASTOMA
Authors: García-Montaño Leopoldo A , Muñoz Yamhilette Licón , Martinez Frank , Gallegos Kandee , Bowers Christian A , Kang Huining , Piccirillo Sara G M
Published: November 2024

Glioblastoma (GBM) is the most common malignant brain tumor in adults and is characterized by heterogeneous nature, invasive potential, and poor treatment response. Work from The Cancer Genome Atlas (TCGA) identified the tumor suppressor gene TP53 as a GBM driver. In contrast to several cancers, only ~35% of GBM cases carry mutations in TP53. Work from our lab showed that TP53 mutations emerge as ‘late’ events during GBM growth. Therefore, we hypothesized that wild-type (wt) p53 function is impaired in GBM. We used the TCGA data of 591 GBM patients to compare the clinical and molecular characteristics of wt and mutant TP53 patients. Gene expression data were analyzed to compare the correlation of TP53 with the expression of key p53 regulators and identify differentially expressed regulators between our groups. Furthermore, we evaluated the expression of p53 and selected regulators in patient-derived cells (PDCs) and control lines with known TP53 status. Our results show that wt TP53 patients live less than mutant patients and both groups respond similarly to treatment. No differences in age, sex, race, TP53 levels, and MGMT methylation status were observed between the groups. Gene expression analyses revealed that MAPK8, a p53 activator, negatively correlates with TP53 in the wt group. Moreover, ~21% of p53 regulators are differentially expressed between wt and mutant patients. Among these, we selected SIRT3, a p53 repressor, for experimental validation. We verified the p53 genetic status of PDCs through western blot and confirmed Sirt3 expression in wt and mutant TP53 PDCs. By CRISPR-Cas9-based genomic editing, we are currently evaluating the impact of SIRT3 knockout in GBM-PDC and patient-derived xenografts. We expect that SIRT3 knockout will restore p53 function in the wt group. In conclusion, our results suggest that p53 function is impaired in wt patients and provide insights into mechanisms affecting its activity.
CSIG-31. ANNEXIN A7 ALTERNATIVE SPLICING IN GLIOMA STEM CELLS FACILITATES THE DEGRADATION OF EGFR BY PHOSPHORYLATING TYROSINE RESIDUES EXCLUSIVE TO PROTEIN ISOFORM 1
Authors: Merati Aran , Nair Sindhu , Rajbhandari Rajani , Johnson Nicholas , Bredel Markus
Published: November 2024

The majority of GBMs express aberrant receptor tyrosine kinase (RTK) activity, which are canonically endocytosed and degraded. This process is disrupted in GBM to promote receptor recycling and resulting in hyperactive RTK signaling. Exon six of Annexin A7 (ANXA7) can be alternatively spliced to yield two distinct protein isoforms through its inclusion (I1) or exclusion (I2). We investigated ANXA7 isoform differences for epidermal growth factor receptor (EGFR) trafficking fates in PDX glioma stem cells (GSCs). We demonstrated that ANXA7 exon skipping supports the impaired endosomal trafficking of RTKs to favor recycling in GBM. JX14 GSCs were made to overexpress ANXA7-I1 with lentivirus to conduct immunofluorescence experiments measuring EGFR-ANXA7 colocalization (Pearson) with markers of the endocytic pathway for the early endosomes (EEA1), recycling endosomes (Rab4/Rab11), and lysosomes (LAMP1). EV and I1 cells were also incubated with siRNA targeting both ANXA7 isoforms to determine the impact of ANXA7 loss on endosomal EGFR trafficking. Interestingly, we found drastic differences in endosomal EGFR trafficking in I1 expressing cells. EGFR colocalized with EEA1 in both EV and I1 cells (R2=0.01336, P>0.6275). In EV cells, EGFR was recycled via fast/slow recycling endosomes demonstrated by Rab4/Rab11 colocalization while I1 did not (R2=0.9267, P<0.0001). Furthermore, I1 cells and not EV preferentially degraded EGFR as seen by LAMP1 colocalization (R2=0.9398, P<0.0001). On the other hand, ANXA7 siRNA KD in I1 cells impaired EGFR sorting via a 40% increase (P<0.0010) in total EGFR protein and a 40% reduction (P<0.0001) in colocalization with EEA1 to prefer recycling again while EV cells were unaffected. I1 overexpression significantly reduced EGFR signaling through degradation, which is driven by the phosphorylation of I1-exclusive tyrosine residues in phosphomimetic (p<0.01) and non-phosphorylatable protein mutants. I1-induced reduction in EGFR signaling suggests a new therapeutic vulnerability for GSCs by potentially reducing tumorigenicity or improving the efficacy of EGFR inhibition.
CSIG-34. TYROSINE PHOSPHORYLATION OF NON-CANONICAL NF-ΚB P52 PROMOTES GLIOMA GROWTH AND CHEMORESISTANCE IN GBM
Authors: Driscoll Riley , Wu Longtao , Bernal Giovanna , Dalmage Mahalia , Spurr Liam , Yamini Bakhtiar
Published: November 2024

