bluuebunny/crossref_metadata_2025 huggingface dataset:
QOLP-20. DIETARY, ACTIVITY, AND QUALITY OF LIFE METRICS IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA IMPLEMENTING A KETOGENIC DIET: RESULTS OF A PHASE 1 CLINICAL TRIAL
Authors: Nelson Thomas , Gresham Gillian , Welborn Amelia , Amaral L J , Noorvash Brandon , Lockshon Laura , Tighiouart Mourad , Kim Sungjin , Mack Alexandra , Rudnick Jeremy , Irwin Scott , Freedland Stephen , Hu Jethro
Published: November 2021

BACKGROUND

Emerging evidence suggests that a ketogenic diet (KD) may limit neoplastic growth, but limited data exist regarding the effect of KD on daily activity, cognition, and health-related quality-of-life (HRQOL) for patients with glioblastoma.

METHODS

Newly diagnosed GBM patients participating in a single-arm phase 1 trial of a 16-week KD plus standard-of-care measured BID blood glucose and ketone levels (Keto-Mojo), captured continuous activity data (Fitbit), and completed quality-of-life (QLQ30) surveys and Montreal Cognitive Assessments (MoCA) at baseline, Week 8, and study end (up to 16 weeks). NCT03451799.

RESULTS

All patients (n = 14; 57% female; median age 55 years) maintained blood ketones above 0.3 mM > 50% of study duration (mean per-patient days in ketosis = 87%). Mean glucose (mg/dl) and ketone levels decreased through the study – Weeks 1/2: glucose 94.9 (SD:16.5), ketones 1.44 (SD:5.82); Weeks 3/4: glucose 94.1 (SD:12.9), ketones 1.34 (SD:0.9); Final two weeks: glucose 92.3 (SD:13.3), ketones 1.13 (SD:0.7). On average, patients walked 6,836 steps/day (SD:5,129), spending 14.3 hours sedentary (SD:6.45) and 43.6 minutes (SD:60.4) in high-intensity activity. Sleep duration was 6.8 hours (SD:2.26). Patients (n = 9) with OS > 14.6 mo from diagnosis demonstrated greater minutes of high-intensity activity (58.2 vs 20.7, p = 0.001), downtrending glucose (p = 0.001), and higher ketone levels (1.40 vs 1.11, p = 0.026). Activity data corroborated the tolerability of KD with stable-to-increased activity by study end. MoCA scores were stable from baseline (mean 23.4/30, SD:4.16) to study end (mean 24.8/30, SD:7.12; p = 0.38). When viewed as a composite score, HRQOL was stable-to-improving in 10/14 patients at Week 8 and EOS.

CONCLUSION

The use of wearable technology and at-home testing allowed for remote monitoring of activity and diet adherence. Good adherence and stable HRQOL and activity levels were observed in this phase 1 trial.
QOLP-25. PERFORMANCE STATUS OF PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS TREATED IN A TERTIARY CENTER IN MEXICO, A SINGLE-CENTER EXPERIENCE
Authors: Madrigal-Avila Claudia , Ruvalcaba-Sanchez Rafael , Perez-Bañuelos Alfonso , Escamilla-Asiain Gabriela , Ellis Andrea , Vega-Vega Lourdes
Published: November 2021

BACKGROUND

Central nervous system (CNS) tumors are the most common solid neoplasms in the pediatric age. Despite this, there are no reports of results focused on the performance status of pediatric patients who are treated in a multidisciplinary setting.

OBJECTIVE

Describe the Performance Status of CNS pediatric patients after being treated with a multidisciplinary approach in a tertiary center.

METHODS

We review the chart of the pediatric patients at the Teleton Children Oncology Hospital from December 2014 to December 2019. The performance status was evaluated either using ECOG, Karnofsky, or Lansky scores. The multidisciplinary approach at our hospital includes: A Well-Equipped Diagnostic Center, integrated by a CAP-accredited laboratory, a Molecular Biology Unit, and the Imaging Unit, including a high-quality 2 tesla MRI. The surgical equipment comprises a surgical microscope, bipolar coagulation equipment, microsurgical instruments, and craniotomy equipment. For deep biopsies or functional surgery, we use Frame-Based Stereotactic Systems (FBSS) and neuronavigation systems. We provide first-line chemotherapy protocols and have a radiotherapy unit that can start treatment within a week. We have an Intensive Care Unit for oncologic patients with a 93% of overall survival. We provide ludic therapy and cognitive behavioral therapy, as well as emotional support. The Physical Rehabilitation Clinic uses the Bobath concept, proprioceptive and neuromuscular techniques as well as follow-up visits according to needs.

RESULTS

Of the 56 patients treated, 35 were evaluated with ECOG/Lansky performance status scale during the last follow up visit, resulting in 74.2% with a fully active performance, able to carry on all pre-disease activities without restriction.

CONCLUSION

A multidisciplinary approach is essential in the management of pediatric patients with CNS tumors. Efforts should be aimed at reducing post-surgical morbidity and early rehabilitation to reintegrate patients into society in the long term as we described many of them have an excellent performance status.
RBIO-02. THERAPEUTIC EFFECTS OF RADIOTHERAPY WITH CONCOMITANT IN CHILDREN WITH DIPG
Authors: Lai Mingyao , Li Shaoqun , Li Juan , Hu Qingjun , Zhen Junjie , Zhou Jiangfen , Cai Linbo , Zhou zhaoming
Published: November 2021

OBJECTIVE

To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide（TMZ） versus radiotherapy with concomitant TMZ alone for pediatric diffuse intrinsic pontine glioma (DIPG), and to evaluate the value of radiotherapy and TMZ in the treatment of pediatric DIPG.

