bluuebunny/crossref_metadata_2025 huggingface dataset:
QOL-21. TARGETING FEAR OF CANCER RECURRENCE IN GLIOMA: OPEN PILOT TRIAL RESULTS OF FEARLESS IN NEURO-ONCOLOGY
Authors: Loughan Ashlee , Braun Sarah , Lanoye Autumn , Davies Alexandria , Fox Amber , Kleva Chris , Zarrella Giuliana
Published: November 2023

BACKGROUND

Individuals with glioma endorse fear of cancer recurrence (FCR), but existing interventions for FCR are not entirely translatable to neuro-oncology. We consulted international FCR experts and advisory boards comprised of neuro-oncology professionals, patients, and caregivers to assist in creating a 6-module psychotherapy targeting FCR in glioma patients and caregivers: FearLess in Neuro-Oncology. Intervention modules will be discussed in-depth.

METHODS

The ongoing telehealth FearLess pilot aims to enroll 24 participants (6 glioma patients, 6 caregivers, 6 dyads) with clinical levels of FCR. Participants complete pre- and post-intervention surveys in addition to an exit interview. Data collection includes rates of screening, enrollment, module duration, session satisfaction, and intervention recommendations.

RESULTS

Of the 32 individuals screened, 16 enrolled (patients n = 6; caregivers n = 4; dyads n = 3), to date. All enrolled participants completed baseline assessments, with 15 trial initiators. 100% of trial initiators completed post-intervention surveys. Administration of the 6-module intervention averages 10 weekly, 60-minute sessions necessary for completion. All FearLess intervention completers have found it beneficial (100%) and would recommend to others (100%). Two patients recommended a shorter intervention duration and two caregivers recommended a longer duration. Preliminary analyses show reductions in FCR severity for 10 of 11 completed participants (MFCRI Reduction = 27.1, range = 4-50).

CONCLUSION

FearLess study procedures and intervention appear to be acceptable, thus far. Recruitment feasibility has been variable; caregiver participation is the primary concern given that caregiver and dyad arms remain open to accrual while the patient-only arm achieved its enrollment goal relatively quickly. Additional feasibility data is needed in order to understand how to best recruit caregivers of individuals with glioma into a psychological intervention targeting FCR. Despite the recruitment challenge, some caregivers recommended increased intervention duration, reinforcing the need for support in this vulnerable population. Continued optimization of FearLess in Neuro-Oncology is encouraged prior to larger-scale trials.
QOL-26. A RANDOMIZED, DOUBLE-BLIND PHASE 3 STUDY OF VORASIDENIB VS PLACEBO IN PATIENTS WITH MUTANT IDH1/2DIFFUSE GLIOMA (INDIGO): ANALYSIS OF HEALTH-RELATED QUALITY OF LIFE, NEUROCOGNITION AND SEIZURES
Authors: Peters Katherine , Mellinghoff Ingo , van den Bent Martin , Blumenthal Deborah , Touat Mehdi , Clarke Jennifer , Mendez Joe , Yust-Katz Shlomit , Mason Warren , Ducray Francois , Umemura Yoshie , Burt Nabors L , Holdhoff Matthias , Hottinger Andreas , Arakawa Yoshiki , Sepúlveda Juan , Wick Wolfgang , Soffietti Riccardo , Perry James , Giglio Pierre , de la Fuente Macarena , Maher Elizabeth , Bottomley Andrew , Zhao Dan , Pandya Shuchi , Steelman Lori , Hassan Islam , Wen Patrick , Cloughesy Timothy
Published: November 2023

INTRODUCTION

The Phase 3 INDIGO study (NCT04164901) is a randomized, double-blind evaluation of vorasidenib, an oral, brain-penetrant inhibitor of mutant isocitrate dehydrogenase (mIDH) 1/2 enzymes, compared with placebo, in patients with grade 2 mIDH1/2 diffuse gliomas, whose only prior treatment was surgery. The primary endpoint, radiographic progression-free survival by blinded independent review committee, and the key secondary endpoint, time-to-next-intervention, were significantly improved with vorasidenib versus placebo. As these patients are young, with several years’ life expectancy, impact of treatments on health-related quality of life (HRQoL), cognition and symptomatic burden is of interest.

METHODS

HRQoL, assessed by Functional Assessment of Cancer Therapy-Brain (FACTBr) questionnaire, was a secondary endpoint. FACT-Br was collected at baseline, Cycles 2 and 3, then every 3 months. Scores were interpreted using an estimate of clinically meaningful deterioration change from baseline for each arm. Exploratory endpoints included neurocognitive function, assessed by a validated battery of cognitive performance instruments, and seizure frequency and severity, assessed using a subject diary.

RESULTS

331 patients were randomized to vorasidenib (n = 168) or placebo (n = 163) (median age, 40.0 years; Karnofsky performance scale = 100, 53.5%; ongoing medical history of seizures, 54.1%). Median follow-up was 14.2 months. No clinically meaningful deterioration from baseline FACT-Br total score and subscales were observed at any timepoint through the median treatment duration (Cycle 13) in either arm. At baseline, active seizures (≥ 1 seizure in the previous 30 days) were reported in 20/168 (11.9%) vorasidenib patients and 20/163 (12.3%) placebo patients. On-treatment seizure frequencies and cognition outcomes will be presented by arm.