p52 is a nuclear factor-κB (NF-κB) transcription factor that comprises the non-canonical NF-κB pathway. The impact and mechanism of non-canonical NF-κB signaling remains understudied in glioblastoma (GBM). Subunit post-translational modification is a known mechanism of NF-κB activation, however phosphorylation of p52 has never been demonstrated. Elevated tyrosine kinase activity is a known-feature of GBM and portends worse survival. Further, p52 has been shown to upregulate factors that likely promote invasion of GBM, thereby reducing survival. Activation of p52 may serve as a link between increased kinase activity and poor survival in GBM. p52-knockout cell lines were generated using the CRISPR-Cas9 system and assessed for growth and survival differences in vitro and in syngeneic murine glioma models. Public glioma datasets and an institutional cohort were surveyed to corroborate p52-dependent survival differences in GBM. To determine whether p52 is post-translationally modified, we performed tandem mass spectrometry on p52 in GBM cells. Interacting factors were also analyzed and tested for site-specific modification of p52 via co-IP studies. We then generated PTM-null, knock-in glioma cell lines using CRISPR-CAS9 editing to demonstrate the functional significance of p52 PTMs, which were assessed using assays of relative cell growth, stemness, chemosensitivity and survival. Finally, we performed unbiased analysis of the p52 PTM-dependent transcriptome via RNA-seq. p52 loss significantly reduced glioma growth rate in vitro and improves murine survival. Retrospective analysis of GBM in patients suggests that p52 levels are negatively prognostic. Mass spectrometry identified multiple p52 PTMs with tyrosine phosphorylation sites as top hits. Identified phospho-tyrosine residues specifically interact with SRC-family kinases. PTM site editing significantly reduces glioma cell growth and stemness while enhancing chemosensitivity, reflecting broad transcriptome level changes. In sum, p52 activity enhances GBM growth and chemoresistance, which is partially modulated by tyrosine-specific phosphorylation. p52 warrants investigation as a therapeutic target in GBM, possibly in combination with kinase inhibitors and standard alkylating chemotherapy.
CSIG-35. RAB3B DICTATES MTORC1/S6 SIGNALING IN CHORDOMA AND PREDICTS RESPONSE TO MTORC1-TARGETED THERAPY
Authors: Meng Tong
Published: November 2024

Chordoma is a rare mesenchymal malignancy, exhibiting a high tendency to postoperative recurrence and poor prognosis. To date, its tumorigenic regulatory mechanisms remain elusive leading to a lack of effective therapeutic targets and drug sensitivity indicators. Here, via transcriptome and proteome analyses, we unveiled RAB3B as the prominent oncogenic regulator in chordoma. Multidimensional tissue samples further indicated its overexpression and enhancer-associated high transcriptional activity in chordoma. Notably, RAB3B ablation attenuated the chordoma cell growth, stemness, migration and tumorigenicity in vivo and in vitro. Through determining the RAB3B-mediated program in chordoma, we identified that RAB3B was highly associated with PI3K-AKT-mTOR signaling and directly bound to S6. Mechanistically, RAB3B increased the S6K-mediated phosphorylation of S6 by physically interacting with dephosphorylase DUSP12, to block its dephosphorylating of p-S6 specifically at S235/236. Pharmacological targeting mTORC1 pathway via dactolisib and rapamycin dramatically impeded the RAB3B-induced chordoma cell oncogenesis, while RAB3B knockout desensitized mTORC1 inhibition. Clinically, RAB3B/p-S6 suggested a good prognostic value and response to mTORC1 inhibitors for chordoma patients. Altogether, this work uncovers RAB3B as a novel activator of mTORC1 pathway, and suggests the oncogenic and predictive roles of RAB3B/p-S6 in chordoma, indicating therapeutic potentials of mTORC1-targeted therapy in advanced chordoma patients with aberrant RAB3B/p-S6 hyperactivation.
RADT-04. SEQUENCING OF CHECKPOINT INHIBITORS AND RADIOTHERAPY IN MELANOMA BRAIN METASTASES: A META-ANALYSIS OF COMPARATIVE STUDIES
Authors: Haddad Philip , Kantamani Deepti , Gupta Ankita
Published: November 2024

OBJECTIVE

Melanoma brain metastases significantly worsen prognosis, with incidence rates as high as 50%. While both immunotherapy and radiotherapy improve survival, the optimal sequencing remains undetermined. This meta-analysis aims to define the most effective treatment sequence for improving progression-free survival (PFS) and overall survival (OS).

METHODS

A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of melanoma brain metastases, comparative studies of immune checkpoint inhibitors given before or after radiotherapy, and those that reported overall (OS) and progression-free (PFS) survival. Studies that reported mixed data that included concurrent immune checkpoint inhibitors with radiotherapy were excluded. A meta-analysis using the fixed effects and random effects models was conducted.

RESULTS

Our analysis included six retrospective studies encompassing 213 patients, with a median age of 62 years and follow-up of 22 months. The results indicate a clear disadvantage in PFS when immunotherapy precedes radiotherapy (HR=1.77; 95% CI 1.21-2.60; p=0.003; I2=13.5%). Similarly, initiating treatment with immune checkpoint inhibitors followed by radiotherapy showed a trend towards poorer OS compared to the reverse sequence, although this finding was of borderline significance (HR=1.39; 95%CI 0.97-1.99; p=0.07; I2=0%).