METHODS

The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010 and March 31, 2020 were collected. The inclusive criteria included (1) receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated with concomitant TMZ chemotherapy, and (3) with or without adjuvant TMZ chemotherapy. A total of 85 pediatric patients were eligible for the study. The Kaplan-Meier method was used for survival analysis, and a multivariable Cox proportional hazards regression model was used to assess the independent prognostic factors.

RESULTS

Among 85 cases with a median age of 7 years (range 2-16 years), the median follow-up was 9 months (range 3-28 months) and the median survival time was 9 months. The median survival time of 66 patients treated with radiotherapy with concomitant and adjuvant TMZ was 10 months, longer than 6 months of the other 19 patients treated with radiotherapy with concomitant TMZ alone, with statistical differences (p=0.002). Moreover, bevacizumab and nimotuzumab didn't bring survival benefits to patients with disease recurrence or progression. The prognosis in DIPG patients with H3K27M positive expressed is poor. Hematological toxicity (Grade IV) was not found.

CONCLUSION

Radiotherapy with concomitant and adjuvant TMZ prolongs the survival time of children with DIPG.
RBIO-03. INITIAL RESULT OF DEVELOP ROBUST DEEP LEARNING MODEL FOR DETECTING GENOMIC STATUS IN GLIOMAS AGAINST IMAGE DIFFERENCES AMONG FACILITIES
Authors: Takahashi Satoshi , Takahashi Masamichi , Kinoshita Manabu , Miyake Mototaka , Sese Jun , Kobayashi Kazuma , Ichimura Koichi , Narita Yoshitaka , Hamamoto Ryuji , glioma Consortium of Molecular Diagnosis of
Published: November 2021

BACKGROUND

The importance of detecting the genomic status of gliomas is increasingly recognized and IDH (isocitrate dehydrogenase) mutation and TERT (telomerase reverse transcriptase) promoter mutation have a significant impact on treatment decisions. Noninvasive prediction of these genomic statuses in gliomas is a challenging problem; however, a deep learning model using magnetic resonance imaging (MRI) can be a solution. The image differences among facilities causing performance degradation, called domain shift, have also been reported in other tasks such as brain tumor segmentation. We investigated whether a deep learning model could predict the gene status, and if so, to what extent it would be affected by domain shift.

METHOD

We used the Multimodal Brain Tumor Segmentation Challenge (BraTS) data and the Japanese cohort (JC) dataset consisted of brain tumor images collected from 544 patients in 10 facilities in Japan. We focused on IDH mutation and TERT promoter mutation. The deep learning models to predict the statuses of these genes were trained by the BraTS dataset or the training portion of the JC dataset, and the test portion of the JC dataset evaluated the accuracy of the models.

RESULTS

The IDH mutation predicting model trained by the BraTS dataset showed 80.0% accuracy for the validation portion of the BraTS dataset; however, only 67.3% for the test portion of the JC dataset. The TERT promoter mutation predicting model trained by the training portion of the JC dataset showed only 49% accuracy for the test portion of the JC dataset.

CONCLUSION

IDH mutation can be predicted by deep learning models using MRI, but the performance degeneration by domain shift was significant. On the other hand, TERT promoter mutation could not be predicted accurately enough by current deep learning techniques. In both mutations, further studies are needed.
RTID-03. DESIGN AND INITIATION OF PIVOTAL STUDIES FOR BERUBICIN, A NOVEL, POTENT TOPOISOMERASE II POISON FOR THE TREATMENT OF RECURRENT GLIOBLASTOMA MULTIFORME (GBM)
Authors: Silberman Sandra , Hsu Sigmund , Muczyczenko Zena , Picker Donald , Sipowicz Marek , Żak Ewa , Buczyńska Agnieszka , Olejniczak Mariusz , Priebe Waldemar
Published: November 2021

Berubicin (WP744) is a doxorubicin analog that crosses the blood-brain barrier (BBB), shows significant CNS uptake, and induces more DNA damage but lower lethality than doxorubicin at equivalent doses. Berubicin also prolongs the survival time of intracranial orthotopic glioma models in mice compared to temozolomide, currently the standard of care in GBM. A Phase 1 study at MD Anderson in patients with recurrent glioma treated with escalating doses of Berubicin administered qdx3 repeated q21 days showed that it was well tolerated, with myelosuppression (neutropenia and thrombocytopenia) as the dose-limiting toxicity. Of 25 patients evaluable for efficacy, there was 1 complete response (13+ years), 1 partial response, and 10 patients with stable disease for a clinical benefit rate of 48%. To assure a rapid and economically practicable development program, two companies have collaborated to conduct trials in the US and EU, leading to a potentially more rapid approval of Berubicin for treating GBM in patients with limited options. CNS Pharmaceuticals, Inc. has initiated a randomized, controlled clinical trial of Berubicin vs. lomustine in adults with recurrent GBM. WPD Pharmaceuticals has sub-licensed Berubicin to study recurrent GBM in adults in an open-label trial. This is a unique collaboration in which the same overall design, eligibility criteria, procedures, and database for patients receiving Berubicin are used by both companies, ensuring that there will be a more robust and substantial data set for evaluation of activity and safety. The primary endpoint of the CNS study, to be conducted in the US and Europe, is overall survival (OS). The WPD study conducted in the EU has a primary endpoint of overall response rate (ORR). The data from these two trials are expected to provide sufficient information to support a potential registration program in both the US and EU for the treatment of patients with glioblastoma.
RTID-04. GLIOTARGET: A DANISH NATIONWIDE PHASE I/II PLATFORM TRIAL FOCUSING ON INDIVIDUALIZED TARGETED TREATMENT FOR NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS BASED ON GENOMIC PROFILING
Authors: Fougner Vincent , Hasselbalch Benedikte , Urup Thomas , Lassen Ulrik , Poulsen Hans
Published: November 2021