CONCLUSION

INDIGO is the first randomized Phase 3 study of targeted therapy in grade 2 mIDH1/2 diffuse glioma. HRQoL, as measured by FACT-Br, was maintained during treatment with vorasidenib. These data support the clinical benefit of vorasidenib in this patient population for whom chemotherapy and radiotherapy are being delayed.
QOL-28. THE LIVED EXPERIENCE OF PATIENTS WITH CHORDOMA – A RETROSPECTIVE CASE SERIES
Authors: Mauritson Emmaline , Nguyen Minhdan , Truong Judy , Chow Jared , Wagle Naveed , Carrillo Jose , Kesari Santosh , Juarez Tiffany , Barkhoudarian Garni , Kelly Daniel , Lekovic Gregory , Sharma Akanksha
Published: November 2023

BACKGROUND

Chordoma is a rare malignant tumor arising from the skull base or spine with limited treatment options and poor prognosis. Patients with chordoma experience significant physical and emotional symptoms deleterious to quality of life (QOL). Current literature detailing the experiences of patients with chordoma, including end of life, is limited. Each patient’s course differs depending on tumor location, lesion size, metastatic nature of disease, and treatments. We sought to better understand the lived journey of the chordoma patients seen in our center.

METHODS

This was a retrospective chart review that evaluated a cohort of chordoma patients seen at our center from March 2017 to May 2023. RESULTS/

CONCLUSION

A total of 18 patients were included. Average patient age at diagnosis was 53.3 years old (range: 23 to 87 years). Majority were female (67%) and 78% were White/Caucasian. Clival tumors were most common (55%), followed by spine (sacral (28%) and cervical (17%)). Nearly all tumors were recurrent (94%), almost half were metastatic (44%). All patients underwent tumor resection; the average number of surgeries underwent per patient was 2.7. Fifteen patients received radiation (83%) and sixteen patients participated in at least one clinical trial (88%). The average Karnofsky Performance Scale (KPS) at the initial outpatient visit was 80, which decreased to 72.2 by last outpatient visit. Most reported symptoms included emotional distress (78%), neuropathic pain (72%), muscular and bone pain (56%), vision changes (44%), dysphagia (39%), and headaches (39%). The average survival from diagnosis was 3.7 years (range: 2 to 23 years). Eight patients (45%) have passed, 5 of whom were enrolled on hospice at the time of death. Causes of death included seizures (1), respiratory failure due to tumor progression (3), bowel ischemia (1), medical aid in dying (1) and failure to thrive (1).
RBIO-03. BENEFICIAL CLOSTRIDIUM SPP ORAL SUPPLEMENTATION MITIGATES RADIATION-INDUCED COGNITIVE DYSFUNCTION WITH GUT MICROBIOTA MODULATION IN RICD MICE
Authors: Bekal Mahesh , Das Tushar , Blasco-Conesa Maria P , Jagadeesan Gayathri , Ballester Leomar , Ganesh Bhanu Priya , Esquenazi Yoshua
Published: November 2023

Radiation therapy (RT) a critical treatment for brain tumors; often leads to radiation-induced cognitive dysfunction (RICD), which significantly impacts patients' quality of life. The gut microbiome and its metabolites play a crucial role in regulating CNS function, RT disturbs the balance of the gut microbiota causing dysbiosis (imbalance in beneficial microorganisms), and Gut-dysbiosis have been linked to various cognitive disorders. This study aims to investigate the effects of RT on the gut-microbiome and cognitive function, C57BL/6 mice were exposed to Sham/9Gy/15Gy cranial irradiation and conducted cognitive tests using the Y-maze and Novel Object Recognition Test at different time points. Both 9Gy and 15Gy irradiation led to significant cognitive dysfunction at 10 and 30 days post-irradiation. We collected fecal samples before RT and at 10 and 30 days after RT to extract microbial DNA. The 16S rRNA gene was sequenced and analyzed using the ATIMA visualization toolkit. By comparing pre-irradiation samples with samples at 10 and 30 days post-irradiation, we observed significant gut dysbiosis in both 9Gy and 15Gy irradiated mice. The 15Gy group exhibited more pronounced and consistent changes in fecal microbiome diversity following RT. Notably, the Clostridium group at the order, family, and genus levels consistently decreased in the 15Gy irradiated mice. Certain Clostridium species are known as major producers of Short Chain Fatty Acids (SCFAs) in the gut. Based on this, we hypothesized that oral supplementation with beneficial SCFA-producing bacteria could ameliorate RICD. To test this hypothesis, a separate group of mice received 15Gy RT along with oral gavage containing a cocktail of Clostridium strains. After a 20-day post-irradiation, cognitive tests revealed that the group supplemented with Clostridium spp exhibited significantly improved cognitive performance. Our findings suggest that gut dysbiosis may contribute to RICD, and oral supplementation of SCFA-producing bacteria could be a potential strategy to mitigate RICD.
RBIO-06. COMBINING FLASH RADIOTHERAPY WITH GD2-CAR T CELL IMMUNOTHERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Soderholm Haille , Kiger Zara , Kim Wonju , Majzner Robbie , Lau Bonnie
Published: November 2023

Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of brain tumor related deaths in pediatric cancers. DIPG is completely lethal, and palliative radiation therapy (RT) to control symptoms is currently the standard-of-care treatment for DIPG, therefore effective treatment is urgently needed. In recent phase 1 clinical trials, the promising potential for using chimeric antigen receptor T cell immunotherapy against the disialoganglioside GD2 (GD2-CART) has been established, where 75% of patients exhibited clinical and radiographic improvement. There has also been emerging evidence advocating for the combined use of GD2-CART therapy with conventional radiation (CONV-RT) to enhance the immune response in other solid brain tumors. Ultra-high dose rate radiotherapy, abbreviated as FLASH-RT, is an emerging radiation technique shown to reduce normal brain tissue damage while preserving tumor control, as compared to CONV-RT. It is currently unknown how FLASH-RT will affect CART therapy. We hypothesize that effective treatment for DIPG can be achieved by combining FLASH-RT with GD2-CART immunotherapy. We have shown FLASH-RT to equivocally kill DIPG cells as well as the standard-of-care, CONV-RT; Given the neurological tissue sparing effects of FLASH-RT, this radiotherapy alone could be an improvement for DIPG treatment. Additionally, we have validated that GD2 is highly expressed in our DIPG cell line, suggesting high GD2-CART target specificity. Additionally, we have found that GD2 expression on DIPG tumor cells remains unchanged upon treatment with FLASH-RT. Therefore, we can utilize FLASH-RT to target GD2 CART while sparing normal tissue and minimizing neurotoxicity, allowing for a promising avenue of combination treatment for this devastating pediatric cancer.
SURG-07. CLIVAL CHORDOMA: A COMPREHENSIVE META-ANALYSIS OF OPERATIVE MARGINS, PROGRESSION FREE SURVIVAL, AND OVERALL SURVIVAL
Authors: Brown Nolan , Kuo Cathleen , Nguyen Oanh , Neil Zachery , Gendreau Julian
Published: November 2023

