bluuebunny/crossref_metadata_2025 huggingface dataset:
NCMP-10. NEURO-OPHTHALMOLOGICAL FINDINGS IN CHILDREN AND ADOLESCENTS WITH MEDULLOBLASTOMA - A RETROSPECTIVE ANALYSIS
Authors: Lippolis Maria Aliotti , Koinig Sabine , Azizi Amedeo , Dorfer Christian , Pemp Berthold
Published: November 2022

BACKGROUND

Medulloblastoma represents the most common malignant pediatric brain tumor. Ophthalmic complications are possible sequelae.

METHODS

Pediatric medulloblastoma (MB) patients treated at the Medical University of Vienna from January 2012 to August 2021 were analyzed and their last ophthalmic assessment was reviewed.

RESULTS

Fifty-six MB patients could be included (71.4% non-WNT/non-SHH, 16.1% SHH-activated, 8.9% WNT-activated, 3.6% non-specified). Mean age at diagnosis was 7.2 years (range 0-19). Median follow-up to last ophthalmological assessment was 19.7 months (range 0.1-93.2). Thirty-four children underwent tumor resection at our hospital, their tumor localizations were: vermis (55.9%), floor of the 4th ventricle (26.5%), cerebellar hemispheres (11.8%), lateral recess (5.9%). Symptoms at presentation were evaluable for 51 children: 92.2% had symptoms of elevated intracranial pressure, 76.5% ataxia and 21.6% visual disturbances. Postoperative posterior fossa syndrome was observed in 11.1% of 54 children. 98.2% had chemotherapy as part of their initial treatment and all children older than four years (85.7%) received postoperative irradiation of the posterior fossa. In 13 (23.2%) intraventricular chemotherapy was applied. At the last follow-up 21 patients experienced relapse after primary treatment. At the final assessment, frequent neuro-ophthalmological abnormalities included: oculomotor disturbance (75%), esotropia (35.7%) including abducens palsy (12.5%), other cranial nerve palsies (21.4%), horizontal gaze-evoked nystagmus (51.8%), spontaneous nystagmus (16.1%), ocular tilt reaction (21.4%), and optic disc abnormalities (14.3%). Good visual acuity (≥20/25) was maintained in 62.5% patients. Visual field and optical coherence tomography was successfully performed in 75% and 66.1% of patients, respectively. Optic pathway lesions were detected in 4 patients (7.1%), including two cases with occipital metastases, one with optic nerve metastasis and one with leptomeningeal carcinomatosis. Orthoptic treatment with prisms and strabismus surgery was required in 14.3% and 7.7% of children, respectively.

CONCLUSION

Children with MB frequently suffer from neuro-ophthalmological late-effects. Regular monitoring is warranted to initiate appropriate management.
NCMP-14. NEUROTOXICITY AFTER A SINGLE CYCLE OF INTRAVENOUS CYTARABINE
Authors: Herbst John , Grommes Christian , Schaff Lauren
Published: November 2022

Cytarabine neurotoxicity is well-documented, typically occurring after intrathecal treatment or a cumulative systemic dose of 36 g/m2. Encephalopathy, myelopathy, and acute cerebellar syndrome have all been described, with risk factors including advanced age and renal dysfunction. Here, we report a case of acute cerebellar syndrome after a single cycle of intravenous cytarabine 3 g/m2. This 65 year old man with history of chronic kidney disease (baseline creatinine 2.0 mg/dL) and primary central nervous system lymphoma had unconfirmed complete response after induction therapy with rituximab, methotrexate, and vincristine. Methotrexate was dosed between 1 -2 g/m2 due to renal dysfunction and delayed clearance. Given patient’s performance status and comorbidities, high-dose cytarabine consolidation was chosen. He received 3 g/m2 intravenously on days 1 and 2 of a 28-day cycle. On day 5, he developed acute truncal ataxia and was no longer able to sit or stand unsupported. He then presented to the emergency department on day 8 with persistent symptoms. Vital signs showed mild hypertension without orthostatic hypotension. Neurologic exam revealed postural instability, titubation, and inability to maintain seated posture with eyes closed. He had no dysmetria on finger-nose or heel-shin testing. Blood values were notable only for an elevated creatinine of 2.1 mg/dL. CT head revealed no acute pathology. MRI brain showed no infarct or recurrent disease. He was discharged home and symptoms resolved by day 10. Given clinical syndrome of truncal ataxia shortly after cytarabine, we diagnosed cytarabine-related neurotoxicity. Further cycles of consolidation were withheld for close observation. While cytarabine-related neurotoxicity is more common after an increased cumulative dose, it can occur after only a single cycle of 3 g/m2. Our patient’s age and baseline renal dysfunction likely predisposed him. Cytarabine dose-reduction can be considered in patients with these risk factors.
NCMP-16. UNIQUE PARANEOPLASTIC SYNDROME ASSOCIATED WITH CLL
Authors: Boldig Catherine , Warman Mark , Verma Neha , Mokhtari Sepideh
Published: November 2022