CONCLUSIONS

This meta-analysis, the first and largest to date, provides compelling evidence that initiating treatment with radiotherapy followed by immune checkpoint inhibitors significantly improves PFS with a trend for a better OS in patients with melanoma brain metastases. These findings suggest that radiotherapy should precede immunotherapy to optimize clinical outcomes in this patient population. Further research, particularly prospective studies, is necessary to confirm these results.
RADT-10. CEREBELLAR RE-IRRADIATION AFTER WHOLE BRAIN RADIOTHERAPY SIGNIFICANT SYMPTOM RELIEF WITH MINIMAL TOXICITY IN METASTATIC BRAIN PATIENTS
Authors: Haisraely Ory , Lawerence Yaccov , Taliansky Alicia
Published: November 2024

INTRODUCTION

Whole-brain irradiation (WBRT) remains a standard treatment for patients with extensive brain metastases, providing symptom relief and prolonging survival. However, patients often experience recurrent metastases, necessitating re-irradiation. This study evaluates the efficacy and safety of cerebellar-only re-irradiation for improving symptoms and reducing toxicity in patients with recurrent cerebellar metastases following WBRT.

METHODS

A retrospective review was conducted on patients who underwent cerebellar re-irradiation between 2017 and 2023 after prior WBRT for symptomatic cerebellar metastases. Clinical, dosimetric, and outcome data were collected. Symptom improvement was assessed based on patient, caregiver, and physician reports three months post-treatment.

RESULTS

The study included 56 patients with a median age of 53 years. Symptom domains included gait dysfunction, nausea/vomiting, dysarthria, movement disorder, dizziness, and headache. Breast cancer was the most common histology. The median interval from WBRT to cerebellar re-irradiation was 15 months. Symptomatic improvement was observed in 75% of patients, with notable improvements in nausea/vomiting (84.6%) and headache (80%). Age, dose deliver and time from WBRT were significant for clinical improvement. Dexamethasone use decreased in 76.3% of patients post-treatment. Radiological responses correlated with clinical improvements in 90% of cases. Only one patient developed symptomatic radiation necrosis. Six-month overall survival and progression-free survival were 50% and 39.2%, respectively.

CONCLUSION

Cerebellar-only re-irradiation is an effective and safe option for managing recurrent cerebellar metastases, significantly improving symptoms with minimal toxicity. This approach also allows for subsequent systemic therapy or radiosurgery for supratentorial lesions, potentially reducing the need for additional WBRT. Further studies are required to validate these findings in larger cohorts.
RADT-16. ADJUVANT CHEMO-RADIATION THERAPY AS A RISK FACTOR FOR POSTOPERATIVE HYDROCEPHALUS FOLLOWING RESECTION OF HIGH-GRADE GLIOMA: A PROPENSITY-MATCHED CASE SERIES
Authors: Das Nikita , Dhamija Ravi , Sridharan Preety , Swetz Joseph , Harper Elleson , Perez Jaime , Newton Herbert , Vempati Prashant , Hodges Tiffany
Published: November 2024

The discovery of the neural glymphatic network in the past decade has significant implications for clinical investigations on hydrocephalus. With emerging understanding of how meningeal lymphatics and perivascular pathways impact cerebrospinal fluid dynamics, it is conceivable that inflammatory and fibrotic changes induced by radiation and chemotherapy may contribute to the pathogenesis of postoperative hydrocephalus, a well-documented sequela of resective neurosurgery. This study investigates differences in adjuvant chemo-radiation therapy patterns between patients who develop hydrocephalus following high-grade glioma resection and those who do not experience this postoperative complication. A retrospective chart review identified 328 adult patients who underwent tumor resection at our institution between 2010-2020, of which 257 had high-grade gliomas. Demographic and clinical data were collected, including resection history and adjuvant chemotherapy and radiation history. Propensity Score Matching generated comparative cohorts (n=27) using covariates sex, age at first surgery, surgery type, tumor location, extent of first resection, tumor-associated seizures, ventricular opening, number of additional resective surgeries, and pre-surgical Karnofsky Performance Scale score. Independent t-tests assessed differences in adjunctive chemo-radiation trends between patients who developed hydrocephalus within 3 years postoperatively and those who did not. 27 of 257 patients (10.5%) who underwent resection for high-grade glioma developed hydrocephalus within 3 years of their first surgery. Patients who developed hydrocephalus were more likely to have initiated the Stupp protocol(P=0.004), completed the Stupp protocol(P=0.02), and undertaken multiple cycles of the Stupp protocol(P=0.0004). Additionally, these patients had a smaller time window between surgery and adjuvant chemo-radiotherapy initiation than patients who did not develop hydrocephalus (P=0.02). Importantly, engagement in other clinical trial regimens with chemotherapy or radiation therapy did not differ significantly between groups(P=0.08, P=0.49, respectively). Shortened time to initiation of chemo-radiation therapy postoperatively and increased number of chemo-radiation cycles may increase a patient’s susceptibility to develop postoperative hydrocephalus following resection of high-grade glioma.
RADT-19. PILOT STUDY OF VELOCITY-SELECTIVE ARTERIAL SPIN LABEL MRI (VSASL-MRI) DERIVED RELATIVE CEREBRAL BLOOD FLOW TO DISTINGUISH IMAGING CHANGES AFTER RADIOSURGERY (SRS) FROM PROGRESSIVE BRAIN METASTASIS (BM)
Authors: Zhu Dan , Xu Feng , Liu Dapeng , Katulis Lisa , Lin Doris , Kleinberg Lawrence
Published: November 2024