Despite their precarious behavioral classification (histopathologically benign (low-grade), behaviorally malignant), great strides have been taken to improve prognostication and treatment paradigms for patients with skull base chordoma. However, due to the rarity of this tumor, prior investigations remain limited to small retrospective series. Accordingly, we performed a systematic review and meta-analysis in order to profile surgical and survival outcomes for skull base chordoma. Fixed and random-effect meta-analyses were performed for categorial variables including number of males, GTR, STR, 5-year OS, 10-year OS, 5-year PFS, and 10-year PFS. Following the systematic search and screen, 47 studies published between 1993-2020 reporting data for 2204 patients remained eligible for analysis. Sex distribution was comparable between males and females, with a slight predominance of male-identifying patients (0.5625 [0.5418;0.3909]). Average age at diagnosis was 42.4 ± 12.5 years, while average age of treatment initiation was 43.0 ± 10.6 years. Overall, there was a substantial degree of heterogeneity across the 47 studies (I^2=56.3% [44.0%; 65.9%]). With respect to operative margins, the rate of GTR was 0.3323 [0.2824; 0.3909], I^2 = 91.9% [90.2%; 93.4%], while the rate of STR was significantly higher at 0.5167 [0.4596; 0.5808], I^2 = 93.1% [91.6%; 94.4%]. Interestingly, 5-year OS rate was 0.7113 [0.6685; 0.7568], I^2 = 91.9% [90.0%; 93.5%]. Furthermore, 10-year OS rate was 0.4957 [0.4230; 0.5809], I^2 = 92.3% [89.2%; 94.4%], which was comparable to both 5-year PFS rate of 0.5054 [0.4394; 0.5813], I^2 = 84.2% [77.6%; 88.8%] and 10-yr PFS rate of 0.4949 [0.4075; 0.6010], I^2 = 14.9% [0.0%; 87.0%]. There were 55 reported deaths for a perioperative mortality rate of 2.5%. The most common complication was CSF leak(5.4%). Overall, these results indicate good 5-year outcomes; however, 10-year prognosis for skull base chordoma remains poor due to its radiotherapeutic resistance and high recurrence rate.
SURG-11. RISKS AND BENEFITS OF REPEATED RESECTION FOR GLIOBLASTOMA: A SINGLE INSTITUTION REVIEW OF CHARACTERISTICS AND OUTCOMES OF RESECTION OF RECURRENT GLIOBLASTOMA
Authors: D'Agostino Erin , Beach Isidora , Liebelt Brandon , Thomas Alissa
Published: November 2023

Maximal safe resection is standard for newly diagnosed glioblastoma, but for recurrent glioblastoma the value of resection is less clear. We performed a retrospective, single-institution analysis of sequential patients undergoing re-resection for recurrent glioblastoma and analyzed pre-operative risk factors, progression free and overall survival from time of re-resection to death or last follow-up (PFS/OS), and complication rates. Between 2017 and 2022, 38 patients underwent re-resection of glioblastoma (defined by 2016 WHO criteria, 86.8% IDH wild type) and were followed for an average of 157 weeks (range 17-553). The cohort had a mean age of 59.4 years (range 39-87), was 55% male, and included 68.4% MGMT unmethylated tumors. Preoperatively, median Karnofsky Performance Score (KPS) was 80 (range 50-100), and median modified frailty index (mFI-5) was 0 (range 0-4). Re-resection occurred an average of 55.3 weeks after initial resection (SD 59.6, range 5-314), 25.0 weeks after chemotherapy (SD 51.8), and 39.9 weeks after radiation (SD 45.1). Mean OS after re-resection was 67.4 weeks (SD 91.5, range 1-505 weeks), median 59.5 weeks. Average PFS was 24.5 weeks (SD 25.3, range 1-139). The complication rate was 34.2% (n = 15), including 6 patients (15.8%) with a wound infection and 5 (13.1%) with symptomatic hemorrhage. 12 (31.6%) patients had a new neurologic deficit. Postoperative KPS was lower than preoperative KPS (p = .002). Patients with <20 weeks between surgeries, mFI >1, or KPS <80 had higher rates of complications (respectively p = .04, p = .03, p = .03). Patients with mFI >1 or KPS <70 were more likely to die within 30-days of surgery (respectively p = .014; p = .018). Re-resection demonstrated a survival benefit, especially for patients younger than 65 with a mFI of < 2. Though complications were common, post-operative complications were not associated with a shorter overall survival. Consideration for age, frailty, KPS, and timing of surgery may guide selection of patients for re-resection.
SURG-15. RIGHT FRONTAL-PARIETAL PILOCYTIC ASTROCYTOMA WHO GRADE I ASSOCIATED WITH HEMORRHAGIC COMPONENT AND ESSENTIAL HYPERTENSION IN AN ADULT
Authors: Kamabu Larrey , Kiryabwire Joel
Published: November 2023

