Tumor Progression Research Articles

TMIC-31. MOLECULAR PROGNOSTIC FACTORS OF THE PROGRESSION OF VESTIBULAR SCHWANNOMA AFTER PRIMARY TUMOR RESECTION

Abstract BACKGROUND Although vestibular schwannoma is a benign tumor, 10% of the tumor regrow after primary tumor resection. The factors associated with tumor progression from several reports remain controversial, and the role of the tumor microenvironment in vestibular schwannoma is still unclear. In this study, we analyzed the prognostic factors associated with the tumor progression after primary resection. METHODS We retrospectively reviewed the medical records of patients who underwent surgical resection and were diagnosed with vestibular schwannoma between January 2005 and June 2020. We performed RNA sequencing to identify the prognostic factors and immunohistochemistry to assess the tumor microenvironment, including analysis of the CD80 and CD206 expression of macrophages. We compared the progressed group whose tumor size got larger than 2mm after primary resection or who underwent additional treatment because of regrowth with the stable group. RESULTS Fifty-five patients underwent surgical resection for newly diagnosed vestibular schwannoma, and 12 of them had tumor regrowth. RNA sequencing revealed that the significantly upregulated pathways in the stable group was related to immune systems, while that of the progressed group was related to cell cycle. In addition, there were more myeloid cells, especially M2 macrophage infiltration in the stable group. Immunohistochemistry also showed higher M2 macrophages in the stable group. CONCLUSION In this study, multiomic analysis revealed the upregulation of immune-related pathways in the stable group and the cell cycle pathway in the progressed group. Altering the tumor microenvironment may offer a therapeutic strategy in vestibular schwannoma after primary resection.

EXTH-30. GENETIC ALTERATIONS THAT DEREGULATE RB AND PDGFRA SIGNALING PATHWAYS DRIVE TUMOR PROGRESSION IN IDH2-MUTANT ASTROCYTOMA

Abstract In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain unclear. In this presentation, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recur- rent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K and TP53R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astro- cytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. On the other hand, in accord with our previous study that IDH1 inhibitor was not sufficient to induce anti-tumor effects in IDH1-mutant high-grade gliomas (Tateishi K et al. Cancer Cell. 2015), we did not find decreased cell viability nor histone methylation status changes after mutation specific IDH2 inhibitor treatment of recurrent cells. These findings underlie that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

CNSC-42. PROGNOSTIC VALUE OF INTERLEUKIN-6 IN PATIENTS WITH GLIOBLASTOMA

Abstract Interleukin-6 (IL-6), a pro-inflammatory cytokine, has been implicated in the invasiveness and progression of glioma. However, the association between serum IL-6 levels at specific time points during treatment and patient prognosis remains unclear. This study was aimed to investigate the prognostic value of IL-6 measured at milestones in the treatment of patients with glioblastoma. Between January 2021 and December 2022, consecutive patients with newly diagnosed glioblastoma were enrolled. Serum IL-6 concentrations were measured at different time points, including preoperative, pre- and post-radiation period, and two-month intervals thereafter. Patients with incomplete data were excluded, and increase of IL-6 values due to the overlapping with systemic infection were also excluded from the analysis. During the study period, 26 patients and 270 IL-6 levels at different time points were evaluated. The median follow-up time was 11 months. Tumor progression was evident in 19 patients (73.1%) and 13 patients (50%) were expired. Preoperative and pre-radiation IL-6 values were available in 20 and 23 patients with the median 5.25 and 4.5 pg/mL, respectively. With the cut-off value of pre-radiation IL-6 at 4.5 pg/mL, high IL-6 group showed significantly worse progression-free survival and overall survival than low IL-6 group (p = 0.027 and 0.008, respectively). However, IL-6 levels at other milestone were not related to the patient prognosis. Serum IL-6 elevation in pre-radiation period is an unfavorable prognostic factor in tumor progression and patient survival. Further research is necessary to validate the prognostic role of IL-6 and explore the underlying mechanisms.