Management of imaging progression on standard contrast enhanced MRI (cMRI) after SRS for brain metastasis is challenging as treatment effect/necrosis appears similar to progressive tumor. VSASL-MRI uses water labeled based on velocity, rather than spatial location, as an endogenous contrast agent and is therefore insensitive to transit delay impacting other ASL-MRI techniques. Other advantages include no IV contrast, limited susceptibility artifact, and absence of confounding leakage of gadolinium contrast into tissues. VSASL-MRI was performed (median 15 (4-123) months after SRS) to evaluate SRS treated solid tumor BM with clinician determined imaging progression on cMRI to evaluate the hypothesis that VSASL-MRI may distinguish biologic tumor (hyperperfused compared with normal brain) from treatment effect/necrosis (hypoperfused). 17 patients (19 progressing lesions) were enrolled. 13/19 index lesions had hypoperfusion. Of these, 3/13 had resection with no tumor present, 8/13 were conservatively managed and appeared to be treatment effect/necrosis as they stabilized or improved on follow-up cMRI without further BM directed intervention, and 2/13 had resection for further progression with active tumor present. For 6 index lesions that were hyperperfused: 3/6 had pathology were confirmed to be tumor, whereas the other 3/6 continued to progress (one got additional RT, two expired with progression). In addition, two pts had concurrent identification of new non-index previously untreated lesions on cMRI that were hyperperfused on VSASL-MRI and were treated. One of these patients had subsequent VSASL-MRI demonstrating post-SRS resolution of perfusion 2 months after treatment. This pilot data supports the hypothesis that VSASL-MRI may be useful in distinguishing tumor progression from radiation related imaging changes and/or be an early biomarker of radiosurgery response. We are initiating further study (1R01CA282928-01, PI; Qin) to refine the technique and prospectively assess the value of this approach in a larger number of patients.
RADT-26. RADIATION FRACTIONATION IN THE MANAGEMENT OF ELDERLY PATIENTS WITH GLIOBLASTOMA BY AGE
Authors: Afzal Rimsha , Kim Michelle , Wahl Daniel , Lawrence Theodore , Takayesu Jamie
Published: November 2024

Multiple studies have investigated hypofractionated radiation (HFX) for elderly patients with glioblastoma (GBM), using varying age cut-offs. This leads to uncertainty about who benefits most from a hypofractionated course. This study examines the use of and outcomes with HFX, between two commonly used cut offs to define elderly GBM: 65 versus 70 years old. In this retrospective review, 309 patients diagnosed with GBM who were treated with radiation at a single academic institution were included. The Kaplan-Meier method was used to analyze overall survival. A Chi-square test was conducted to compare the use of SFX and HFX and the median survival between those 65-69 versus 70-74 years old. Patients aged 70-74 were more likely to receive HFX radiation compared to those aged 65-69 (80.00% vs. 42.65%, p=0.0002). Median survival for the entire cohort was 12 months. Among those 65-69 years old, SFX was associated with a significantly higher median survival compared to HFX (14 months vs. 7 months, HR 2.00, 95% CI 1.16 – 3.46, p=0.03). This was also true for those 70-74 years old, (18 months vs. 4 months, HR 4.50, 95% CI 1.84 – 11.01, p=0.03). We demonstrate a decrease in the use of SFX in patients 65 years or older, and that that standard fractionation is associated with longer survival in older patients with GBM. This suggests that in a well selected population, SFX should be considered even among elderly patients. Additional work is needed to determine whether these findings are causal or due to patient selection. Performance status and MGMT methylations status, for instance, should guide clinical decision making. Such results highlight the importance of further studies to fine tune radiation dose and fractionation elderly patients with GBM.
RADT-31. EMBRACING HYPOFRACTIONATED RADIOTHERAPY FOR GLIOBLASTOMA IN A RESOURCE CONSTRAINED SETTING
Authors: Menon Durgapoorna , G Kiron , Panikar Dilip , Warrier Arun , Sasi Sandra
Published: November 2024

BACKGROUND

Various hypofractionated schedules of radiation have been tried in glioblastoma with limited success. Though the shorter fractionation is appealing and there is evidence (since 2017) to use the 40Gy in 15 fractions regime in the elderly, the fear of toxicity limits its use, especially in the developing nations. We have tried this regime in younger patients (not eligible for supportive care alone) who had a poor Performance status or if only a biopsy had been performed.

METHODS

25 patients treated for glioblastoma from 2017 to 2023 using 4000cGy delivered in 15 fractions were included in the study. The patient details were obtained retrospectively from the medical records and the Eclipse Treatment Planning system.

RESULTS

There were 16 males and 9 females. Median age was 62 years (range 52 to 77 years). 56% of the patients had an ECOG performance score of 3; and the rest 2. 12 lesions were on the Right side, 9 in the left and the rest extended across the midline. Surgery was limited to biopsy alone in 8; almost as many (n=7) had a Near Total Resection; the rest underwent decompression. Surprisingly, almost half the patients were MGMT unmethylated. 16 patients were on steroids either during or after radiation. All 25 maintained their Performance Status and completed radiation as planned. The mean GTV Volume - 53.48 cc (Range 6-201). Dmax was never above 103%; Brainstem and Optic Apparatus Dmax were also kept below 100%. In the majority, 3 beams of mixed energy were used. 19 patients received both Concurrent and adjuvant temozolomide; only adjuvant was given to 6. The median overall survival was 7.7 months (range 2-60.6 months) and the Disease free survival was 7.5 months (Range 1-60.5 months).