Pilocytic astrocytoma (PA) is a primary glial neoplasm and low-grade tumor. After total resection, the prognosis is very good. A poor prognosis results from leptomeningeal spreading and bleeding, both of which are extremely uncommon in Pilocytic Astrocytoma patients. Case presentation We report the case of a 43-year-old male that presented with a 4 days’ history of right sided frontal headache, non-radiating and mostly felt in the morning. Not associated with vomiting and fever. In addition, there was a sudden decline in level of consciousness with no associated stool or urine incontinence. The patient also developed three episodes of tonic clonic convulsions, lasting less than 3 minutes associated with urine incontinence and frothing from the mouth. Two days later, there was a sudden onset of left sided weakness involving upper and lower limbs. However, there is no history of trauma or hypertension. He was identified as having a hemorrhagic right frontal-parietal PA evidence on MRI associated with essential hypertension. The patient had an intervention combination of medical treatment and craniotomy via fronto-temporal approach plus excision of lesion. Histopathological examination of specimen determined that it was PA WHO grade I. He was treated with oral anti-epileptic therapy (Phenytoin 300 mg once a day), folic acid supplementation (400 mcg once a day), anti-hypertensive therapy (Amlodipine 10 mg and Losartan 50 mg once daily) and he showed marked improvement and was discharged home after 1 month and followed up by primary neurosurgeon, oncologist and physician. CONCLUSION: This case report raises awareness of Pilocytic Astrocytoma among adults and emphasizes the value of early diagnosis and management of patients with Pilocytic Astrocytoma associated with essential hypertension can prevent complications, reduce morbidity and mortality.
SURG-21. THE PROGNOSTIC ROLE OF RE-RESECTION FOR RECURRENT GLIOBLASTOMA: A REPORT OF THE RANO RESECT GROUP USING A NOVEL CLASSIFICATION FOR EXTENT OF RESECTION
Authors: Karschnia Philipp , Dono Antonio , Young Jacob , Juenger Stephanie T , Häni Levin , Teske Nico , Sciortino Tommaso , Mau Christine Y , Bruno Francesco , Nunez Luis , Morshed Ramin , Haddad Alexander F , Weller Michael , van den Bent Martin , Beck Juergen , Hervey-Jumper Shawn , Molinaro Annette , Tandon Nitin , Rudà Roberta , Vogelbaum Michael A , Bello Lorenzo , Schnell Oliver , Grau Stefan J , Chang Susan , Berger Mitchel , Esquenazi Yoshua , Tonn Joerg-Christian
Published: November 2023

BACKGROUND

The role of re-resection in recurrent glioblastoma remains controversial since leaving certain tumor volumes deliberately behind cannot be ethically justified. We aimed to (I) analyze the prognostic value of re-resection using the novel RANO resect classification for quantification of residual tumor, and (II) explore factors that favorably consolidate the effects of re-resection on outcome.

METHODS

The RANO resect group retrospectively accumulated a global, eight-center cohort of patients with first recurrence from a previously resected glioblastoma. The associations of re-resection and clinical factors with outcome were analyzed. Propensity score-matched analyses were constructed to mimic randomized clinical trials comparing different residual tumor volumes.

RESULTS

We analyzed 681 patients with first recurrence of IDH-wildtype glioblastoma, including 310 patients who underwent re-resection at first recurrence. The use of re-resection was associated with prolonged survival also when stratifying for molecular and clinical confounders (HR:0.65, CI:0.5-0.8; p = 0.001). Smaller post-operative contrast-enhancing (CE) tumor volumes were favorably associated with outcome of re-resected patients (HR per cm3:1.04, CI:1.0-1.1; p = 0.009), and ≤ 1 cm3 residual CE tumor translated into improved survival compared to non-surgical management. Accordingly, ‘maximal resection’ (class 2) had superior survival compared to ‘submaximal resection’ (class 3) (mOS after recurrence: 12 vs. 9 months; p = 0.003). Adjuvant chemotherapy further augmented the beneficial effects of lower residual CE tumor. Conversely, ‘supramaximal resection’ of non-CE tumor (class 1) was not associated with prolonged survival but frequently accompanied by post-operative deficits, hampering further treatment. The prognostic role of residual CE tumor was confirmed in propensity score analyses.

CONCLUSION

Residual CE tumor is highly prognostic in recurrent glioblastoma and the RANO resect classification serves to stratify patients accordingly. Chemotherapy may favorably contribute to the prognostic associations of re-resection. When pursuing re-resection of non-CE tumor, intraoperative mapping strategies to minimize the risk of post-operative deficits are recommended.
SURG-24. FACTORS PREDICTING REMISSION AND RECURRENCE AFTER SURGICAL TREATMENT OF ACTH SECRETING PITUITARY ADENOMAS - CUSHING’S DISEASE
Authors: Suri Ashish , Khadgawat Rajesh , Sharma M C , Garg Ajay
Published: November 2023

Despite recent advances in management, disease persistence and recurrences are common in patients with ACTH secreting pituitary adenomas-Cushing’s disease (CD). The study aims to determine clinical, biochemical, radiological, histological factors that correlate with persistence and recurrence in patients with CD, and also aims to understand the clinico-pathological significance of EGFR-MAPK, NF-kB, SHH pathway activation. Clinical data of 167 patients who underwent surgical treatment (n = 174 surgeries) for CD was ambispectively analysed with median follow-up of 8.1years(1-13.29 years). Among the 174 surgeries performed, 140 were primary, 22 were redo, 24 were for paediatric patients and 12 surgeries were performed in Nelson syndrome. In the primary surgery cohort, 74.3% were females and the average age was 28.73years(SD = 10.15). 75% of patients experienced remission after primary surgery compared to 47.4% in redo surgery. The remission rate in paediatric patients was 55.5%. Post-operative day-1 plasma cortisol (p < 0.001;AUC = 0.8894[0.8087-0.9701]) and ACTH (p < 0.001;AUC 0.9[0.7386-1]) levels were seen to be strong independent predictors of remission in primary surgery cohort. Remission rates after endoscopic trans-sphenoidal surgery- TSS were more than those after microscopic TSS, in patients undergoing primary surgery (81.08%vs57.14%;p = 0.008). Presence of adenoma on histopathological examination(HPE) was also strong predictor of disease remission (p = 0.020). On categorising based on surgical approach and HPE, microscopically operated patients without histopathological evidence of adenoma had significantly higher odds of non-remission (OR 38.1;95%CI-4.2-348.3) compared to endoscopically operated patients with adenoma on HPE. Lower immune reactivity score (IRS) of NR4A1 was found to correlate with higher remission rates (p = 0.074). However, none of the molecular markers studied - NR4A1, c-Fos, c-Jun, GLI1, pMEK, p44 showed a significant correlation with the preoperative cortisol values. Post-operative day-1 serum cortisol and ACTH are reliable predictors of remission. Additionally, endoscopic approach and histopathological evidence of adenoma are associated with higher remission rate, with both features together raising the odds significantly.
SURG-33. LATERAL VERSUS MIDLINE APPROACHES TO RESECTION OF SKULL BASE CHORDOMAS: A META-ANALYSIS
Authors: Brown Nolan , Kuo Cathleen , Nguyen Oanh , Gendreau Julian
Published: November 2023