NIMG-03. USE OF ARTERIAL SPIN LABELING TO DIFFERENTIATE ICTAL PHENOMENON FROM TUMOR PROGRESSION IN HIGH GRADE ASTROCYTOMA

Abstract A 39-year-old female with grade-3 left parietal IDH-mutant astrocytoma following resection presented with convulsive status. EEG showed electrographic seizures arising from the left parietal region. MRI-brain showed the left temporoparietal post-treatment bed without any contrast enhancement (Fig-1A). Arterial spin labeling (ASL) – MR perfusion showed markedly increased cerebral blood flow (CBF) in the left temporoparietal lobe (Fig-1 C, D) with corresponding diffusion restriction (Fig-1B). Repeat imaging two weeks after the seizure control showed complete resolution (Fig-2) suggesting the imaging abnormalities to be a peri-ictal phenomenon.1 ASL-MR perfusion is a highly sensitive marker of increased CBF with its emerging application in distinguishing tumor progression (increased CBF) from post-treatment changes such as radiation necrosis (reduced CBF).1,2 This case highlights the utility of ASL-MR perfusion in differentiating peri/post-ictal phenomenon (increased CBF without T1-contrast enhancement) from tumor progression (increased CBF with T1-contrast enhancement) when employed routinely in clinical oncology practice.

EPCO-10. PROTEIN GENERATOR ENABLES PROTEOMICS-BASED SUBTYPING OF IDH MUTANT ASTROCYTOMA

Abstract The understanding of the proteomic landscape of IDH mutant astrocytoma has been limited in previous studies. To address this knowledge gap, we developed an innovative approach using artificial intelligence (AI) to generate proteomic profiles of tumors based on their transcriptome data. Particularly, we employed a combination of Variational Auto-Encoder and Contrastive Language Image Pretraining techniques to develop an AI model. The model was trained on publicly available databases containing matched RNA and protein data. Leveraging this extensive dataset, we applied the trained model to infer proteomic profiles for over one thousand adult IDH mutant astrocytoma specimens using their transcriptome sequencing data. This novel approach allowed us to explore and identify previously undiscovered subtypes based on the predicted proteomic profiles. As a result, we identified seven distinct clusters: IDHmut-noncodel-Proliferative, IDHmut-noncodel-Mesenchymal, IDHmut-noncodel-Mitochondrial, IDHmut-NFkB-signal, IDHmut-codel-Proliferative, IDHmut-Metabolism, and IDHmut-Neuronal. Of particular clinical significance, the IDHmut-noncodel-Proliferative and IDHmut-noncodel-Immune-Mesenchymal subtypes displayed the worst prognoses, while the IDHmut-Neuronal, IDHmut-NFkB-signal, and IDHmut-Metabolism subtypes exhibited relatively better survival outcomes. Remarkably, within the IDHmut-noncodel-Proliferative cluster, we observed a high prevalence of CDKN2A homozygous deletion, providing a potential explanation for its poor survival prognosis. Conversely, the IDHmut-noncodel-Mesenchymal cluster did not demonstrate any significant genetic events but exhibited elevated expression of mesenchymal marker genes. Furthermore, this cluster displayed notable characteristics, including the presence of gemistocytic differentiated tumor cells and infiltration of activated CD8 T lymphocytes. Moreover, we encompassed an evolutionary analysis of 189 initial-recurrent IDH mutant astrocytoma pairs, and discovered that gemistocytic differentiation represents an early event in tumor progression. In summary, we introduced a novel method utilizing an AI model to generate proteomic profiles, thus enabling the discovery of previously unknown subtypes of IDH mutant glioma with clinical relevance. These findings contribute to a deeper understanding of the molecular landscape of IDH mutant astrocytoma, potentially leading to improved prognostication and personalized treatment strategies.

CTNI-37. INTERIM SAFETY ANALYSIS OF THE PHASE IB/II RANDOMIZED ANTI-GLUTAMATERGIC DRUG REPURPOSING TRIAL GLUGLIO IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NCT05664464)