INTRODUCTION

The survival in glioblastoma has been unchanged since 2005. The introduction of targeted treatments, which have improved survival in several cancers has yet to influence the treatment of glioblastoma. In Gliotarget, we will individualize the targeted treatment, and give it in the primary setting alongside standard therapy with the intention to improve the likelihood of effect.

METHODS

Gliotarget is a biomarker enriched phase I/II platform trial with initially 4 predefined biomarker selected arms, one miscellaneous biomarker arm and one control arm. All patients receive standard therapy with concomitant radiochemotherapy and adjuvant Temozolomide. The experimental treatment is given alongside the adjuvant Temozolomide. Molecular analysis, including Whole Genome Sequencing, is performed on all patients, to identify actionable biomarkers. The miscellaneous arm gathers patients with not previously defined biomarkers upon which the weekly molecular tumor board decides to treat. Gliotarget includes newly diagnosed IDH-wt glioblastoma patients. In addition, to exclude the patients where the inherent poor prognosis might conceal the drug efficacy, the patients must have a 50% probability of being alive 12 months after initial surgery, according to a prognostic model developed in our institution.

The sample size is calculated with Simon’s two-stage design using treatment effect at 9-months progression free survival (PFS9). We anticipate 9 patients for stage one and 24 in total, for each arm. Treatment effect is defined as 65% of the patients in an experimental arm reaching PFS9. For the survival analysis, supplementing the control arm data with leveraged external controls taken from our prospectively registered database will decrease the probability of false positive results.

CONCLUSION

Gliotarget complements the field of ongoing platform trials with its distinctive trial design. The chosen biomarkers and treatments will be presented at the annual meeting. Enrollment is set to open in Q4 2021.
SURG-06. THE SAFETY PROFILE OF TUMOR TREATING FIELDS (TTFIELDS; 200 KHZ) CONCOMITANT WITH VENTRICULO-PERITONEAL SHUNTS IN PATIENTS WITH GLIOBLASTOMA AND HYDROCEPHALUS
Authors: Oberheim-Bush Nancy Ann , Shi Wenyin , McDermott Michael , Grote Alexander , Stindl Julia , Lustgarten Leonardo
Published: November 2021

INTRODUCTION

Hydrocephalus is a common development in patients with glioblastoma (GBM) requiring treatment with ventriculo-peritoneal (VP)-shunts (programmable/non-programmable). To maximize outcomes in this high-risk population, evaluation of VP-shunt usage concomitant with GBM treatments is necessary. Tumor Treating Fields (TTFields; 200 kHz; anti-mitotic, loco-regional cancer modality) non-invasively delivers continuous, alternating electrical fields per scalp-placed arrays. TTFields treatment has obtained FDA-approval/CE-mark in adult patients with newly-diagnosed GBM (ndGBM) and recurrent GBM (rGBM). Due to insufficient TTFields/VP-shunt usage data, label does not currently advise concurrent use. We report on safety data from adult patients utilizing TTFields/VP-shunts in the real-world, clinical-setting.

METHODS

This retrospective, post-marketing, safety surveillance analysis evaluated unsolicited data from adult patients with GBM/hydrocephalus who were TTFields-treated in the presence of a VP-shunt. Available data from >18,000 patients with GBM prescribed TTFields (November 1, 2012 to April 15, 2021 [cut-off date]) were screened for eligibility. Included were 156 adult patients (≥ 18 years of age) with confirmed GBM/hydrocephalus and TTFields/VP-shunt (46 programmable; 110 non-programmable/unknown) usage. Patients were further analyzed by diagnosis (ndGBM, n=92; rGBM, n=64).

RESULTS

Of 156 TTFields/VP-shunt-treated patients (median age 52), 66% were male and 81% from the United States (19%; Europe/Middle-east/Africa). Overall, no TTFields-related shunt-failures or differences by GBM diagnosis in shunt-type and TTFields-related AEs were observed. Commonly-reported TTFields-related adverse events (AEs) >10% were beneath-array skin reactions (∼43%), electric sensations (∼14%; tingling), headache (∼13%), fatigue/malaise (∼12%), and heat sensation (∼11%; warmth); headache and fatigue/malaise are also associated with other concomitant treatments/disease burden. There were 5 serious AEs (all skin AEs) potentially-related to TTFields at the shunt-site (2 events, wound dehiscence; 3 events, skin erosion).

CONCLUSIONS

Adult patients with GBM/hydrocephalus treated with TTFields (200 kHz)/VP-shunts in the real-world, clinical-setting suggests feasibility and a tolerable safety profile; with no evidence of disrupted VP-shunt effectiveness. TTFields safety profile was consistent with prior-studies.
SURG-07. ERAS IN NEURO-ONCOLOGY
Authors: moro mario , Bartoletti Viola , Giordan Enrico
Published: November 2021

BACKGROUND

We performed a retrospective study assesses the efficacy and safety of a protocol for the enhanced clinical recovery of neuro-oncology patients undergoing surgery for supratentorial gliomas and metastasis. The protocol developed and applied to the Ca'Foncello Hospital in Treviso starts from the recommendations on the subject that the medical literature reported up to December 2018. Briefly, three main sections:1) preoperative functional status evaluation, preoperative oral carbohydrate loading; 2) minimally invasive surgery, scalp incision anesthesia, nonopioid analgesia; 3) early urinary-catheter removal, standing and feeding resumption within 3-4 hours from surgery.