INTRODUCTION

Though it remains a rare and devastating tumor, great strides have been taken to improve prognostication and treatment paradigms for patients with skull base chordoma. With respect to surgical techniques, lateral transcranial (TC) approaches have traditionally been used, however endoscopic endonasal approaches (EEA) have been advocated for midline lesions. However, due to the rarity of this tumor (0.2% of all intracranial neoplasms), investigations within the literature remain limited to small retrospective series.

METHODS

Accordingly, we performed a systematic review and meta-analysis in order to profile surgical outcomes for midline versus lateral approaches to resection of skull base chordoma. Meta-analysis of pooled mortality rates and sub-analyses of operative margin and surgical complications were used to compare midline versus lateral approaches via the Mantel-Haenszel method. We considered all p-values < 0.05 to be statistically significant.

RESULTS

Fifty studies published between 1993-2022 reporting data for 2252 patients remained eligible for analysis. Average age at diagnosis was 42.4 ± 12.5 years, while average age of treatment initiation was 43.0 ± 10.6 years. The relative risk for mortality (Figure 2) in patients undergoing surgical intervention was -0.93 [-1.03,-0.97], I^2=95%, (p < 0.001), indicating low surgery-related mortality rates. From the seven studies eligible for formal meta-analysis, we found that there was no statistically significant difference between midline and lateral approaches with respect to rates of GTR or recurrence. Nor was there a significant difference between rates of postoperative cranial nerve dysfunction, although the result trended toward favoring midline approaches. Finally, midline approaches exhibited a lower odds for peri- and post-operative complications, including CSF leak (OR 0.59 [0.35, 0.97], I^2 = 0%, p = 0.04).

CONCLUSION

Ultimately, there are no striking differences between midline versus lateral approaches to resection of skull base chordoma, particularly as they relate to operative margins, recurrence, or rates of cranial nerve palsy.
SURG-38. SAFETY AND EFFICACY OF COMBINATORIAL IMMUNE CHECKPOINT BLOCKADE AND LASER INTERSTITIAL THERMAL THERAPY
Authors: Haskell-Mendoza Aden , Wachsmuth Lucas , Srinivasan Ethan , Jackson Joshua , Zaidi Saif , Gonzalez Ariel , Reason Elle , Lerner Emily , Fecci Peter
Published: November 2023

INTRODUCTION

Treatment of intracranial lesions with laser interstitial thermal therapy (LITT) allows for simultaneous cytoreduction and the potential to generate an anti-tumor immune response. The safety and efficacy of combination immune checkpoint blockade (ICB) and LITT has not been determined.

METHODS

All patients who received LITT for neuro-oncologic indications at a single NCI-designated cancer center from 2015 – 2022 were included. Simultaneous ICB was defined as receipt of therapy within 6 weeks of LITT. Demographic, clinical, and survival data were collected. Immune-related and intracranial adverse events (iRAEs and IAEs) were graded according to Common Terminology Criteria.

RESULTS

Twenty-four patients received simultaneous LITT and ICB. Median age was 62 (range 40 - 78) and 12 (48%) were female. Median KPS was 80 (50 – 100). Use of ICB increased during the study period (r = 0.69). The most common pathology was non-small cell lung cancer (15 patients, 62.5%), followed by melanoma in 3 (12.5%) and 2 (8.3%) patients each with renal cell carcinoma or high-grade glioma. Twenty-three (96%) patients received single agent ICB, with pembrolizumab most common (12, 50%), followed by nivolumab (6, 25%). The median interval between LITT and ICB was 2.56 (0.85 – 4.98) weeks. The most common iRAE was hypothyroidism in 4 (16.6%) patients, with grade 3 pneumonitis in one patient. The most common IAE was seizures in 4 (16.6%) patients. Local progression was seen in 4 patients (16.6%), with a post-LITT overall survival of 20.6 (1.0 – 36.1) months for the cohort.

CONCLUSIONS

Combination LITT and ICB appears safe and effective, with iRAEs commensurate with trials of checkpoint inhibition. High-grade intracranial toxicity was rare. Prospective studies of combinatorial LITT + ICB are needed to establish biomarkers and optimal timing.
SURG-40. AWAKE CRANIOTOMY IN A MIDDLE-INCOME COUNTRY. CHALLENGES AND TECHNICAL NUANCES
Authors: De Leon Alvino , Wong Eduardo , Villarreal Maria Antonia
Published: November 2023

OBJECTIVES

Describe the first experience in this technically challenging procedure

RESULTS

on morbidity

INTRODUCTION

Awake craniotomy allows for maximal safe resection and lower incidence of adverse events. Nonetheless, it represents a technical challenge.