Abstract The advent of cancer neuroscience has significantly advanced our understanding of brain tumor biology, yet the clinical implications remain largely unexplored. Glutamate, the most abundant excitatory neurotransmitter, presents a potential therapeutic target in brain tumors. Glioblastoma cells synthesize and secrete large amounts of glutamate, driving epilepsy, neuronal death, tumor growth, and invasion. Several brain-penetrating drugs, approved for other conditions, can inhibit glutamate synthesis, secretion, and signaling. These drugs include: (i) gabapentin, an anti-seizure medication that inhibits the glutamate synthesis enzyme branched-chain amino acid transaminase 1; (ii) sulfasalazine, an anti-inflammatory drug that blocks the cystine-glutamate exchanger system Xc, reducing glutamate secretion; and (iii) memantine, a cognitive enhancer that prevents glutamate-driven, calcium-induced neuronal death and tumor cell invasion by blocking N-methyl-D-aspartate type glutamate receptors. The multi-center, open-label, parallel-group, two-arm, 1:1 randomized phase Ib/II trial GLUGLIO is investigating the efficacy of a daily oral anti-glutamatergic triple combination of gabapentin, sulfasalazine, and memantine until tumor progression, in conjunction with standard chemoradiotherapy, compared to chemoradiotherapy alone. The primary endpoint is progression-free survival at 6 months (PFS-6). A sample size of 120 patients was determined to detect an increase in PFS-6 from 50% to 70%, with 80% power, using exploratory hypothesis testing at a one-sided significance level of 10%. Secondary endpoints include overall survival, seizure-free survival, response rate, quality of life for patients and caregivers, symptom burden, cognitive functioning, tumor glutamate levels (measured by magnetic resonance spectroscopy), and the use of anti-convulsants and steroids. Each drug is dosed up to the maximum approved amount. Results from the phase Ib part of the trial, including an interim safety analysis, will be presented at the conference.

PATH-22. SINGLE-CELL RNA (SCRNA) SEQUENCING OF PAIRED PRIMARY AND RECURRENT ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT) REVEALED MOLECULAR DIFFERENCES AND THERAPY-RESISTANT PRIMARY TUMOR CELLS

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors during infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). AT/RT are associated with a dismal outcome, and 50% of the patients suffer a progress or recurrence of the tumor. Molecular mechanisms of disease recurrence are currently unclear. Here, we identified molecular characteristics of AT/RT primaries and recurrences, which could help to improve the therapy for relapsed patients. Previously, we investigated tumor tissue from 26 patients revealing signatures of recurrences in comparison to matched primary tumor samples using histology, DNA methylation analysis, and bulk RNA sequencing. To further identify mechanisms regarding tumor progression and recurrence, we performed single-cell RNA (scRNA) sequencing for five of these primary-recurrence pairs so far using formalin-fixed paraffin-embedded (FFPE) tissue. Using Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction, we observed a distinct separation in the gene expression profiles of primary and recurrent tumor cells. In addition, we aimed to identify primary tumor cells which potentially persisted after therapy and developed to recurrences. Therefore, we identified primary tumor cells showing highest similarity to recurrent tumor cells using CIBERSORT and trajectory analysis. Differentially expressed genes of these specific primary tumor cells were investigated. They are involved in cell migration, -adhesion, -proliferation, and -stability, among others. Overall, molecular characteristics that occur in the course of the disease were identified, which may help to define new therapeutic targets for AT/RT recurrences.

TMIC-03. CARD9 BLOCKADE OFFERS A NEW OPPORTUNITY TO REPROGRAM TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM), one of the deadliest primary tumors of the central nervous system, is characterized by a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME and substantially contribute to immunosuppression, tumor progression, and treatment resistance. Elucidating the molecular mechanisms underlying TAM behavior is crucial to the development of effective immuno-therapeutic strategies for treating GBM. The adaptor protein, Caspase Recruitment Domain-containing protein 9 (CARD9) is primarily expressed in myeloid cells and its activation triggers assembly of the CARD9-BCL10-MALT1 (CBM) complex, which then promotes activation of NF-κB and/or MAPK pathways. The aim of this study was to investigate the role of the CBM complex in the GBM TME and assess its potential as a therapeutic target. METHODS/RESULTS In silico analyses revealed that GBM tumors demonstrate increased CARD9 and MALT1 expression in comparison to non-tumor brain tissue, with CARD9 expressed only within the myeloid compartment. Using co-culture, scratch wound, and transwell assays, we found that GBM tumor cells induce macrophage M2 polarization and migration via a mechanism that is dependent on CARD9/MALT1 signaling within macrophages. scRNA-Seq and flow-cytometric analysis of orthotopic syngeneic immunocompetent GBM tumor models revealed that the GBM TME is dominated by macrophages. Disruption of MALT1 protease activity within the TME leads to reduced tumor infiltration by immunosuppressive TAMs, remodeling of TAMs toward an immunoreactive anti-tumor phenotype, and improved survival of GBM-bearing mice. Additionally, we found that tumor growth was abrogated when GBM-bearing mice were treated with either a MALT1-protease inhibitor or a CARD9 inhibitor. CONCLUSIONS Our study suggests that blockade of the CARD9-MALT1 signaling axis impairs GBM-induced macrophage recruitment and M2 polarization and inhibits tumor progression. These findings nominate the CARD9-MALT1 signaling axis as a new target for TAM-directed immunotherapy for the treatment of GBM.