Chronic lymphocytic leukemia is a hematologic malignancy characterized by overproduction of monoclonal B cells. Most people diagnosed with CLL do not immediately undergo treatment due to treatment guidelines. There are few cases of paraneoplastic syndrome associated CLL. This case is unique in that it is a paraneoplastic KLHL 11 antibody associated CLL. The patient is a 68-year-old female who originally presented to the hospital with abdominal pain and upon further imaging was found have retroperitoneal lymphadenopathy. After further studies including flow cytometry, she was diagnosed with CLL. She failed trials of Pembrolizumab, ibrutinib, and Obinutuzumab due to side effects. The patient then started experiencing excessive fatigue, bilateral temporal headache, nausea, vomiting, vertigo, tremor of bilateral upper extremities, and head bobbing. Her brain imaging was negative for acute abnormalities. Lumbar puncture was positive for CLL cells and the paraneoplastic panel came back positive with KLHL 11 antibodies. The patient’s symptoms continued to persist and her tremor and dysmetria continued to worsen. Due to the positive paraneoplastic panel, the patient was started on intravenous immunoglobulin but did not experience improvement. She was then trialed on intravenous methylprednisolone and still experienced no relief. She then underwent plasma exchange. Finally, she was given rituximab infusions with slight improvement. Her imaging remained negative for signs of leptomeningeal enhancement. Given the patient’s symptoms, negative brain imaging, and positive paraneoplastic panel, it was determined that the patient developed an irreversible paraneoplastic syndrome related to her CLL versus possible leptomeningeal disease. There are a few cases of paraneoplastic syndrome associated CLL involving paraneoplastic phemphigus, hypercalcemia, and nephrotic syndrome. This case is unique in that her symptoms presented with an ataxic syndrome with positive KLHL11 antibodies. It is important to be aware that some cases of CLL can present with unique paraneoplastic syndromes.
NCMP-20. NUMB CHIN SYNDROME: ATYPICAL PRESENTATION OF METASTATIC BREAST CANCER
Authors: Bureau Britta , Connelly Jennifer , Barkhaus Paul , Brennan Ryan
Published: November 2022

OBJECTIVES

1. To report a variation of Numb Chin Syndrome (NCS) 2. Raise awareness and early localization of NCS to more efficiently develop a targeted treatment plan to prevent tumor spread and potentially improve clinical outcomes and survival.

INTRODUCTION/BACKGROUND

NCS is an uncommon but known complication of cancer. Prompt recognition is imperative to directed treatment. In some instances, numb chin may be complicated by other findings.

CASE REPORT

A 53-year-old female with past medical history of estrogen receptor positive invasive ductal breast carcinoma underwent partial mastectomy, chemotherapy, and radiation. After 6 years remission, new lung and liver metastases occurred, and chemotherapy resumed. Imaging was negative. Eight weeks later, she developed left chin numbness followed by progressive difficulty retaining food and drink. Her left lower lip weakened. Neurological examination revealed left lower lip weakness (showing a “droop” with attempted smile). The area of decreased sensation to sharp touch had expanded from the left chin to the nasolabial fold. The remainder of her neurological examination was unremarkable. Contrast-enhanced MRI was repeated which revealed a 1.9 cm enhancing left parotid mass. SUMMARY/