METHODS

We enroll forty patients, 18 women, and 22 men. Due to the lack of a navigation system, craniometrics points became paramount to craniotomy planning. Ultrasound is used to compensate for brain shift and confirm the tumor's exact location. We engaged in cortical and subcortical mapping and clinical evaluation of motor and sensory functions. Linguistic tests were applied. The first 24 hours are in the ICU, and an MRI is obtained.

RESULTS

The mean age was 51, and the mean Karfnosky scale was 80. The median size was 12 cm3. Locations were: Thirteen precentral gyri. Ten insular cortex. Eight cingulate gyri. Six supplementary motor gyri Two Supramarginal gyri. One paracentral lobe tumor. Four patients had obese morbidity, three had depression, and two had a midline displacement treated with steroids. Intraoperative, we encountered three seizures managed with cold saline, two speech arrest, and one transient hand motor deficit. Post-op adverse events were one central facial paralysis, one upper limb, and one lower limb paresthesias; all improved after 72 hours. The median length of stay is 48 hours. The median extent of resection is 93%. The mean KPS was 80 at discharge. We undertook a median of 18 months follow-up. 38 Glioblastomas(GMB) and 2 Low-Grade Gliomas(LGG) were found. The standard oncology treatment was Temozolomide and stereotaxic radiosurgery(SRS). The median time from surgery to SRS was 4.3 months. The median SRS marginal and maximal dose were 15Gy and 26Gy. The median overall survival(OS) was sixteen months, and the Progression-free survival(PFS) was ten months.

CONCLUSION

An awake craniotomy without the navigation system is possible; however, careful planning is essential.
TMET-17. LEVERAGING METABOLIC VULNERABILITIES INDUCED BY TERT EXPRESSION FOR GLIOBLASTOMA THERAPY IN VIVO
Authors: Udutha Suresh , Taglang Celine , Batsios Georgios , Gillespie Anne Marie , Viswanath Pavithra
Published: November 2023

Telomerase reverse transcriptase (TERT) is essential for telomere maintenance and tumor immortality. Although TERT is an attractive therapeutic target, targeting TERT directly is hampered by toxicity to stem cells that also rely on TERT for proliferation and the lag period before telomere attrition is observed. Targeting metabolic reprogramming associated with TERT is an alternate strategy. Our studies indicate that TERT is essential for redox homeostasis in glioblastoma cells (GBM; GBM6 and U251). Specifically, TERT increases levels of glutathione (GSH) via upregulation of the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme in de novo GSH synthesis. Inhibiting GCLC using buthionine sulfoximine (BSO) or siRNA reduces synthesis of 13C-GSH from [U-13C]-glutamine and inhibits viability of GBM6 and U251 cells. However, GCLC inhibition causes a compensatory increase in synthesis of glutamate, aspartate, and pyrimidine nucleotides from [U-13C]-glutamine via upregulation of two key glutamine-utilizing enzymes i.e., glutaminase (GLS), the enzyme that generates glutamate from glutamine, and carbamoyl phosphate synthetase II (CPSII), the enzyme that converts glutamine to carbamoyl phosphate during pyrimidine biosynthesis. We then examined the therapeutic potential of inhibiting GLS and CPSII in combination with GCLC in GBMs. 6-diazo-5-oxy-L-norleucin (DON), a potent inhibitor of glutamine-utilizing enzymes including GLS and CPSII, synergizes with BSO in inhibiting viability of GBM6 and U251 cells. This effect is specific to TERT-expressing GBM cells because the combination of DON and BSO does not affect viability of normal astrocytes or astrocytomas that use the ALT pathway for telomere maintenance. Importantly, in vivo stable isotope tracing confirmed that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH, aspartate, and pyrimidine nucleotides from [U-13C]-glutamine and induces apoptotic death in mice bearing intracranial GBM6 tumors.Collectively, our studies highlight the therapeutic potential of targeting metabolic vulnerabilities induced by TERT expression in GBMs in vivo.
TMIC-03. TARGETING THE COLLAGEN RECEPTOR DDR1 PROMOTES ANTI-GLIOMA IMMUNITY BY REMODELING COLLAGEN FIBER ARCHITECTURE
Authors: Faisal Syed M , Varela Maria , Comba Andrea , Argento Anna , West Molly , Brumley Emily , Abel II Clifford , Clewner Jarred , Stack Brooklyn , Haase Santiago , Mujeeb Anzar , Banerjee Kaushik , Barissi Marcus , Abbud Grace , Castro Maria , Lowenstein Pedro
Published: November 2023

Glioblastoma (GBM), characterized by its aggressive nature and profound immunosuppression, poses a significant therapeutic challenge with limited treatment options. We previously demonstrated that targeting Col1α1 eradicates oncostreams and improves survival in murine models. However, the underlying mechanisms by which collagen reshapes the glioma tumor microenvironment (TME) remain unknown. Through RNA-seq analysis we identified that DDR1, a collagen receptor, is overexpressed in genetically engineered glioma mouse models (GEMMs) including NPA (NRAS/shp53/shATRX), and NPD (NRAS/shp53/PDGFβ), compared to healthy brain tissue. Pharmacological inhibition of DDR1 enhanced radiosensitivity, disrupted oncostreams in vitro, and ex vivo, imaged with time-lapse confocal microscopy. GEMMs of DDR1 knockdown (NRAS/shp53/shATRX/shDDR1) using the Sleeping Beauty transposase system significantly increased median survival by over 50%. Gene Ontology analysis of differentially expressed genes between wild-type and DDR1 knockdown gliomas revealed enrichment in immune reactivity, cytokine-chemokine activity, and extracellular matrix. Inhibition of DDR1 enhanced intratumoral infiltration of CD45+, CD8+, and CD3+ immune cells, accompanied by a decrease in the abundance of immune-suppressive cells, suggesting that gliomas exploit DDR1-mediated mechanisms to promote immunosuppression and facilitate tumor growth. We hypothesize that DDR1 in glioma impedes immune surveillance by promoting collagen fiber alignment, as evaluated using collagen-specific second-harmonic generation microscopy. Furthermore, analysis of human datasets demonstrated a negative correlation between DDR1 expression and CD8, suggesting DDR1’s role as a key regulator of immune surveillance in gliomas. Interestingly, when DDR1 knockdown gliomas were implanted in immune deficient mouse models, NSG (NOD-scid-IL2Rγnull) or CD8−/− immune-deficient mice, no significant differences in survival were observed, indicating DDR1 expression in glioma cells dampens anti-glioma immunity. In conclusion, we propose that DDR1 within glioma cells induces an immune-inhibitory TME, reprograms cytokine and chemokine profiles, and promotes collagen fiber alignment, thus inhibiting anti-glioma immunity. Our data highlight DDR1 as a promising therapeutic target, providing a novel avenue for GBM treatment with significant potential.
TMIC-10. TGF-Β2 DRIVEN SURVIVAL IN DMG AND GBM
Authors: Trieu Vuong
Published: November 2023