CXCR6 expression predicts prognosis and immunotherapeutic benefit in muscle-invasive bladder cancer

BackgroundIncreasing evidence suggests that the CXC chemokine receptor 6 (CXCR6) is involved in tumor progression and the regulation of tumor immunity. However, its role in muscle-invasive bladder cancer (MIBC) remains largely unexplored.MethodsData from 391 MIBC patients in the TCGA, 212 patients from GEO, 131 patients from our center, 195 patients in the IMvigor210 cohort, and single-cell RNA sequencing (scRNA-seq) data from 9 bladder cancer patients (GSE222315) were analyzed. Additionally, data from the GEPIA 2, TISCH2, TIMER2.0, and UALCAN platforms were utilized to investigate the prognostic and immunotherapeutic significance of CXCR6 in MIBC.ResultsWe observed that CXCR6 expression was significantly reduced in bladder cancer tumors and correlated with tumor stage and grade. Low CXCR6 expression was associated with poor recurrence-free survival (RFS) and overall survival (OS) in the TCGA cohort, a finding validated in both the meta-GEO dataset and our center’s cohort. Multivariate analysis confirmed that low CXCR6 expression was an independent predictor of poor OS and RFS. A nomogram incorporating CXCR6 expression and other independent prognostic factors was developed to accurately predict 3- and 5-year OS. Gene set enrichment analysis indicated that immune activation-related pathways were significantly enriched in tumors with high CXCR6 expression. CIBERSORT analysis revealed that CXCR6 expression was positively correlated with CD8+ T cells, CD4+ T cells, activated NK cells, M1 macrophages, and activated dendritic cells in TCGA, findings further validated by TIMER2.0. scRNA-seq data showed that CXCR6 was predominantly expressed in T and NK cells and facilitated T/NK-myeloid interaction via the CXCR6-CXCL16 axis. Importantly, CXCL16+ macrophages and dendritic cells recruited CXCR6+ T and NK cells, which exhibited enhanced cytotoxicity, thereby amplifying anti-tumor immunity. Clinically, in the IMvigor210 immunotherapy cohort, higher CXCR6 expression was associated with improved anti-PD-L1 therapeutic outcomes.ConclusionOur findings highlight CXCR6 as a critical biomarker for predicting prognosis and immunotherapeutic response in MIBC.

CTNI-25. TUMOR TREATING FIELDS (TTFIELDS) THERAPY WITH CHEMORADIATION, FOLLOWED BY MAINTENANCE TTFIELDS THERAPY/TEMOZOLOMIDE (TMZ), IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM). RESULTS OF PHASE II CLINICAL STUDY

Abstract INTRODUCTION Tumor-Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cancer cell function and tumor progression via a multimodal mechanism of action. Following the phase 3 pivotal EF-14 study, TTFields therapy concomitant with temozolomide (TMZ) maintenance therapy became approved for newly-diagnosed glioblastoma (ndGBM). Pre-clinical data and pilot clinical studies suggests synergistic effect of concomitant TTFields treatment with radiotherapy (RT). OBJECTIVE To assess the efficacy and safety of first line TTFields therapy concomitant with RT/TMZ vs RT/TMZ alone in adult patients with ndGBM. Design: 69 patients with ndGBM and KPS≥70 stratified by MGMT status, extent of resection, and age, were randomized 1:1. The experimental arm received TTFields therapy from the first day of chemoradiation, the control arm started 4 weeks after completion of chemoradiation. Patients continued TTFields therapy until second disease progression or 24months. The primary endpoint was 1-year PFS rate, and secondary endpoints included PFS, OS, and safety. Kaplan-Meier estimates were used to assess whether PFS and OS were improved with first line TTFields therapy/RT/TMZ vs RT/TMZ with delayed TTFields therapy. RESULTS Overall, 46 patients received maintenance chemotherapy and TTFields therapy. Mean age was 62 years (range:27–77). One-year PFS rate was 36% and 19% in the experimental and control arms, respectively (p-value=0.10). Median PFS was 9.9 and 5.6 months (HR 0.53, p-value 0.049). Median OS was 25.9 and 17 months (HR 0.85, p-value=0.6). Two-year OS rates were 52% and 31% (p-value 0.07). Among patients with high TTFields usage (≥75%) 2-year OS rates were 78% and 34% (p=0.01). CONCLUSIONS The addition of concomitant TTFields to standard treatment with temozolomide and RT for patients with ndGBM appears to be another step in improving the outcome of this patients population. This is further investigated in the large-scale TRIDENT study.