CONCLUSION

NCS is defined as an ipsilateral loss of chin sensation. If there is no history of trauma or dental injury and especially if the presentation is atypical, then cancer is the most likely etiology. This case began as an uncomplicated NCS that rapidly expanded to involve a greater portion of the trigeminal nerve distribution, in addition to a branch of the facial nerve. Thus, each focal deficit was not the result of separate distal nerve lesions, but rather partial proximal cranial neuropathies at their parotid gland propinquity.
NCMP-24. RISK FACTORS OF SURGICAL SITE INFECTION IN GLIOMA SURGERY
Authors: Kuwano Atsushi , Nitta Masayuki , Saito Taiichi , Ikuta Soko , Tsuzuki Shunsuke , Koriyama Shunichi , Kawamata Takakazu , Muragaki Yoshihiro
Published: November 2022

BACKGROUND

Surgical site infection(SSI) in neurosurgery can increase mortality and worsen functional outcome. There are few reports on risk factors for SSI in glioma surgery. In this study, we investigated the risk factors for SSI in glioma surgery at our institution.

METHODS

We included 1013 patients with gliomas who underwent craniotomy between November 2013 and March 2022 at our institution. SSI was defined as requiring surgical treatment. Various factors including age, gender, number of operations, prior radiology, prior chemotherapy, use of intraoperative MRI, operation time, tumor WHO grade were investigated.

RESULTS

Among 1013 craniotomies, 31 (3.06%) cases of SSI required surgical procedure. In univariate analysis, the most significant factors were multiple prior craniotomy (p = 0.0067) and prior radiation therapy ( p = 0.0286). Among these factors, multivariate analysis revealed the number of surgeries ( p = 0.0151) as a significant independent factor for infection.Discussion and

CONCLUSION

Patients with gliomas often requires multiple craniotomy due to tumor recurrence. Although there have been reported the reoperation is an independent risk factor for postoperative infection, the is the first time that a specific number of prior surgeries ( 2 or more) has been reported. Radiotherapy is said to cause skin damage at a threshold of 10 Gy or less. Since radiation therapy for gliomas is given a dose of 50 Gy or more and irradiated scalp causes radiation dermatitis, and patients who have undergone prior radiotherapy must be carefully monitored.
NCOG-04. RANO-BM RESPONSE CRITERIA VERIFICATION STUDY IN A SRS-TREATED COHORT
Authors: Douri Keiss , Iorio-Morin Christian , Mercure-Cyr Rosalie , Figueiredo Gabrielle , Touchette Charles , Masson-Côté Laurence , Mathieu David
Published: November 2022

Brain metastases are frequently seen in neurosurgical practice. Standardised criteria are created to better classify these common pathologies in research studies. This study’s goal was to evaluate RANO-BM (Response Assessment in Neuro-Oncology - Brain Metastases) criteria’s current thresholds in a cohort of patients with brain metastases managed by stereotactic radiosurgery (SRS). We performed a retrospective metastasis-level analysis of patients treated with SRS for brain metastases. The data collected included cohort demographics, metastases characteristics, outcomes, and the rate of true positives, false negatives, true negatives and false positives as defined by RANO-BM criteria at last follow-up before second SRS. 251 metastases in 50 patients were included in the analysis. RANO-BM criteria using current thresholds yielded a sensitivity of 38%, a specificity of 95%, a positive predictive value of 71% and a negative predictive value of 84%. Modified RANO-BM criteria using absolute diameter differences of 2.5 mm yielded a sensitivity of 83%, a specificity of 87%, a positive predictive value of 67% and a negative predictive value of 94%. Pseudoprogression occurred significantly earlier than tumor progression, with a median time of onset of 6.9 months and 12.1 months respectively. Current RANO-BM criteria unreliably identifies clinically relevant tumor progression, but are useful in assessing diameter increases caused by tumor progression and pseudoprogression.
NCOG-08. IMPACT OF IMMUNOTHERAPY ON PREVALENCE OF BRAIN METASTASES IN MALIGNANT MELANOMA: A REAL-WORLD POPULATION-LEVEL ANALYSIS
Authors: Bhanja Debarati , Baroz Angel , Stahl Caleb , Wilding Hannah , Mansouri Alireza
Published: November 2022