METHODS

We collected and analyzed data on 28 patients operated on ERAS protocol and compared them to a control group (22 patients). The main clinical variables are: Charlson comorbidity index; times urinary-catether removal, adherence ambulation, taking food by mouth; hospital long of stay (LOS). We also collected studies from 2016 to 2020 describing data about ERAS and craniotomy and we pooled these into a meta-analysis.

RESULTS

Times urinary-catheter removal (3.1 vs 25 hours.), adherence to ambulation (4 vs 25 hours) and taking food by mouth (5.25 vs 23.72 hours) were significantly (p< 0.001) reduced in the ERAS group. Median hospital LOS was 2.85 days in the ERAS group and 4.77 days in the control group (p< 0.001). Our results overlapped those of the literature; the same trend was highlighted by our meta-analysis, with postoperative pain rates and hospital LOS significantly lower in ERAS patients (7.9 vs. 2.9 days, p < 0.001). A further important finding was that elderly patients (≥ 65 years) got the same outcomes as younger ones.

CONCLUSIONS

Our protocol for ERAS in neuro-oncology appears to have significant benefits over conventional management: it may improve patient outcomes, accelerate functional recovery, decrease length of stay, and enable patients to begin adjuvant chemotherapy and/or radiation in a more expeditious manner.
SURG-08. SARCOPENIA IS A PROGNOSTIC FACTOR OF 90-DAY MORTALITY AND OVERALL SURVIVAL IN ELDERLY PATIENTS WITH GLIOBLASTOMA
Authors: Morshed Ramin , Young Jacob , Casey Megan , Wang Elaina , Aghi Manish K , Berger Mitchel , Hervey-Jumper Shawn
Published: November 2021

Elderly patients with glioblastoma (GBM) have worse overall prognosis compared to younger patients and are less likely to undergo tumor resection and adjuvant therapy. The goal of this study was to identify patient and treatment factors as well as preoperative imaging features associated with worse overall survival and death within 3 months of surgery in elderly GBM patients. A single-center retrospective study was conducted with patients who met the following inclusion criteria: 1) age ≥ 79 at surgery (past the average age of life expectancy), 2) underwent biopsy or resection of an IDH-wildtype WHO Grade IV GBM at the time of initial diagnosis, and 3) had no prior radiation or chemotherapy. Patient, imaging, and treatment data were collected retrospectively from the electronic medical record. Univariate and multivariate Cox proportional hazard and logistic regression analyses were performed to identify factors associated with overall survival and 90-day mortality. The cohort consisted of 110 patients with a mean age of 82.8 (range 79 to 94.1) at surgery and a median preoperative KPS of 80. Thirty-seven (33.6%) and 73 (66.4%) patients underwent biopsy and resection, respectively. Adjuvant chemo- and/or radiation therapy were used in 72.5% of cases. On multivariate analysis, age (HR 1.13 by year, p=0.01), increased masseter thickness (HR 0.88 by mm, p=0.049), adjuvant therapy (HR 0.05, p< .0001), and surgical resection rather than biopsy (HR 0.38, p=0.0007) were associated with improved survival. Decreased masseter thickness was the only preoperative factor on analysis that predicted 90-day mortality in the cohort (p=0.038). GBM patients past the average age of life expectancy still fare better when undergoing resection followed by adjuvant chemotherapy and radiation therapy. In addition to treatment factors that predict survival, smaller masseter diameter on preoperative imaging, a marker of sarcopenia, is associated with shorter survival and death within 90 days of surgery.
TAMI-02. DEPLETION OF INTRATUMORAL TUMOR-ASSOCIATED MACROPHAGES AND MICROGLIA (TAM/M) IMPROVES CHECKPOINT-INHIBITION THERAPY FOR BRAIN METASTASIS FROM LUNG CANCER
Authors: Karschnia Philipp , Xu Tao , Fitzinger Esther , Saliger Julia C , Blobner Jens , Teske Nico , von Muecke-Heim Iven-Alex , Langer Sigrid , Konhäuser Marcel , Ishikawa-Ankerhold Hellen , Thon Niklas , Tonn Jörg-Christian , von Baumgarten Louisa
Published: November 2021

BACKGROUND

Brain metastases dramatically limit prognosis of lung cancer patients. Unlike systemic disease, brain metastases from lung cancer poorly respond to checkpoint-inhibition therapy. Targeting the immunosuppressive tumor-associated macrophages and microglia (TAM/M) and their receptor CSF1R may increase efficacy of checkpoint-inhibitors.

METHODS

Cranial windows were prepared in fully immunocompetent, transgenic CX3CR1GFP/wt-mice with green-fluorescent TAM/M. Intracranial injection of red-fluorescent Lewis Lung Carcinoma-cells was performed, and mice received one of the following three treatments: PD1-inhibition only (n = 8); PD1-inhibition combined with an anti-CSF1R-antibody (exhibiting limited blood-brain-barrier permeability under physiologic conditions, n = 8); or PD1-inhibition combined with a small molecular CSF1R-inhibitor (exhibiting high blood-brain-barrier permeability, n = 7). Tumor growth and TAM/M were followed by repetitive two-photon laser-scanning-microscopy over weeks.