NCOG-19. FUNCTIONAL OUTCOME AFTER RE-RESECTION OF TUMOR PROGRESSION, MIXED LESION OR TREATMENT-ASSOCIATED EFFECTS IN IRRADIATED DIFFUSE GLIOMAS (GRADE 2-4): IDENTIFYING CLINICAL AND RADIOLOGICAL DETERMINANTS

Abstract In cases of radiological progression in patients with irradiated diffuse gliomas, recurrence-resection is frequently performed. In our previous histological evaluation 19% of these re-resection cases were found to be due to treatment-associated effects (TAE). Limited literature substantiating which patients will benefit from surgery and which patients will deteriorate postoperatively is available. We aim to (a) describe the functional outcomes after re-resection of an irradiated diffuse glioma in adult patients; (b) compare early functional outcomes between patients with TAE versus progressive disease; (c) identify predictors of early functional outcome. In this single-center, retrospective, cohort study, we included consecutive adult patients with diffuse glioma who underwent first-line radiotherapy and, upon radiological progression, a re-resection. Re-resection tissue was classified histologically (based on mitosis presence/absence) and by the multidisciplinary tumor board as tumor progression, TAE or mixed lesion. The primary endpoint was the functional outcome 30 days postoperatively, expressed as the Karnofsky Performance Scale (KPS). Univariable and multivariable logistic regression were used to identify clinicoradiological predictors of KPS deterioration of any severity. Of 159 included patients, 41 (25.8%) experienced mild KPS deterioration (10 points) and 25 (15.9%) a clinically relevant KPS deterioration (20 or more). KPS improvement (10 points or more) occurred in 31 patients (19.4%). Histological diagnosis groups did not differ significantly in KPS outcome. Pre-operative steroid usage (any dose) was an independent predictor of KPS deterioration (OR 2.46, 95%CI 1.12-5.39, p=0.025). Analysis of pre-operative radiological determinants is in progress. In conclusion, in this large single-center cohort of diffuse gliomas undergoing re-resection with systematic clinical evaluation, clinically relevant deterioration after re-resection occurred in 15.9% of all patients. Risk of deterioration is comparable in all histological diagnosis groups. Pre-operative steroid usage was identified as predictor for deterioration (of any severity). These results may provide clinical guidance in identifying which patients will benefit from re-resection.

Establishing a new-onset diabetes-related metabolism signature for predicting the prognosis and immune landscape in pancreatic cancer.

New-onset diabetes (NOD) is a common condition among patients with pancreatic adenocarcinoma (PAAD) and is related to poor clinical outcomes. The potential impact of NOD on PAAD progression and the tumor microenvironment remains unclear. Here, we revealed that NOD in PAAD was associated with metabolic disorders. Utilizing three machine learning algorithms, a new-onset diabetes-related metabolism signature (NRMS) was established. Validated in three independent cohorts, patients with a high NRMS score exhibited worse prognosis. Moreover, an elevated NRMS score was associated with an immunosuppressive microenvironment and diminished response to immunotherapy. Further experiments demonstrated that ALDH3A1, a key feature in NRMS, was significantly up-regulated in tissues from PAAD patients with NOD and played a crucial role in tumor progression and immune suppression. Our findings highlight the potential of NRMS as a prognostic biomarker and an indicator of immunotherapy response for patients with PAAD.