INTRODUCTION

Melanoma brain metastases (MBM) are often associated with poor prognosis. Over the last decade, the treatment paradigm for malignant melanoma shifted with the introduction of immunotherapies (ITs), including ipilimumab (ipi) and nivolumab (nivo). Recent clinical trials suggest that IT offers a survival benefit in MBM and may suffice as the sole intervention in those with small, asymptomatic lesions. Secondary trial analyses suggest IT may reduce rates of BM. The goal of this study was to assess the potential impact of IT in reducing prevalence of MBM in a real-world population-level analysis.

METHODS

A retrospective query of TriNetX, a database that collates clinical data from 92 healthcare organizations, was performed. Melanoma patients without brain metastases at diagnosis were stratified as: 1) ipi and nivo (dual-IT), 2) ipi alone (single-IT), or 3) no IT treatment (no-IT). A new diagnosis of MBM, from one month of initiating IT to any time after, was compared among cohorts. Median overall survival (OS) of MBM patients were calculated and compared using Kaplan Meier analysis and log-rank tests.

RESULTS

732,555 melanoma patients were included (717,408 no IT, 4,585 dual-IT, 4,101 single-IT). Mean ages at MBM diagnosis were 66.9, 61.5, and 63.2 years, respectively. MBM prevalence was 1.5%, 9.6%, and 15.6%, for the respective cohorts (p < 0.0001). Dual-IT was associated with a lower rate of MBM compared to single-IT (OR [95%CI], 0.64 [0.61-0.77]). After propensity score matching for age, sex, and comorbidities, median OS were not statistically different between the no-IT, dual-IT, and single-IT cohorts (347, 400, 414 days) for MBM patients.

CONCLUSION

This analysis of real-world data suggests that dual-IT for malignant melanomas decreased the incidence of MBMs compared to single-IT. However, survival outcomes remain comparable once patients succumb to the MBM diagnosis. Prospective studies are underway to look at MBM prevalence given various dual-IT.
NCOG-10. SURGERY FOR RECURRENT GBM: A RETROSPECTIVE CASE-CONTROL STUDY
Authors: Voisin Mathew , Zuccato Jeffrey , Wang Justin , Zadeh Gelareh
Published: November 2022

OBJECTIVE

The role of surgery in recurrent GBM remains a controversial topic. The goal of this study was to perform a case-control analysis including time to tumor recurrence as an additional prognostic factor in order to determine which patients benefit most from repeat surgery.

METHODS

Our brain tumor database was reviewed over a ten-year period for all adult (≥ 18 years old) patients with primary IDH wildtype GBM that received surgery for recurrent disease. These patients were then age, sex, and treatment-matched to case-controls from our institution that received medical therapy for recurrent disease.

RESULTS

A total of 174 adult patients with GBM were included in the study, 87 patients that received surgery for recurrent GBM (surgery cohort) and 87 patients that did not receive surgery for recurrent GBM (non-surgery cohort). The surgery cohort had longer overall survival (p = 0.0003) and post recurrence survival (p = 0.001) than the non-surgery cohort. When the surgery cohort was split into two groups based on time to tumor recurrence, the long time to recurrence group ( > 6 months) demonstrated significantly increased survival compared to the short time to recurrence group (p < 0.0001). Multivariate analysis of both cohorts demonstrated surgery for recurrent GBM was independently significant after adjusting for age, KPS, and time to tumor recurrence (p < 0.0001).

CONCLUSIONS

Surgery for recurrent GBM leads to improved survival independent of age, KPS, and time to tumor recurrence. Patients with time to tumor recurrence greater than 6 months benefit most from additional surgery.
NCOG-12. IMPACT OF TUMOR-RELATED SEIZURES ON MENTAL HEALTH DISORDER ORDER IN LOW-GRADE GLIOMA
Authors: Bhanja Debarati , Ba Djibril , Tuohy Kyle , Wilding Hannah , Trifoi Mara , Padmanaban Varun , Liu Guodong , Sughrue Michael , Zacharia Brad , Leslie Douglas , Mansouri Alireza
Published: November 2022

INTRODUCTION

Majority of LGG patients experience seizures during their disease course, requiring anti-epileptic drugs (AEDs). Frequent seizures negatively impact health-related quality of life (HRQoL). AEDs, moreover, are hypothesized to have mood-modulating effects. As survival for LGG patients has been improving, it is essential that the impact of seizure burden and AEDs on mental health disorders (MHD) be considered. The objective was to measure an association of tumor-related seizures with MHD onset among LGG patients.