CONCLUSIONS

Hypofractionated radiotherapy of 4000 cGy in 15 fractions seems to be a kinder treatment in glioblastoma patients with a poor performance status.
RADT-32. FREQUENT MULTIFOCAL INTRATUMORAL HEMORRHAGE IN MULTIPLE BRAIN METASTASES FROM HEPATOCELLULAR CARCINOMA
Authors: Ishi Yukitomo , Nishioka Kentaro , Yamaguchi Shigeru , Okamoto Michinari , Motegi Hiroaki , Oki Sogo , Mori Takashi , Aoyama Hidefumi , Fujimura Miki
Published: November 2024

OBJECTIVE

Brain metastasis (BM) rarely occurs in hepatocellular carcinoma (HCC); however, it frequently causes intratumoral hemorrhage (ITH). We investigated the clinical manifestations of ITH in patients with multiple BMs from HCC (HCC-BM).

METHODS

Patients who underwent treatment for multiple BMs with more than two metastatic sites were retrospectively reviewed and those diagnosed with HCC-BM were further analyzed. The multifocality of hemorrhage was classified into two groups, spatial and temporal multifocality, according to the radiological findings. The characteristics of multifocal hemorrhage in HCC were compared with those of BMs from other cancer types.

RESULTS

Fifteen out of 636 (2.36%) cases of multiple BMs were due to HCC metastasis. Out of 15 HCC-BM cases, 13 (86.7%) presented multifocal hemorrhage and 1 presented unifocal hemorrhage during the follow-up period. Spatial and temporal multifocality were observed in 9 and 5 cases, respectively, among 13 cases of multifocal hemorrhage. Among 636 cases of multiple BMs, HCC cases showed the highest frequency of multifocal hemorrhage, and HCC was significantly associated with multifocal hemorrhage compared with other primary-site cancer types (30/621 cases, 4.8%). Out of 15 patients with multiple HCC-BMs, 12 underwent whole-brain irradiation (WBI), and their median overall survival was 147 days. In one patient (8.3%), although treatment was stopped due to neurological deterioration by ITH, local BM control was favorable after the completion of WBI, and the only cause of death in six patients who completed WBI and were radiologically followed up until death was the progression of extracranial lesions.

CONCLUSIONS

Multiple HCC-BMs frequently present with multifocal ITH compared with BMs from other cancer types. Despite poor treatment outcome, WBI may show favorable local control considering the potential hemorrhagic event by tiny metastases that would not be detected radiologically. Immediate commencement of treatment before hemorrhage progression will be required for the treatment of multiple HCC-BMs.
RADT-37. PROTON THERAPY REIRRADIATION FOR RECURRENT MALIGNANT GLIOMA: PROSPECTIVE ANALYSIS FROM THE PROTON COLLABORATIVE GROUP
Authors: Gal Omer , Mihalcik Stephen , Zeng Jing , Chang John H , Rosen Lane , Choi Isabelle , Simone Charles B , Vargas Carlos E , Tsai Henry K , Press Robert H
Published: November 2024

BACKGROUND

Standard of care treatment for recurrent malignant glioma after prior radiotherapy (RT) is not well established. Proton therapy (PT) is increasingly used for reirradiation (ReRT) at the time of recurrence; however, treatment outcomes, toxicity, and prognostic factors for patients treated with PT-ReRT remain poorly defined.

METHODS

The prospective, multi-institutional Proton Collaborative Group (PCG) registry was queried for patients with malignant glioma who previously received RT and underwent PT-ReRT between 7/2011-12/2023. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method, and Cox proportional hazards regression was used for uni- and multivariate analysis (UVA and MVA). Dose was calculated using equivalent dose in 2-Gy fractions (EQD2).

RESULTS

143 consecutive patients were identified. Median follow-up was 11.2 months and median time interval (TI) from prior RT (median 58.5 Gy) to PT-ReRT (median 44.6 Gy) was 42.4 months. Primary histology was glioblastoma (n=74), astrocytoma (n=35), and oligodendroglioma (n=34). Median PFS and OS were 8.1 and 11.2 months, respectively. On UVA, improved OS was associated with oligodendroglioma (HR 0.37) and astrocytoma histology (HR 0.53) compared to glioblastoma, TI >60 months (HR 0.2), CNS WHO Grade 2 compared to 4 (HR 0.42), and ECOG performance status 0 (HR 0.47). On MVA, improved OS remained associated only with oligodendroglioma (HR 0.42) and TI >60 months (HR 0.49). Acute and Late Grade 3 toxicity occurred in 7% and 4% of patients. Acute Grade 3 toxicity was associated with poor performance status (HR 16.15).