CNSC-43. NEUROTRANSMITTER DEPENDENCY UNDERLIES TUMOR GROWTH IN HUMANIZED PEDIATRIC LOW-GRADE GLIOMA MODELS

Abstract Brain tumors arise in close association with neurons, suggesting that these non-neoplastic cells may be critical stromal drivers of brain tumor initiation and growth. Previously, we have shown that murine low-grade optic glioma formation and progression in the setting of Neurofibromatosis type 1 (NF1) is dictated by neurons and neuronal activity. In these studies, these neuronal dependencies reflected neuronal activity-driven enzymatic cleavage of a growth factor (neuroligin-3) from oligodendrocyte precursors cells (tumor initiation) or neuronal production of a paracrine factor to stimulate T cell support of optic glioma growth (tumor progression). Since neurons typically communicate with other neurons through neurotransmitters, we sought to explore the possibility that neurotransmitters operate to modulate low-grade glioma growth using humanized mouse models of pilocytic astrocytoma (PA). Leveraging single cell RNA sequencing of three independent sets of pediatric PAs, we identified neurotransmitter pathway enrichment in the tumor cells. This neurotransmitter pathway enrichment reflected aberrant expression of specific neurotransmitter receptors, which we confirmed in three independently generated PA tissue microarrays and in five distinct primary PA cell lines grown in vitro. Moreover, this aberrant neurotransmitter receptor expression established differential neurotransmitter PA growth dependencies in vitro. Importantly, interruption of neurotransmitter signaling in human PA xenografts attenuated tumor growth and ERK activation in Rag1-/- mice in vivo. Finally, we discovered crosstalk between neurotransmitter receptor and receptor tyrosine kinase signaling that revealed another target for therapeutic inhibition. Taken together, these findings elucidate a previously unknown neurotransmitter PA growth dependency amenable to therapeutic targeting.

INNV-12. CUTANEOUS TOXICITIES OF MITOGEN-ACTIVATED PROTEIN KINASE INHIBITORS IN CHILDREN AND YOUNG ADULTS WITH NEUROFIBROMATOSIS-1

Abstract BACKGROUND Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. Cutaneous adverse events (CAEs) are common and may hinder patients’ abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS We reviewed institutional medical records of patients under 30 years with a diagnosis of “NF1,” “NF2,” or “other neurofibromatoses” on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS The median age of 40 patients with NF1 was 14 years old. Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%) (Table 1). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%) (Figure 1). Twenty-three out of the 28 cases of acneiform eruption were in post-pubertal patients (82.1%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi (Table 2). There was no significant association between CAE presence and tumor response (p=0.39). CONCLUSIONS MEK inhibitors have been demonstrated as a valuable treatment, but CAEs complicate the ability to stay on the treatment. Most patients in our cohort developed a CAE, demonstrating its prevalence in this population. Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

SURG-14. PATTERNS OF PROGRESSION OF TEMPORAL LOBE GLIOBLASTOMAS: EVIDENCE FOR THE ROLE OF TEMPORAL LOBECTOMY

Abstract Glioblastomas extend beyond the contrast-enhancing tumor, and supramaximal resections into non-enhancing (NE) tumor improves survival. Yet, supramaximal resection is difficult to achieve in most cases. For temporal lobe tumors, supramaximal anterior temporal lobe resection is feasible and safe. Case series have shown a survival advantage by resecting the anterior temporal lobe. This study aims to explore patterns of tumor progression in temporal lobe glioblastomas and whether the presence of NE tumor in the temporal tip could be used as a biomarker to predict the site of progression. We searched a single institution tumor database looking for patients who had glioblastomas in the temporal lobe, who underwent complete resection of enhancing tumor, and went on to have chemoradiotherapy. Patients needed to have imaging demonstrating first progression. We determined pre-operatively if NE tumor had extended into the temporal tip. At progression, the direction of tumor progression was recorded and assessed if it would have been resected should a lobectomy have been performed. We identified 55 patients that fulfilled our entry criteria (mean age 57.7 years, range 19.6-72.9; 37 male). In 16 cases, the anterior temporal lobe was resected; these patients were not used in further assessments. In 25 cases (64.1%), the tumor progressed into the residual anterior temporal lobe. In 16 cases (41.0%), a lobectomy would have encompassed the area of progression. NE tumor was seen in the tip in 28 cases (71.8%). This could predict progression into the anterior temporal lobe with a sensitivity of 76.2% (95%CI: 54.9-90.6%) and specificity of 33.1% (95%CI: 11.8-61.6%). The likelihood ratio of tumor progression was 1.14 (95%CI: 0.75-1.74). We conclude that temporal lobe glioblastomas most commonly progress into the anterior temporal lobe, but NE tumor is not a suitable predictive biomarker. Developing suitable biomarkers and biomarker-driven trials of temporal lobectomy for glioblastomas are needed.