RESULTS

Following intracranial injection, metastases were detected in all three treatment groups within eight days. In mice receiving PD1-inhibition only, metastases showed exponential growth which was paralleled by intra- and peritumoral accumulation of TAM/M. Treatment with an anti-CSF1R-antibody resulted in significantly lower numbers of intratumoral TAM/M given increased tumoral blood-brain-barrier permeability, but did not substantially affect peritumoral TAM/M or TAM/M localized in the healthy contralateral hemisphere. In contrast, treatment with a small molecular CSF1R-inhibitor not only reduced the number of intratumoral TAM/M, but also of peritumoral and contralateral TAM/M. Compared to PD1-inhibition only, the addition of either an anti-CSF1R-antibody or a small molecular CSF1R-inhibitor resulted in decreased tumor growth (tumor size on day 12: 8.3 mm2 (PD1-inhibition only) versus 0.9 mm2 (PD1-inhibition + anti-CSF1R-antibody) versus 2.5 mm2 (PD1-inhibition + small molecular CSF1R-inhibitor)) (p = 0.01). The beneficial effects of the small molecular CSF1R-inhibitor in reducing tumor growth were similar to those of the anti-CSF1R-antibody.

CONCLUSION

Targeting intratumoral TAM/M using CSF1-inhibition may increase the efficacy of checkpoint-inhibition therapy for cerebral lung cancer metastases. This approach warrants further evaluation in preclinical and clinical studies.
TAMI-06. TUMOR CELL-DERIVED CYTOKINE EXPRESSION CHANGES ASSOCIATED WITH BRAIN METASTASIS IN A SYNGENEIC MOUSE MODEL OF BREAST CANCER
Authors: Morshed Ramin , Haddad Alexander , Jain Saket , Gill Sabraj , Spatz Jordan , Aghi Manish K
Published: November 2021

Breast cancer is the most common malignancy in women in the United States, and brain metastases occur in almost a third of patients with metastatic dissemination. Immunoediting is a critical component of metastatic tumor cell elimination, and tumor clones that develop immune-escape mechanisms are associated with progression and metastatic dissemination. We hypothesized that breast cancer brain metastatic cells harbor immunomodulatory cytokine expression changes that promote an immunosuppressive environment to avoid immune cell-mediated elimination. To study this, a syngeneic mouse model of metastatic breast cancer was used. A brain metastatic line derived from the 4T1 breast cancer parental cell line was created by serially selecting brain metastatic populations of cells after intracardiac injection (4T1 BrM). A gene-expression analysis using an 800-gene cancer immunology-specific microarray panel was performed comparing the 4T1 parental and 4T1 BrM lines. 4T1 BrM cells demonstrate gene expression changes promoting immunosuppression including significant upregulation of IL18 and Lgals9 (Galectin-9) and downregulation of CD40, IL2rg, CCL2, and EOMES. When compared to 4T1 parental lines, the 4T1 BrM line demonstrated decreased expression of CCL2 and increased expression of GM-CSF on a cytokine array, corresponding to results obtained from gene expression analysis. These results suggest tumor-intrinsic cytokine expression changes that may mediate an immunosuppressive environment.
TAMI-07. TUMOR-EDUCATED PLATELETS GUIDE BREAST CANCER BRAIN METASTASIS AND PROMOTE THERAPEUTIC RESISTANCE
Authors: Tabet Elie , Tannous Bakhos
Published: November 2021

BACKGROUND

Platelets have been shown to play an important role in systemic and local tumor modulation. Once encountered by tumor cells, platelets are educated to collect and release pro-tumor factors in the tumor/microenvironment, serving as a guiding partner for metastasis. This educational program, however, is not well understood.

METHODS

Wild-type platelets (WTPs) were isolated from blood of healthy humans or mice, whereas tumor-educated platelets (TEPs) were isolated from blood of breast cancer patients or from tumor-bearing donor mice. The tumorigenic and modulatory effect of these two types of platelets on breast cancer was examined in-vitro and in-vivo.

RESULTS

Here, we show that TEPs acquire tumor promoting functions and drive breast cancer progression, metastasis to distal sites specifically the brain, as well as therapeutic resistance. Importantly, TEPs promoted an increased pro-tumorigenic effect on metastatic breast cancer, compared to their wild-type counterpart, promoting epithelial to mesenchymal transition through NF-κB/STAT3 signaling axis via C/EBPβ transcription factor.

CONCLUSION

Our findings point to the important role of TEPs in breast cancer brain metastasis and therapeutic resistance, which could have a major implication in other tumor types, endorsing TEPs as a potential therapeutic target.
TAMI-11. INCREASED M1 MACROPHAGE INFILTRATION CORRELATED WITH POOR PROGNOSIS OF WHO IV GLIOMAS
Authors: Zhou zhaoming , Lai Mingyao , Zhou Jiangfen , Hu Qingjun , Ai Ruyu , Li shaoqun , Zhou Cheng , Cai Linbo
Published: November 2021

BACKGROUND

Gliomas are the malignancy with a poor prognosis. Our previous database mining study demonstrated that M1 macrophage infiltration predicted the survival of GBM patients. Here in this study, we further explored the findings.