CONCLUSIONS

In the largest series of glioma PT-ReRT reported to date, retreatment appears well tolerated with variable outcomes based on clinical prognostic factors. Toxicity rates were acceptable compared to historical photon-based literature despite a high median prescription dose.
RADT-41. RADIOSURGERY FOR GLOMUS TUMORS: IMPACT OF MRI-PET FUSION ON TREATMENT PLANNING AND OUTCOMES
Authors: Sreenivasan Sanjeev , Jung Jessica , Calugaru Emel , Schulder Michael , Goenka Anuj
Published: November 2024

Paragangliomas present a challenge for stereotactic radiosurgery (SRS) treatment planning, particularly regarding the delineation of tumor boundaries. We propose that integrating 68Ga-DOTATATE PET scans alongside MRI in SRS planning will facilitate superior target identification and tumor coverage compared to reliance on MRI alone. A retrospective analysis of 9 patients diagnosed with paraganglioma who underwent MRI and 68Ga-DOTATATE PET imaging over a 20-month period was conducted. Images were imported into GammaPlan treatment planning software, partitioned into separate sessions: one with MRI and another with MRI-PET fusion. A single evaluator contoured paragangliomas as gross tumor volume (GTV) initially using MRI alone and subsequently with PET/MRI fusion. The pre- and post-PET fusion GTV volumes were compared. The standard deviation of the percentage increases in volume was calculated to assess variability across the sample. Of included 9 patients, 7 were females and median age was 58.3 years. Four patients had prior surgery. Seven patients were treated with Gamma Knife, while 2 with LINAC. Two patients were treated with single fraction SRS while 7 with hypofractionated SRS. Across all treated patients (n=9), GTV volumes significantly increased with PET fusion, with an average volume increase of 26.02% (n=8). One patient reported dryness of throat after SRS. Significant PET avidity over structures like temporal bone, internal jugular vein, petrous internal carotid artery and sigmoid sinus-IJV junction were included in PET/MRI fusion GTVs, which were missed on isolated MRI contours. At median 6-month follow up, all patients had a stable radiological response. Integration of 68Ga-DOTATATE PET scans with MRI enhances the visualization of paragangliomas in patients undergoing SRS. Further extensive studies are warranted to validate this observation and to better understand the variability in treatment response observed across the patient population. Our practice has initiated routine utilization of DOTATATE-PET imaging in paraganglioma patients undergoing SRS planning.
RADT-44. EARLY CLINICAL EXPERIENCE WITH PROTON CRANIOSPINAL IRRADIATION FOR THE TREATMENT OF LEPTOMENINGEAL DISEASE
Authors: Marciscano Ariel E , Ehret Felix , Yuan Ammy M , Zieminski Stephen , Leland Peggy A , Khandekar Melin J , Oh Kevin S , Shih Helen A
Published: November 2024

BACKGROUND

Leptomeningeal disease (LMD) is a uniformly terminal event of advanced cancer with limited therapeutic options, with survival ranging from weeks to a few months. Recently, proton craniospinal irradiation (pCSI) has been demonstrated to confer a progression-free and overall survival benefit in select patients with LMD as compared to more limited site radiotherapy. Early results from an institutional experience of pCSI for patients with LMD from solid tumor malignancies are reviewed.

METHODS

All patients with LMD and treated with pCSI at our institution were reviewed, specifically with regards to baseline patient characteristics, radiation dosimetry parameters and clinical outcomes.

RESULTS

Between February 2023-April 2024, nine patients were treated with pCSI for a range of primary tumor histologies, including two with triple-negative breast cancer and one each with ER+/PR+/HER2- breast cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, esophageal cancer, pancreatic cancer and ovarian cancer. All patients received 30Gy(RBE) in 10 fractions to the craniospinal axis, with one patient receiving an intracranial boost (6Gy(RBE)). Median age and performance status was 58 years and KPS 80, respectively. Five (56%) patients underwent CSF diversion prior to pCSI, 22% of patients had undergone prior CNS-directed radiotherapy, and all patients received at least one line of systemic therapy in the metastatic setting prior to pCSI. Median survival from the first day of pCSI was 4.3 months (range 1.3-10.7mo). Median survival among patients undergoing CSF diversion prior to pCSI (n=5) was 5.3 months (vs. 2.9mo with no CSF diversion). Median survival among patients who received systemic treatment after pCSI (n=5) was 9.1 months (vs. 2.9mo for patients who did not).

CONCLUSIONS

Careful patient selection is imperative to identify those who will best benefit from pCSI with suggestion of patients undergoing pre-pCSI CSF diversion and receiving post-pCSI systemic therapy achieving superior survival.
RADT-48. ANALYSIS OF PROTON RADIATION THERAPY INDUCED CONTRAST ENHANCEMENT: A SINGLE INSTITUTION, RETROSPECTIVE STUDY
Authors: Puri Sushant , Huang Ellen , Li Anne , Tarui Yurika , Redmond Kristen , Kut Carmen , Page Brandi , Croog Victoria , Laterra John , Kleinberg Lawrence
Published: November 2024