METHODS

This retrospective cohort study queried data from the IBM Watson Health MarketScan® Claims and Encounters Database (2005-2014) to identify LGG patients without prior MHD history who experienced glioma-related seizures. Presence of seizures was determined by anti-epileptic drug fills within one year following LGG diagnosis. Patients with new onset of MHDs were identified using ICD-9 codes for MHDs and psychotropic drug fills in the 12 months post-LGG diagnosis period. Unadjusted odds ratios measured associations between seizures and MHD prevalence.

RESULTS

11,458 LGG patients with no history of MHD were included; 1,799 (15.7%) experienced seizures within 12 months of LGG diagnosis. Among them, 494 (27.5%) developed MHD in the post-LGG diagnosis period. Patients who experienced seizures were more likely to develop an MHD compared to patients who did not (OR, 2.19, 95% CI, 1.95–2.47). MHD incidence was significantly associated with female gender (OR, 1.14, 95%, 1.03–1.26) and age range of 35–44 (OR, 1.20, 95%, 1.03–1.39) compared to 18–34.

CONCLUSION

These findings demonstrated that tumor-related seizures were associated with MHD onset. This highlights the burden of seizures and regular AED use on mental health. The psychosocial and neurological aspects related to seizures and AEDs likely contribute to the multifaceted mental health disorder onset seen among these LGG patients. Proactive counseling, diagnosis, and management of MHDs in LGGs, particularly those with seizures, is warranted.
NCOG-15. A PILOT STUDY ON RETINAL FEATURES AND COGNITIVE FUNCTION IN PATIENTS WITH LOW GRADE GLIOMAS
Authors: Liu Yin Allison , Aboud Orwa , Daly Megan , Bloch Orin , Yiu Glenn
Published: November 2022

BACKGROUND

Retinal structure and vascular changes are used as biomarkers for preclinical Alzheimer disease. We conducted a cohort study to evaluate the feasibility of obtaining these data in patients with low-grade gliomas (LGGs) who completed chemoradiation therapy with and without self or family reported cognitive concerns.

METHODS

Optical coherence tomography (OCT) and angiography (OCTA, OptoVue, Inc.) images were obtained from 6 LGG patients and 2 healthy controls using 4.5 x 4.5 mm peripapillary and 6x6 mm macular scan patterns. We measured OCTA parameters including radial peripapillary capillary density for the peri-optic disc region, whole macular density, and foveal avascular zone (FAZ).

RESULTS

We analyzed two eyes of two control subjects, an LGG patient with normal cognition, and 5 LGG patients with cognitive impairment (mean age 45 years, range of 3 months to 10 years after chemoradiation). Both controls had normal eye exams. Average retinal nerve fiber layer thickness was thinner in patients with and without cognitive dysfunction (104 um and 106 um, respectively) than controls (123 um). A similar pattern was seen in macula thickness (283 um and 290 um vs. 325 um). The average peripapillary vessel densities were lower in patients with and without cognitive dysfunction (47.7% and 48.3%, respectively) than controls (51.9%). The whole macular vessel densities were similar in three groups (46.7 %, 48.0%, and 48.0 %). Average FAZs were larger in patients with cognitive dysfunction (0.254 mm2) than the patient with normal cognition (0.204 mm2) and controls (0.226 mm2).