METHODS

RNA-seq was performed on 90 WHO IV glioma tissue samples. The sequencing data was investigated with xCell for the cell infiltration levels, and the M1 macrophage infiltration was further analyzed for the prognostic prediction effect with overall survival (OS) data. Differentially expressed genes (DEGs) were calculated between groups and the hub genes were determined by the MCC models in Cytoscape. The survival risk score (SRS) calculating models were established by several machine learning methods, including the least absolute shrinkage and selection operator (LASSO), generalized linear model (GLM), and linear discriminant analysis (LDA).

RESULTS

Compared with M1 macrophages none infiltration, WHO IV gliomas with M1 macrophages infiltration was associated with poor prognosis, and this result remained significant in multivariate analyses (hazard ratio [HR], 0.219; 95% CI, 0.047–0.723; P = 0.035). Protein-to-protein (PPI) network analysis of top 200 up-regulated DEGs determined 10 hub genes (P4HB, PDIA6, LAMB1, PRKCSH, CSF1, LAMB2, LGALS1, RCN1, CALU, and TNC). Further analysis determined that the 10 hub genes were enriched in the ECM-receptor interaction signaling pathway, and six out of the ten gene expressions were confirmed by immunohistochemistry staining. Based on the 6 genes, a survival risk score (SRS) was established by machine learning methods. SRS was able to distinguish the high-risk and low-risk WHO IV gliomas with an AUC = 0.80 [95% CI: 0.74 – 0.86, P < 0.01].

CONCLUSIONS

M1 macrophage infiltration was an unfavorable prognostic biomarker for WHO IV gliomas. ECM-receptor interaction signaling pathway was involved in M1 macrophage infiltration. Hub genes in the signaling pathway could be the potential therapeutic targets for WHO IV gliomas.
TAMI-31. GLIOBLASTOMA GENETIC DRIVERS DICTATE THE FUNCTION OF TUMOR-ASSOCIATED MACROPHAGES/MICROGLIA AND RESPONSES TO CSF1R INHIBITION
Authors: Rao Rohit , Han Rong , Ogurek Sean , Wu Lai Man , Zhang Liguo , Hu Jian , Garrett Matthew , Phoenix Tim , Waggoner Stephen N , Lu Qing Richard
Published: November 2021

Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting. We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth and progression. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment compositions and functions between the proneural-like and mesenchymal-like glioma models. We found that the growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal human GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas mesenchymal RAS-driven gliomas elicited TAMs enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and tumor mass in RAS-driven gliomas. Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of microenvironment landscape characterization to optimally stratify glioma patients for TAM-targeted therapy.
TAMI-33. DYNAMICS OF MICROGLIAL ACTIVATION AND EXPRESSION OF CYTOKINES IN THE SITE OF GLIOBLASTOMA TUMOR RESECTION
Authors: Ortiz-Rivera Jescelica , Kucheryavykh Lilia , Albors Alejandro
Published: November 2021

Glioblastoma (GBM) is the most aggressive type of brain cancer. GBM tumors are made up of a large percentage of microgliawhich support the invasive nature of tumor and the resistance to therapy. In the tumor, microglia cells can polarize into M1 and M2 phenotypes. M1 phenotype is distinguished by its ability to eliminate tumor cells, and secrete proinflammatory cytokines, whileM2 phenotype is associated with tumor cell survival and secrete anti-inflammatory cytokines. Tumor resection is one of the primary steps to treat GBM, thus, resulting in tissue damage and causing microglia activation in the surgical area. The activation state of microglia in the site of resection and the impact of microglia on glioma regrowth is unclear. The purpose of this study is to investigate the state of microglia in the tumor resection area and kinetics of microglial activation.C57BL/6/GL261 mouse glioma implantation model was used. 14 days after in-brain implantation of GL261 cells tumors were surgically resected and then re-grown tumors were analyzed at 0 hours,1, 4, 7, 14 and 21 days after tumor resection, together with the originally resected primary tumors. Microglia were purified from tumors with use of magnetic beads. Western blot analysis of microglia, purified from primary and re-grown tumors, demonstrated increase of CD86 (M1) during the first 7 days after resection and then up-regulation of Arginase (M2) in a period from 14thto 21st days after tumor resection. The cytokine expression analysis revealed significant up-regulation of Vascular Endothelial Growth Factor (VEGF) and Monocyte Chemoattractant Protein 1 (MCP1) in microglia purified from re-grown tumors. PCR analysis confirmed these data, indicating increase of VEGF, MCP1 gene expression in tumor infiltrating microglia in re-grown tumor. We can state that microglia infiltrating primary tumor and tumor re-grown after surgical resection, represent significantly different cytokines expression patterns, favorable to increased vascularization and tumor progression.
TAMI-37. STEAROYL-COA DESATURASE 1 IS ESSENTIAL FOR THE GROWTH OF IDH MUTANT GLIOMA
Authors: Yamasaki Tomohiro , Zhang Lumin , Dowdy Tyrone , Lita Adrian , Gilbert Mark , Larion Mioara
Published: November 2021

BACKGROUND

Increased de novo lipogenesis is a hallmark of cancer metabolism. In this study, we interrogated the role of de novo lipogenesis in IDH1 mutated glioma’s growth and identified the key enzyme, Stearoyl-CoA desaturase 1 (SCD1) that provides this growth advantage.

MATERIALS ANDMETHODS

We prepared genetically engineered glioma cell lines (U251 wild-type: U251WT and U251 IDHR132H mutant: U251RH) and normal human astrocytes (empty vector induced-NHA: NHAEV and IDHR132H mutant: NHARH). Lipid metabolic analysis was conducted by using LC-MS and Raman imaging microscopy. SCD1 expression was investigated by The Cancer Genome Atlas (TCGA) data analysis and Western-blotting method. Knock-out of SCD1 was conducted by using CRISPR/Cas9 and shRNA.