NCOG-50. LONG TERM-SURVIVAL OF AN ELDERLY PATIENT WITH GIANT CELL CEREBELLUM GLIOBLASTOMA (GBM)

Abstract INTRODUCTION Primary cerebellar glioblastoma (GBM) in adult is very rare and accounts for 1% of all GBM. Giant cell variant cerebellar GBM is even rarer. Because of the rarity, its molecular feature, the response to the standard treatment, and biological behavior of tumor progression are not well understood. CASE REPORT An 80 yo male presented with headache, nausea, vomiting and ataxia in 2019. Brain MRI was notable for a large enhancing cerebellar mass. Surgical resection was completed, and pathology was giant cell GBM. Molecular studies showed IDH-wildtype, CDKN2A/B copy number loss, positive TP53 G262V mutation as well as KIT and KDR amplification. The patient underwent standard 6-week concomitant temozolomide (TMZ) and radiation therapy. He only completed 3 cycles of low dose adjuvant temozolomide and two cycles of lomustine due to intolerance of both chemotherapy agents. After that the patient has been off treatment and received brain MRI surveillance over past 4 years. Two years later, his brain MRI showed new punctuate lesions in the radiation field. Suspecting the radiation necrosis; the patient underwent observation. Later, more nodular enhancing lesions developed at the outside region of the radiation field. Tumor progression was considered but the patient wished no biopsy or re-radiation. The new small nodular lesions on MRIs over past two years have behaved unusually with small fluctuations among mild progression, stabilization, or regression. His physical functions have been preserved with a Karnofsky Performance Status scale of 90% with normal cognition. DISCUSSION The patient, who is now 85 years old, has surpassed a 4.5-year survival mark, which is remarkable compared to the supratentorial and the cerebellar GBM with a few months’ survival mark in elderly patients. Our experience emphasizes the different behavior (good response) of a very rare giant cell cerebellar GBM to the standard treatment for newly diagnosed GBM.

Integrating transcriptomic data and digital pathology for NRG-based prediction of prognosis and therapy response in gastric cancer

Background Cancer is characterized by its ability to resist cell death, and emerging evidence suggests a potential correlation between non-apoptotic regulated cell death (RCD), tumor progression, and therapy response. However, the prognostic significance of non-apoptotic RCD-related genes (NRGs) and their relationships with immune response in gastric cancer (GC) remain unclear. Methods In this study, RNA-seq gene expression and clinical information of GC patients were acquired from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Cox and LASSO regression analyses were used to construct the NRG signature. Moreover, we developed a deep learning model based on ResNet50 to predict the NRG signature from digital pathology slides. The expression of signature hub genes was validated using real-time quantitative PCR and single-cell RNA sequencing data. Results We identified 13 NRGs as signature genes for predicting the prognosis of patients with GC. The high-risk group, characterized by higher NRG scores, demonstrated a shorter overall survival rate, increased immunosuppressive cell infiltration, and immune dysfunction. Moreover, associations were observed between the NRG signature and chemotherapeutic drug responsiveness, as well as immunotherapy effectiveness in GC patients. Furthermore, the deep learning model effectively stratified GC patients based on the NRG signature by leveraging morphological variances, showing promising results for the classification of GC patients. Validation experiments demonstrated that the expression level of SERPINE1 was significantly upregulated in GC, while the expression levels of GPX3 and APOD were significantly downregulated. Conclusion The NRG signature and its deep learning model have significant clinical implications, highlighting the importance of individualized treatment strategies based on GC subtyping. These findings provide valuable insights for guiding clinical decision-making and treatment approaches for GC.

TMIC-47. HUMAN BLOOD-BRAIN TUMOR BARRIER ON A CHIP TO INVESTIGATE PERSONALIZED TREATMENT FOR GLIOBLASTOMA PATIENTS

Abstract The inherent characteristics of glioblastoma multiforme (GBM), including tumoral heterogeneity and invasive capacity, combined with the presence of the blood-brain tumor barrier (BBTB), present challenges in developing effective treatment for GBM. Especially, the margins of GBM, where GBM cells infiltrate normal brain tissue, exhibit high resistance to therapies. Despite the difficulties in controlling tumor progression from this region, the GBM margin remains a critical area to be studied. Here we report a microengineered model that mimics the BBTB within the GBM margin, incorporating a 3D network of normal astrocytes and GBM cells isolated from patients newly diagnosed with GBM. The interaction between GBM cells and stromal cells results in increased vascular permeability, reactive gliosis, and alterations in astrocyte behavior to foster tumor invasiveness and progression. We compare patient-specific tumor responses to conventional chemotherapy in our BBTB on a chip model with clinical outcomes, demonstrating the capability of the model to predict personalized drug responses. Our BBTB model may serve as a personalized tool to examine the interactions between tumors and normal brain tissue, ultimately facilitating the screening of personalized medicine for GBM treatment.