Proton radiotherapy (PRT) has superior physical dose distribution with a lesser integral off target radiation dose exposure compared with standard photon radiotherapy resulting in reduced toxicity of uninvolved normal tissues. However, there may be toxicity in areas targeted for high dose treatment as a result of uncertainty about the relative radiobiologic effect (RBE) of proton radiotherapy compared with photon radiotherapy and the potential for localized high doses at the end of the proton beam range (Bragg peak). This may result in radiation-induced contrast enhancement (RICE) reflecting transient toxicity or permanent injury, particularly when associated with concurrent chemotherapy. We analyzed 150 consecutive adult patients, with a histopathologic diagnosis of CNS malignancy, who underwent only PRT at Johns Hopkins Hospital between 2019 – 2023 with least 1 year of follow-up imaging. RICE was defined as a new post-treatment contrast enhancement on MRI within the radiation field. The determination of disease progression or RICE was confirmed with additional follow-up MRI or pathology. RICE was identified in 14 cases (9.3%). The median age was 48 y (range 19 – 72 years), sex 50% female. Diagnosis was 5 astrocytoma, 3 meningioma, 2 glioblastoma, 1 medulloblastoma, 2 oligodendroglioma, 1 tectal glioma. 4/5 astrocytoma patients were grade 2, 2/3 meningioma was grade 1, 1/3 was grade 2, 2/2 oligodendroglioma was grade 2. The median time since completing PRT to development of RICE was 3.5 months. The median radiation dose was 52.20 Gye (range 23.40 - 60.06). Dexamethasone was used in 11 patients (78 %) and in bevacizumab was used 2. Chemotherapy with temozolomide 7 (50%), PCV 1, and none in 5. 12 (85%) patients were still alive. PRT can also be associated with radiation injury in the target, and more information is needed about the incidence, natural history, and associations with localized dosimetry.
CTIM-01. OUTCOMES AND IMMUNE RESPONSES AFTER PEPTIDE VACCINATION TARGETING HUMAN CYTOMEGALOVIRUS ANTIGEN PP65 IN CHILDREN AND YOUNG ADULTS WITH RECURRENT HIGH-GRADE GLIOMA AND MEDULLOBLASTOMA: RESULTS OF A PHASE 1 TRIAL
Authors: Thompson Eric , Ashley David , Ayasoufi Kathy , Norberg Pam , Archer Gerald , Buckley Evan , Herndon James , Walter Ashley , Archambault Bridget , Balajonda Bea , Flahiff Charlene , Jaggers Denise , Gorski Laura , Vlahovic Gordana , Reap Elizabeth , Schroeder Kristin , Desjardins Annick , Johnson Margaret , Peters Katherine , Khasraw Mustafa , Mitchell Duane , Sampson John , Landi Daniel
Published: November 2024

INTRODUCTION

The human cytomegalovirus (CMV) antigen pp65 is ubiquitously expressed in high-grade glioma (HGG) and medulloblastoma but not in adjacent brain. The primary objective of this phase I trial (NCT03299309) was to assess the safety and feasibility of a novel peptide vaccine targeting pp65 (PEP-CMV) in children/young adults with recurrent medulloblastoma and HGG.

METHODS

PEP-CMV is comprised of a synthetic long peptide of 26 amino acids and is administered as an emulsion in Montanide ISA 51. Patients receive a 5-day course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning to promote dendritic cell migration, then PEP-CMV intradermally in the groin every two weeks for 3 doses, then monthly.

RESULTS

42 patients were enrolled. The mean age was 23.2 ± 9.3 years. 55% of patients were male. The median KPS was 80. The median number of prior chemotherapy regimens was 4 (range 1-15). Of the 38 patients who received PEP-CMV, the maximum grade adverse events (AE) possibly, probably, or definitely related to PEP-CMV were: 17 (45%) Grade 1 AEs, 16 (42%) Grade 2 AEs, 2 (5%) Grade 3 AEs (encephalopathy and pyramidal tract syndrome), and one (3%) Grade 4 AE (cerebral edema). One patient developed cytokine release syndrome (Grade 2). The median PFS was 2.5 months (95% CI:2.2, 3.2) and median OS was 6.4 months (95% CI:3.4, 7.9). The 12-month OS was 26.6% (95% CI:14, 41.1%). Of the 21 patients with evaluable immune monitoring data (received ≥3 vaccines/known CMV status), T cell reactivity on IFNγ pp65 ELISpot was increased after PEP-CMV delivery (median 2 vs 22, P=0.01). PFS and OS were significantly better in patients with low levels of CD56brightCD16dim phenotype NK cells: P=0.029 and P=0.047, respectively. Patients with naïve CD8+ counts over the median had significantly better PFS (P=0.006).

CONCLUSIONS

PEP-CMV is well-tolerated and elicits an antigen-specific immune response in heavily pretreated, multiply recurrent patients with a 12-month OS of 26.6%.
CTIM-07. A PHASE II, OPEN LABEL, SINGLE ARM STUDY OF NIVOLUMAB FOR RECURRENT OR PROGRESSIVE IDH MUTANT GLIOMAS WITH PRIOR EXPOSURE TO ALKYLATING AGENTS
Authors: Yim Eunji , Donovan Laura , Bargo Alicia , Nayak Lakshmi , Odia Yazmin , Wong Eric , Pring Krystelle , Malig Mervin , Genfi Yacha , Wright Nathaniel , Kesari Lakshmi , Russ Alyssa , Chang Rae , Torres Denisse , Manjrekar Kriti Bagri , Ana Sarah Sta , Sender Naomi , Mistretta Suzanne , Iwamoto Fabio
Published: November 2024

BACKGROUND

Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are an important prognostic factor in patients with gliomas. IDH-mutant gliomas are prone to develop hypermutation after exposure to alkylating agents; in other solid tumors, hypermutation may be a predictive biomarker for PD-1 inhibitor response. In this study, we hypothesize that this specific subgroup of patients would clinically benefit from nivolumab as measured by overall response rate (ORR), duration of response (DOR), median progression-free survival (PFS), and overall survival (OS).

METHODS

Patients aged 18 years and older with recurrent/progressive IDH-mutant (WHO Grades 2-4) gliomas and prior exposure to alkylating agents were included. Nivolumab was given 240 mg q2w for 8 cycles, then 480 mg q4w until progression, toxicity, study withdrawal, or completion at 2 years. Efficacy was evaluated by ORR of partial (PR) and complete responses (CR) per RANO criteria; low-grade glioma RANO criteria was used for patients with non-enhancing disease. Secondary endpoints included median PFS, median OS, DOR. Toxicity and survival were followed every 3 months until death/study completion.