RESULTS

Previously, we showed that IDH1 mut glioma cells have increased monounsaturated fatty acids (MUFAs). TCGA data revealed IDH mut glioma shows significantly higher SCD1 mRNA expression than wild-type glioma. Our model systems of IDH1 mut (U251RH, NHARH) showed increased expression of this enzyme compared with their wild-type counterpart. Moreover, addition of D-2HG to U251WT increased SCD1 expression. Herein, we showed that inhibition of SCD1 with CAY10566 decreased relative cell number and sphere forming capacity in a dose-dependent manner. Furthermore, addition of MUFAs were able to rescue the SCD1 inhibitor induced-cell death and sphere forming capacity. Knock out of SCD1 revealed decreased cell proliferation and sphere forming ability. Decreasing lipid content from the media did not alter the growth of these cells, suggesting that glioma cells rely on de novo lipid synthesis rather than scavenging them from the microenvironment.

CONCLUSION

Overexpression of IDH mutant gene altered lipid composition in U251 cells to enrich MUFA levels and we confirmed that D-2HG caused SCD1 upregulation in U251WT. We demonstrated the glioma cell growth requires SCD1 expression and the results of the present study may provide novel insights into the role of SCD1 in IDH mut gliomas growth.
TAMI-43. HYPOXIC REGULATION OF GLIOBLASTOMA TUMOR GROWTH THROUGH L(3)MBTL1
Authors: Shih Ling-Kai , Mukherjee Subhas , Brat Daniel
Published: November 2021

Glioblastoma (GBM) is the deadliest and most common of all primary brain tumors. Drosophila brain tumor models have uncovered signaling pathways regulating tumor growth that are highly conserved in GBM. Our search for a novel tumor suppressor using Drosophila led to Lethal (3) malignant brain tumor [l(3)mbt], temperature-sensitive mutants of which cause neuroepithelial tumor-like overproliferation in optic lobes. dL(3)MBT and its human orthologs L3MBTL1-L3MBTL4 all harbor Malignant Brain Tumor (MBT) domains that recognize methylated lysines on histone tails. Like dL(3)MBT, hL(3)MBTL1 acts as a chromatin compaction factor that represses transcription and inhibits cytokinesis in GBM cell lines. The highly hypoxic tumor microenvironment (TME) in GBM drives its progression, recurrence, and therapeutic resistance. However, it remains unclear if L(3)MBTL1 is regulated by TME cues to promote GBM growth. Based on this knowledge gap and our preliminary data, we hypothesize that hypoxia directly regulates L(3)MBTL1 in favor of GBM growth. Analysis of TCGA data for IDH-wildtype gliomas revealed that L3MBTL1 gene expression is downregulated in GBM, which are necrotic and severely hypoxic, compared to histologic grade 2/3 gliomas, which do not contain necrosis, indicating that hypoxia could potentially suppress L3MBTL1 to enhance glioma progression. TCGA data also revealed a number of HIF pathway and hypoxia-inducible genes strongly correlating with L3MBTL1 expression, including HIF1a and VHL. Using patient-derived GBM neurosphere cultures, we exposed glioma cells to hypoxia (1% O2 for 24hrs) and found that L3MBTL1 protein levels were suppressed compared to normoxia (21%). Under these same conditions, we found more rapid cell proliferation under hypoxia. Exploration of hypoxic TME regulation of the novel tumor suppressor L3MBTL1 in glioma progression has the potential to uncover novel mechanisms involving epigenetic modulation and potentially new therapeutic strategies.
TAMI-53. CYSTEINE IS A LIMITING FACTOR FOR GLIOMA PROLIFERATION AND SURVIVAL
Authors: Rodado Victor Ruiz , Dowdy Tyrone , Jung Jinkyu , Dios-Esponera Ana , Lita Adrian , Kramp Tamalee , Camphausen Kevin , Gilbert Mark , Larion Mioara
Published: November 2021

BACKGROUND

Little is known about the mechanisms that render cancer cells dependent on certain nutrients from the microenvironment. Cysteine is a non-essential amino acid, since it can be synthetized from methionine through the transsulfuration pathway; moreover, cysteine is also uptake from the diet as cystine. We have investigated the metabolism of cysteine in glioma cell lines, and how cysteine/cystine-deprivation alters their antioxidant response in addition to the effect of this nutrient restriction to viability and proliferation in vitro and in vivo.

METHODS

Cysteine metabolism was investigated through LCMS-based 13C-tracing experiments and the expression levels of key enzymes in the transsulfuration pathway were also explored. Finally, a mouse model of IDH1 mutant glioma was subjected to a cysteine/cystine-free diet and tumor metabolism was analyzed by LCMS.

RESULTS

Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C-tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to upregulate the transulfuration pathway cysteine, which allows methionine to be converted to cysteine in cysteine/cystine deprived conditions. We demonstrated that exogenous cysteine/cystine are crucial for glutathione synthesis, and impact growth and viability. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, with concomitant reductions in glutathione and cysteine plasma levels. At the endpoint higher levels of oxidative stress were detected despite the systemic recovery of cysteine-related metabolites in the plasma.