CONCLUSIONS

Retinal architecture and microvascular changes measured by OCT/OCTA is feasible in LGG patients after chemoradiation. A larger prospective study is needed to investigate the role of OCT/OCTA in detecting peripapillary and perifoveal changes in brain tumor patients with treatment-associated cognitive dysfunction.
NCOG-21. EFFECT OF PNEUMOCYSTIS JIROVECII PNEUMONIA PROPHYLAXIS ON HEMATOLOGIC TOXICITY IN PATIENTS RECEIVING CHEMORADIATION FOR PRIMARY BRAIN TUMORS
Authors: Arnold Lisa , Hoshina Yoji , Lee Hyejung , Haaland Benjamin , Colman Howard , Mendez Joe
Published: November 2022

INTRODUCTION

Management of diffuse gliomas often includes radiation plus concomitant and adjuvant temozolomide. Hematologic toxicities are common from this therapy. Patients frequently receive prophylaxis against pneumocystis jirovecii pneumonia (PJP) during chemoradiation; however, some PJP prophylaxis drugs have the potential to independently cause myelosuppression which could exacerbate the hematologic toxicities from chemoradiation requiring chemotherapy dose reduction or cessation. We seek to understand differences in the frequency of hematologic toxicities during chemoradiation when either trimethoprim/sulfamethoxazole (TMP/SMX) or pentamidine are used for PJP prophylaxis.

METHODS

This was a retrospective chart review of patients with primary brain tumors who were treated with first-time radiation and concurrent temozolomide between April 2014-August 2021 at the Huntsman Cancer Institute. Chi squared analysis was used to evaluate effect of choice of PJP prophylaxis on risk for neutropenia, lymphopenia, or thrombocytopenia within one month of finishing chemoradiation. Logistic regression was performed to evaluate the effect of PJP prophylaxis on the Common Terminology Criteria for Adverse Events (CTCAE) score for the lowest neutrophil, lymphocyte, and platelet count.

RESULTS

217 patients were included in analysis. 144 patients received TMP/SMX, 69 received pentamidine, 1 received dapsone, and 3 received no prophylaxis at initiation of chemoradiation. Of patients who received TMP/SMX, 15.4% developed an absolute neutrophil count < 1,500 cells/µL while this occurred in 7.2% of patients receiving pentamidine (p=0.10). Platelet count < 100,000 occurred in 18.1% of patients who received TMP/SMX and 20.3% of patients who received pentamidine (p=0.70). Worst CTCAE scores for hematologic toxicities were similar between PJP prophylaxis groups.

CONCLUSION

Our study provides preliminary evidence that the type of PJP prophylaxis does not appear to significantly impact risk for hematologic toxicity in patients receiving radiation and concurrent temozolomide; however, there was a trend toward higher rates of neutropenia with TMP/SMX and larger analyses are needed to further evaluate these findings.
NCOG-24. TIME TO FIRST RECURRENCE AND SURVIVAL IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Pan Peter , Joanta-Gomez Adela , Yuen Carlen , Donovan Laura , Haggiagi Aya , Welch Mary , Iwamoto Fabio , Lassman Andrew
Published: November 2022

INTRODUCTION

Time to recurrence is a source of considerable anxiety in glioblastoma. Assuming survival to a certain timepoint without tumor progression, how do odds/outcomes change relative to initial starting conditions? Is there a single timepoint with highest risk of tumor progression, after which "the longer you go, the longer you go"?

METHODS

Newly-diagnosed glioblastomas were retrospectively reviewed (n=209). Pre-2012 diagnoses (n=2) & IDH-mutants excluded (n=8). Median PFS/OS and remaining time to mPFS were calculated for sub-populations without disease progression (POD) at 0, 3, 6, 8, 12, and 24 months post-surgery.

RESULTS

199 IDH-wildtype glioblastomas identified -- 40% women, median age 63 years (range 26-91), 43% gross-total resection, 65% MGMT unmethylated, 65% upfront RT 60Gy (23% 40Gy) -- mPFS 8 months / mOS 19 months. Patients without POD within 3 months had mOS 20 months. Outcomes progressively improve at later timepoints-- mPFS 10/13/20/39 months and mOS 23/27/39/65 months, for patients without POD at 6/8/12/24 months post-surgery respectively. Patients without POD at 24 months comprised 10% of original cohort (n=20; 8 deaths). As a surrogate for risk of tumor progression, remaining time to mPFS was calculated (taken as difference between timepoint in question, and mPFS for the population of patients without POD up to that timepoint) and followed a J-shape curve -- 8 months (at 0 months post-surgery), 4 months (for patients without POD at 6 months post-surgery), 7-8 months (for patients without POD at 10-14 months post-surgery), to 13 and 15 months (for patients without POD at 18 and 24 months post-surgery, respectively).