OT-101 is being developed as immunotherapy for a broad range of cancers. Cancers overexpress TGF-β, which suppresses host innate immune response to the cancers. Treatment with OT-101 lifts the TGF-β cloaking effect and allows innate or therapeutic immunity to attack and eliminate the cancers. OT-101 completed phase 2 for pancreatic cancer and melanoma and phase 2 in glioblastoma with robust efficacy and safety. Here we are presenting data and clinical trial design for OT-101 in DMG (Diffuse Midline Glioma). ADME studies were performed on OT-101 demonstrating perfusion of the brain including the midline by either intracerebral or intraventricular administration. The studies allowed us to bridge intraventricular administration to corpus of CED administered OT-101. Safety studies were performed in two species supporting the safety of OT-101 intraventricular administration. Expression analyses of pediatric brainstem cases of the TCGA database yielded highly significant survival benefit across all four quartiles of TGF-β2 expression. This was not observed for either TGF-β1 and less so for TGF-β3. Expression analyses of all gliomas treated with radiation yielded highly significant survival benefit across all four quartiles of TGF-β2 expression. This was not observed for either TGF-β1 nor TGF-β3. In adult gliomas, OT-101 is noninferior to the most active drugs (TMZ, BCNU, or PCV) in both chemo naïve and chemo-resistant patients. In terms of overall survival when compared to standard chemotherapy (TMZ, BCNU, or PCV) in both G004 and G005 as both the hazard ratio, which was 0.9168, and the 90% upper limit of the confidence interval, which was 1.2245, were both less than the initial non-inferiority bound of 1.25. Together the data support the development of OT-101 for DMG. The phase 2 clinical trial design is being presented for OT-101 in DMG administered using Ommaya reservoir following radiation in newly diagnosed DMG
TMIC-18. CYTOMEGALOVIRUS ONCOMODULATION OF THE GLIOBLASTOMA TUMOR MICROENVIRONMENT: A ROLE FOR THE VIRAL-ENCODED GPCR, US28
Authors: Kelly Michael , Wass Amanda , Silver Daniel , Lathia Justin , O'Connor Christine
Published: November 2023

Glioblastoma (GBM) is a prevalent, malignant glioma, and patient prognosis is poor. Even with surgery and aggressive treatment, survival is a dismal 12-15 months. GBM therapeutic resistance is common, often resulting in tumor recurrence, due in part to cancer stem cells (CSCs) that are resistant to chemo- and radio-therapies. This highlights the need for novel treatments, which requires a deeper understanding of the GBM tumor environment. While controversial, emerging data implicate human cytomegalovirus (CMV) in GBM progression, including findings that CMV drives GBM cell proliferation. Our work confirms CMV accelerates GBM cell proliferation in vitro using patient-derived xenograft (PDX) GBM models. Intracranial injection of these infected cells into murine models also results in decreased survival relative to mock-infected cells, suggesting CMV infection influences survival in vivo. Further, we found the CMV-encoded G-protein coupled receptor (GPCR), US28, influences this, as infection of PDX-derived GBM cells in vitro with US28-deletion virus impacts cell proliferation. In murine models, we find wild type infected PDX-derived GBM cells result in a significant decrease in survival compared to mice receiving cells infected with CMV lacking US28, suggesting US28 expression confers improved overall survival in vivo. Additionally, we find expression of US28 is associated with significantly increased survival for female mice, whereas there was no statistical difference between male mice that received CMV-infected or uninfected GBM cells. This indicates CMV infection, and more specifically, US28 expression, adversely impacts survival of female mice. Collectively, our data further illuminate means by which CMV influences the GBM tumor microenvironment and survival. We are currently working to understand: 1) the impact of US28-mediated signaling pathways on the tumor microenvironment; and 2) the influence of US28 interacting partners on GBM progression, including EphA2, a receptor tyrosine kinase whose increased expression in GBM confers increased CSC invasiveness.
TMIC-46. SINGLE-CELL MAPPING OF HUMAN BREAST CANCER BRAIN METASTASES REVEALS PROGNOSTICALLY RELEVANT IMMUNE LANDSCAPES
Authors: Jassowicz Lena , Wong John , Soller Julia , Sor Furkan , Feng Fangyoumin , Barthel Mandy , Unterberg Andreas , Lichter Peter , Warta Rolf , Zapatka Marc , Seiffert Martina , Herold-Mende Christel
Published: November 2023