CONCLUSION

The results presented herein reveal an alternative therapeutic approach combining cysteine/cysteine-deprivation diets and treatments involving ROS production by limiting the ability of glioma cells to quench oxidative stress through dietary interventions. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.
TAMI-68. DECONVOLUTION OF IMMUNOTHERAPY-TREATED GLIOBLASTOMA IDENTIFIES CELLULAR HETEROGENEITY AND PLASTICITY AT THE SINGLE-CELL LEVEL
Authors: Hendriksen Josephine , Flynn Aidan , Maarup Simone , Poulsen Hans , Lassen Ulrik , Weischenfeldt Joachim
Published: November 2021

Glioblastoma is the most aggressive cancer originating in the brain with an average survival of 15 months. One of the characteristics of glioblastoma is the high level of intra-tumor heterogeneity (ITH), but the composition and complexity at the single-cell level is poorly understood. Here, we aimed to assess the effects and consequences of immune checkpoint inhibitor (ICI) on the cellular and molecular heterogeneity of glioblastoma tumors at the single cell level. In collaboration with the phase I trials unit at Rigshospitalet, we performed paired molecular analysis of glioma cells from primary and relapse surgery after ICI treatment. Samples were analyzed using single-cell RNA sequencing (scRNA-seq) as well as bulk RNA sequencing and whole exome DNA sequencing. In an effort to trace cellular lineages we developed and refined methods to a identify copy number changes using scRNA-seq. To this end, we identified clonal and subclonal tumor cell populations in each sample. We found high levels of ITH prior to treatment, both with respect to the glioblastoma subtype enrichment and the cell type-specific gene expression. Using expression-based cell-type classification, we found defined recurrent cell-type populations present at both surgery time points. The immune checkpoint treatment had consequences on the cellular phenotypes and proportions of tumor cells, suggesting a level of plasticity in the neoplastic cells. Moreover, we identified examples of clonal dynamics and sweeps following ICI treatment, pointing to potential treatment response and resistance in these populations. We additionally found a recurrent pattern of a small population showing high levels of cell cycle activation and simultaneously expressing markers of stem cell potential. In summary, we pursued single cell-focused analysis of ICI treated glioblastoma patients to study the cellular and molecular heterogeneity within and between glioblastoma patients, which pointed to recurrent patterns of cellular responses following ICI treatment.
TAMI-78. STEM CELL IMMUNOTHERAPY MODULATES IMMUNOREGULATORY PATHWAYS IN THE TUMOR MICROENVIRONMENT
Authors: Wildes Tyler , Dean Bayli DiVita , Dean Joseph , Font Laura Falceto , Flores Catherine
Published: November 2021

INTRODUCTION

A major obstacle in efficacious therapeutics against high-grade gliomas has been an inability to overcome powerful regulatory mechanisms within the TME that hamper immune activation. Fortunately, immunotherapy has enabled the enhancement of immune activation within the TME through adoptive immunotherapy and checkpoint inhibition. We found that co-transfer of hematopoietic stem cells (HSCs) with either adoptive immunotherapy or PD-1 blockade significantly improves therapeutic outcomes by manipulating the cellular components that make up the TME in high-grade gliomas. HSC co-transfer with immunotherapy leads to increased in situ downregulation of multiple immune regulatory pathways, activation of tumor-reactive T cells, and significant reduction in the frequency of MDCs and TAMs within the TME.

METHODS

C57BL/6 mice with orthotopic KR158B-gliomas received either adoptive immunotherapy using activated tumor-reactive T cells or αPD-1, either with or without HSC co-transfer. After treatment of late-stage tumors, brains were sectioned and digital spatial profiling (NanoString GeoMx) of the TME was conducted in situ. Briefly, tumor-bearing brain sections were stained for nuclei, CD3, CD45, and GFP (HSC-derived cells); regions of interest (ROIs) containing 200 nuclei were selected and processed for whole genome sequencing. Areas rich in immune cells within the TME were chosen as ROIs and compared between groups. Results were corroborated with flowcytometry and PCR.

RESULTS

Mice that received HSCs with either adoptive cellular therapy or αPD-1 had reductions in expression of multiple regulatory markers in the TME including iNOS, TGFβ, and PD-L1. This was accompanied by reductions in the frequencies of MDSCs and TAMs. An increased relative abundance of activated CD8+ T cells within the TME was also observed. Interestingly, we found that HSC-derived cells provided rich amounts of dendritic cells at the TME when co-transferred with immunotherapy. Host-derived myeloid cells were significantly displaced from the TME in mice receiving HSC plus adoptive cellular therapy or αPD-1.
TMOD-15. CHARACTERIZATION OF THE MINIMAL RESIDUAL DISEASE STATE REVEALS DISTINCT EVOLUTIONARY TRAJECTORIES OF HUMAN GLIOBLASTOMA
Authors: Qazi Maleeha , Salim Sabra , Brown Kevin R , Savage Neil , Mickolajewicz Nicholas , Han Hong , Chokshi Chirayu R , Mansouri Alireza , Venugopal Chitra , Kislinger Thomas , Goyal Sidhartha , Moffat Jason , Singh Sheila K
Published: November 2021

Recurrence of solid tumors renders patients vulnerable to a distinctly advanced, highly treatment-refractory disease state that has an increased mutational burden and novel oncogenic drivers not detected at initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cancer cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profiled barcoded tumor cell populations through therapy at tumor initiation/engraftment, MRD and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors showed distinct patterns of recurrence in which clonal populations exhibited either a priori, pre-existing fitness, or equipotent fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing revealed a tumor-intrinsic immunomodulatory signature with strong prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from GBM patients at all stages of disease. Our results provide insight into the innate and therapy-driven dynamics of human glioblastoma, and the prognostic value of the interrogating of the MRD state in solid cancers.