DISCUSSION

Sub-populations without early progression appear to have improved survival relative to baseline, which has implications for clinical trials without internal controls. Nevertheless, highest risk for tumor progression seems to be at 6 months post-surgery, after which it appears "the longer you go, the longer you go."
NCOG-25. THROMBOCYTOPENIA LIMITS THE FEASIBILITY OF SALVAGE LOMUSTINE CHEMOTHERAPY IN RECURRENT GLIOBLASTOMA: A SECONDARY ANALYSIS OF EORTC 26101
Authors: Le Rhun Emilie , Oppong Felix Boakye , van den Bent Martin , Wick Wolfgang , Brandes Alba , Taphoorn Martin , Platten Michael , Idbaih Ahmed , Clement Paul , Preusser Matthias , Golfinopoulos Vassilis , Gorlia Thierry , Weller Michael
Published: November 2022

BACKGROUND

Thrombocytopenia represents the main cause of stopping chemotherapy for toxicity during the treatment of glioblastoma. Here we explored the incidence and prognostic implications of lomustine modification for thrombocytopenia in recurrent glioblastoma.

METHODS

We retrospectively analysed thrombocytopenia, its consequences for treatment delivery, and associations with outcome in the phase II and III parts of EORTC 26101, a randomized trial to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma.

RESULTS

225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). 129 patients (57%) in group 1 and 187 (66%) in group 2 experienced at least one episode of thrombocytopenia; 36 patients (16%) in group 1 and 93 patients (33%) in group 2 had their treatment modified for thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. Patients with MGMT promoter-methylated glioblastoma treated with lomustine alone experienced more lomustine treatment modification than patients with tumors without MGMT promoter methylation. On adjusted analysis accounting for major prognostic factors, lomustine modification induced by thrombocytopenia was associated with inferior progression-free survival (PFS) in patients with MGMTpromoter-methylated tumors in both groups, suggesting a link to insufficient lomustine exposure. This effect was noted for overall survival, too, but only for group 2 patients. Patients with MGMT promoter-unmethylated tumors who experienced dose modification for thrombocytopenia had longer PFS and overall survival, and this effect was driven largely by group 2 patients.

CONCLUSION

Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine in patients with recurrent glioblastoma. Its association with survival suggests that mitigating thrombocytopenia to allow enhanced lomustine exposure in patients with MGMT promoter methylated tumors might improve outcome.
NCOG-31. ROLE OF AGE IN CSF LEAK FOLLOWING TRANSSPHENOIDAL RESECTION OF CRANIOPHARYNGIOMA: ANALYSIS OF OUTCOMES IN PEDIATRIC VERSUS ADULT POPULATION
Authors: Brown Nolan , Shahrestani Shane , Gendreau Julian
Published: November 2022

Postoperative cerebrospinal fluid (CSF) leak is a serious complication after surgical treatment of craniopharyngioma. The objective of this study is to analyze postoperative CSF leak rates following transsphenoidal resection of craniopharyngioma in adult versus pediatric patient populations. PRISMA guidelines were used to query the Pubmed, Web of Science, and Cochrane databases for studies of craniopharyngioma resection in adult or pediatric patients from the past three decades. The following search terms, ("craniopharyngioma") AND ("cerebrospinal fluid" OR "CSF") AND ("leak" OR "rhinorrhea") AND ("resection" OR "surgery") AND ("transsphenoidal" OR "endonasal"), were used. The primary outcome variable collected was presence of postoperative CSF leak. Pooled analyses were performed to determine the rates of CSF leak in adult and pediatric cases. In addition, a meta-analysis was performed to compare the rates of CSF leak in the adult versus pediatric cohort. Of the 21 included studies, 8 studies reported adult cases, 9 studies reported pediatric cases, and 4 studies reported both adult and pediatric cases, for a total of 468 cases. The majority of studies were level 4 evidence (90.5%, 19/21), while two studies were level 3 evidence (9.5%, 2/21). Analysis of postoperative CSF leak in adult and pediatric cases revealed rates of 29% (95% CI: 21%-39%) and 13% (95% CI: 9%-19%), respectively. Using a random-effects meta-analysis model, we found that there was no significant difference between the two cohorts (RR: 1.56; 95% CI = 0.52-4.71; P = 0.43). The present study is the first to analyze postoperative CSF leak rates in adult and pediatric patients undergoing transsphenoidal resection of craniopharyngiomas. While we found that there is no significant difference in CSF leak rates between adult and pediatric patients, further studies of higher methodological quality are warranted to provide a better understanding of complication profiles following resection of adult and pediatric craniopharyngiomas.
NCOG-33. IDENTIFYING SELF-EFFICACY DIFFERENCES IN ADULT RARE CNS PATIENTS PARTICIPATING IN A NOVEL WEB-BASED NATURAL HISTORY
Authors: Acquaye Alvina , Vera Elizabeth , Christ Alexa , Wall Kathleen , Gilbert Mark , Armstrong Terri
Published: November 2022