Brain metastases are associated with a particularly poor prognosis in breast cancer and improved treatment strategies are much needed. The patient-individual role of immunotherapy and anti-tumor immune control in breast cancer brain metastases (BCBM) is still poorly understood. Here, we characterized the niche-specific tumor microenvironment of BCBM at single-cell resolution in a clinically annotated patient cohort that underwent surgery at Heidelberg University Hospital (n = 156). Quantification of T cell infiltrates across whole tissue sections of n = 137 BCBM revealed strong inter-patient heterogeneity of T cell abundance. Of note, high CD8 T cell densities predicted prolonged overall survival independent of established prognostic factors. Deeper phenotyping of BCBM T cells and matched blood samples by flow cytometry showed a specific enrichment of a CD103+ tissue resident-like CD8 T cell subset expressing high levels of activation markers and checkpoint molecules in BCBM. In contrast to a general T cell enrichment in the stroma, this subset was detected more frequently within tumor islands, which might suggest its anti-tumor reactivity. We investigated potential regulators of T cell infiltration and function in the brain metastatic niche focusing on the triple negative breast cancer sub-cohort (n = 49) concluding the following: i) The quantification of a broad range of immune cells, incl. myeloid cells, NK, and B cells, in whole tissue sections revealed distinct immune ecotypes associated with T cell infiltrates. ii) An in-depth characterization of all major immune and stromal cells by single nuclei RNA-sequencing (n = 28/49) allowed for identification of potential cellular and molecular interaction partners, which was confirmed by iii) analysis of their neighborhoods by spatial transcriptomics in a targeted, single-cell resolving approach (n = 8/28). We anticipate that our findings will reveal immunoregulatory cell subsets and molecules and potentially contribute to improving immunotherapeutic approaches for BCBM patients in the future.
TMIC-53. TRANSGLUTAMINASE 2 EXPRESSION IN GLIOBLASTOMA: EVIDENCE FOR A ROLE IN EFFEROCYTOSIS
Authors: Lorimer Ian , Elgafarawi Mara , Lui Margarita , Sevinc Filiz , Leger Alexa , Munoz David , Keillor Jeffrey , Woulfe John
Published: November 2023

Glioblastoma is the most common type of brain cancer in adults. It is currently incurable and there is a clear need for more effective treatments. The heterogeneity of this cancer and its ability to promote both local and systemic immunosuppression are major obstacles to the development of effective therapies. Previous studies have explored the use of transglutaminase 2 (TGM2) inhibitors for glioblastoma therapy. These studies focussed on TGM2 that is expressed in a subset of glioblastoma cells. We show here that glioblastoma-associated macrophages are a major source of TGM2 in glioblastoma tumours. Analysis of bulk and single cell RNAseq data showed that TGM2 mRNA was expressed at high levels in glioblastoma-associated macrophages. Immunohistochemical and immunofluorescence analysis of TGM2 expression was performed in a mouse xenograft model in which human mesenchymal subtype glioblastoma cells were grown intracerebrally in nude mice. In these xenograft tumours, glioblastoma cells were negative for TGM2 expression, while infiltrating macrophages were strongly positive. The most intense staining for TGM2 was observed in macrophages in the vicinity of necrotic regions. Apoptotic cells were frequently present within the necrotic regions and highly TGM2-positive macrophages were observed to be phagocytosing these. The same patterns of TGM2 expression were also observed in samples from glioblastoma patients. Consistent with a role in phagocytosis, TGM2 co-localized with the endosomal protein CD68 in glioblastoma-associated macrophages. The phagocytosis of apoptotic cells by macrophages, known as efferocytosis, is tolerogenic, both because it clears potentially antigenic material and because it induces an immunosuppressive phenotype in macrophages. As TGM2 has a previously established role in efferocytosis and autoimmunity suppression, our findings suggest that TGM2 has a role in maintaining the glioblastoma immunosuppressive environment and that its inhibition might enhance immunotherapy for this cancer.
TMIC-63. SINGLE CELL SEQUENCING OF RECURRENT GLIOBLASTOMA DEFINES CELLULAR STATES ASSOCIATED WITH THERAPY RESISTANCE
Authors: Tripathi Arushi , Shankar Sunita , Ravikumar Visweswaran , Loper Jackson , Ji Sunjong , Hassan Zainab , Haydin Yacoub , Huang Dah-Luen , Bhadury Sagnik , Regier Jeffrey , Rao Arvind , Al-holou Wajd
Published: November 2023

Glioblastoma (GBM), an aggressive, primary tumor is composed of multiple clonal populations. Resistance to therapy is a hallmark of GBM, making it a deadly disease. Upon therapeutic stress, tumor heterogeneity and glial stem cell plasticity within the primary tumor contributes to reprogramming of the transcriptional activity. This alters the tumor landscape and generates therapy resistant clonal populations. Single cell RNA sequencing studies of primary GBM have defined various tumor cell states namely, the NPC-like (Neuronal precursor-like), OPC-like (oligodendrocyte precursor-like) and MES-like (mesenchymal-like) cellular states. These studies have also defined the immune components and the normal brain cells associated with primary GBM. Yet, there are no studies focused on the single cell analysis of recurrent GBM. To define the tumor landscape at recurrence, we performed single cell RNA sequencing of 180K cells from excised tumor tissue obtained from 11 patients after failure of therapeutic interventions. A corresponding cohort of 240K cells were sequenced from primary tumors obtained from 13 patients. We performed cellular state analyses of tumor cells in both the primary (~70K) and recurrent (~10K) samples. Primary GBM showed higher fractions of AC-like (0.55), compared to NPC-like (0.10), OPC-like (0.20) and MES-like (0.15). On the other hand, recurrent tissues have very low AC-like (0.09) but elevated NPC-like (0.23), OPC-like (0.40) and MES-like (0.27). This data shows a significant decrease in AC-like cells and corresponding increase in MES-like, OPC-like, NPC-like cells after recurrence. Within this dataset we also have matched longitudinal samples for analysis. We are currently performing trajectory analysis to identify genes and transcription programs activated during tumor recurrence. Experimentally, using known markers for the different cellular states we have also performed immunofluorescence analyses to validate the different cell states altered during recurrence. Our efforts to generate comprehensive recurrent GBM atlas will prove to be valuable to the GBM community.