NIMG-14. HEAD-TO-HEAD COMPARISON OF18F-FET PET AND68GA-PSMA-11 PET IN DISTINGUISHING SMALL VOLUME TUMOR PROGRESSION VS TREATMENT-RELATED CHANGE IN POST-STANDARD OF CARE TREATMENT OF HIGH-GRADE GLIOMA USING DYNAMIC ACQUISITION AND KINETIC MODELING

Abstract BACKGROUND The inability to accurately distinguish between tumor progression and treatment-related changes in patients with high-grade glioma on routine imaging can negatively impact patient management and in some cases, outcome. Various imaging methods have been used to address this issue, including 18F-fluoro-ethyl-tyrosine (FET) PET and MR perfusion. However, these methods may not provide reliable results in cases of small lesion size or hemorrhage within the treatment site. The prostate-specific membrane antigen (PSMA) has been observed to be expressed by neovasculature in brain tumors. Since PSMA cannot cross the blood brain barrier, uptake of PSMA in the brain carries high-level of suspicion for residual tumor. Still, further work is needed to better understand PSMA uptake in the tumor bed following standard of care (SOC) treatment and to compare to currently available neuro-oncologic radiotracers, such as FET. We hypothesize that PSMA imaging of glioma neovasculature will provide unique diagnostic information that will aid in the differentiation of small volume tumor progression from treatment-related changes in the post-SOC treatment setting. METHODS Patients who underwent clinical Expanded Access PET/MR imaging with 18F-FET were re-imaged in a research protocol that collected a brain 68Ga-PSMA-11 PET/CT scan, as well as a repeat 18F-FET PET/CT. Kinetic modeling of dynamic radiotracer uptake was performed. Scans were assessed for correlation with subsequent imaging and changes in clinical management. RESULTS All PSMA scans that were performed were concordant with the initial clinical FET scan, subsequent imaging follow up and appropriate changes in clinical management. The PSMA-detected site was confirmed to be tumor in a single case with subsequent tissue sampling. One patient who was started on bevacizumab after their clinical FET demonstrated a significant decrease in uptake on the research FET scan, but persistent uptake on PSMA. CONCLUSION PSMA may effectively show tumor recurrence in post-SOC treatment high-grade glioma patients.

BIOM-72. INTEGRATION OF ULTRASENSITIVE ELECTROLUMINESCENT IMMUNOASSAY AND CELL-FREE DNAMETHYLATION ANALYSIS FOR NON-INVASIVE MONITORING OF ADULT DIFFUSE GLIOMAS

Abstract Gliomas are highly aggressive brain tumors with nearly universal recurrence rate. Despite this, the ability to accurately predict and identify tumor recurrence relies solely on serial MRI imaging, which is marred by treatment effects such as radiation necrosis, and necessarily identifies progression retrospectively. It is believe that tumor undergo molecular changes upon tumor progression, however the resampling of tumors upon recurrence imposes significant risks. This highlights the need for novel non-invasive biomarkers capable of identifying tumor recurrence. Due to the low accuracies of individual biomarkers, we have proposed the use of an integrated, multi-platform approach to biomarker discovery. A cohort of 107 glioma plasma samples, including 30 pairs, underwent plasma proteomic analysis, consisting of a panel of serum proteins (FABP4, GFAP, NFL, Tau and MMP3,4 &7) quantified through ultrasensitive electrochemiluminescence multiplexed immunoassays, and plasma DNA methylation analysis, captured through cell-free methylated DNA immunoprecipitation and high-throughput sequencing. Unsupervised hierarchal clustering revealed robust separation of primary and recurrent tumors through plasma proteomics, associated with a distinct plasma methylation signature. NFL, Tau and MMP3 levels differed between primary and recurrent samples; pair-wise analysis revealed increased in NFL and Tau concentrations upon recurrence. Tau levels predicted outcome independent of WHO Grade and IDH status. A predictive generalized linear regression model created through the integration of the proteomic and methylation signatures allowed for the discrimination of primary and recurrent samples in 83% of cases. This work suggests that the combination of DNA methylation and plasma proteomics may improve the ability of these techniques for the serial monitoring of gliomas patients.