RESULTS

Thirty-three patients (66.7% male) were evaluable at study completion. Histology consisted of oligodendroglioma (N=11; 55% Grade 3) and astrocytoma (N=22; 36% Grade 3, 32% Grade 4). Median number of prior lines of systemic therapy was 1 (range 1-6). Median dexamethasone dose at screening was 0 mg (range 0-4). ORR was 9% with two PR and one CR, median DOR 33 months. 11 (32%) patients had stable disease (7 stable for 6+ months) with median PFS 2.2 months and median OS 29.1 months. There were two treatment-related Grade 3 adverse events (lymphopenia and hypotension). One patient discontinued treatment for Grade 2 transaminitis.

CONCLUSIONS

Though the primary endpoint was not met, three patients have ongoing CR and PR at 54+, 33+ and 24+ months. Future combination therapies with PD-1 inhibitors may increase efficacy in recurrent IDH-mutant gliomas.
CTIM-11. LONG-TERM SURVIVORS FROM A PHASE 1B STUDY OF IGV-001 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Perez-Olle Raul , Pennock Greg K , Scott Charles , Andrews Carrie , Zilberberg Jenny , Hooper D Craig , Judy Kevin D , Exley Mark A , Andrews David W
Published: November 2024

Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed glioblastoma (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers (BDCs) implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM (Andrews et al., 2021), including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. The Phase 1b study enrolled 33 patients in four different cohorts implanted with 10 or 20 BDCs for 24 or 48 hours. Here we report on 6 subjects with survival beyond 4 years, including 5 subjects who survived 5 years or more (15.2%). There were 4 male and 2 female subjects, with a median age of 52 years (range 32-75). At diagnosis the MGMT promoter was methylated in 4 of 5 subjects that survived 5 years or more. We also report on T cell receptor Vβ CDR3 region sequencing of peripheral blood mononuclear cells and tissue infiltrated lymphocytes that was performed in a subset of 9 patients, including 3 subjects who survived beyond 4 years. Immune correlates of IGV-001 suggest an association between peripheral T cell clonal expansion and PFS/OS outcomes. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949) has completed enrollment and results are expected to be available in 2025.
CTIM-13. D2C7-IT IN COMBINATION WITH AN FC-ENGINEERED ANTI-HUMANCD40 MONOCLONAL ANTIBODY (2141-V11) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOLLOWED BY CERVICAL PERILYMPHATIC INJECTIONS (CPLIS) OF 2141-V11 IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM)
Authors: Desjardins Annick , Chandramohan Vidya , Herndon James E II , Threatt Stevie , Bullock Chevelle , Bradbury Claire , Johnson Margaret O , Khasraw Mustafa , Low Justin T , Peters Katherine B , Shoaf Madison , Landi Daniel , Batich Kristen , Friedman Allan H , Friedman Henry S , Ashley David M , Knorr David , Osorio Juan , Ravetch Jeffrey , Bigner Darell D
Published: November 2024

BACKGROUND

The combination of D2C7-IT, an antibody toxin conjugate, and anti-mouseCD40 via CED generates robust antitumor immunity by killing tumor cells, activating microglia, reversing glioma-associated microglia and macrophage (GAMM)-mediated immune suppression, and empowering polyfunctional tumor antigen-specific CD8 T cells in glioma models. In addition to reprogramming GAMMs, anti-CD40 also activated dendritic cells and induced glioma-specific T cell responses in tumor draining lymph nodes. After establishing the phase 2 dose of the combination of D2C7-IT+2141-V11 when infused via CED, we initiated an assessment of the safety and efficacy of the combination of D2C7-IT+2141-V11 CED followed by repeated subcutaneous CPLIs of 2141-V11 ipsilateral to the tumor in patients with rGBM, IDH wild-type (NCT04547777).

METHODS

Eligible are adult patients with solitary supratentorial rGBM; ≥4weeks after chemotherapy, bevacizumab, or investigational agent; adequate organ function; and KPS ≥70%. Patients are treated with D2C7-IT (166μg) and 2141-V11 (3mg), both infused via CED, followed by CPLI of 2141-V11 at 2mg at weeks 2 and 4 post D2C7-IT+2141-V11 CED, followed by every 3 weeks for 1 year and then every 4-6 weeks.

RESULTS

As of May 22, 2024, 18 patients with rGBM (median age of 54) were treated with D2C7-IT+2141-V11 CED followed by CPLIs of 2141-V11. 83% patients remain alive (range 3.3-14.8 months from start of D2C7-IT CED infusion) with a median of 8 CPLIs of 2141-V11 received (range 3-19). No study related grade 4 or 5 adverse events (AEs) were observed. Grade 3 AEs related to D2C7-IT and/or 2141-V11 include one each of hydrocephalus, headache, seizure, and cerebral edema. AEs related exclusively to CPLIs of 2141-V11 consist of grade 1 injection site reaction (n=16).

CONCLUSIONS

The addition of CPLIs of 2141-V11 post CED of D2C7-IT+2141-V11 is feasible and has shown an acceptable toxicity profile. The safety and efficacy results will be updated.