INTRODUCTION

A cancer diagnosis can diminish the sense of control and confidence that is essential for self-management of disease-related factors. Perceived control in coping effectively with the negative effects of a diagnosis has been correlated with improved mood, self-regulation, and decreased symptom distress. We looked at the relationship between self-efficacy in managing emotions (SEMEM) and symptom burden and mood-related interference (REM) in patients with rare CNS tumors.

METHODS

Adult patients (n=166) completed an online survey capturing demographic/clinical characteristics, symptom burden and REM (mood, relations with others, enjoyment of life, scores³ 2= moderate-severe(M-S)) from the MDASI-BT & MDASI-SP and PROMIS SEMEM (t-scores: low=< 40, high > 60).

RESULTS

Evaluated patients (74% female) had a median age of 45 (19-75). Ependymoma was most common (66%). The time from initial symptoms and surgery was 1-4 years. Low SEMEM was identified in 13%. SEMEM decreased as REM worsened in both locations (Brain: r= -0.61; Spine (r= -0.28). Most brain patients reporting low SEMEM also endorsed M-S REM (93%). Top M-S symptoms among brain patients associated with each SEMEM level included: feeling distressed, sadness, and fatigue. Low SEMEM correlated with a longer time to presenting symptoms among brain patients (r= -0.26) and lower education among spine patients (r=0.29). Interestingly, sex (women 92%) among brain patients was associated with low SEMEM, while high SEMEM patients were more likely to be married (82%). Spine patients not currently on treatment reported high SEMEM.

CONCLUSION

We found that patients' confidence in managing emotions worsened with severe mood-related interference. Low self-efficacy was linked to prolonged time between symptoms and initial surgery, education, and gender while treatment and marital status were associated with high self-efficacy. Identifying characteristics associated with self-efficacy can lead to targeted behavioral interventions mitigating distress in adjusting to one’s disease.
NCOG-37. MICROSTRUCTURAL CEREBELLAR INJURY IS ASSOCIATED WITH PROCESSING SPEED DECLINE IN ADULTS WITH PRIMARY BRAIN TUMORS: IMPLICATIONS FOR COGNITIVE PRESERVATION
Authors: Salans Mia , Karunamuni Roshan , Unnikrishnan Soumya , Qian Alex , Connor Michael , Gudipati Suma , Yip Anthony , Huynh-Le Minh-Phuong , Tibbs Michelle , Reyes Anny , Stasenko Alena , Schadler Adam , McDonald Carrie , Hattangadi-Gluth Jona
Published: November 2022

PURPOSE

We investigated associations between imaging biomarkers of cerebellar injury and neurocognitive function among primary brain tumor patients receiving partial brain radiotherapy (RT).

METHODS

On a prospective trial, 65 patients underwent volumetric brain MRI, diffusion tensor imaging, and memory, executive function, language, attention, and processing speed (PS) assessment pre-, 3, 6, and 12 months post-RT. Delis-Kaplan Executive Function System Trail Making [DKEFS-TM] Visual Scanning and Number and Letter Sequencing and Wechsler-Adult Intelligence Scale-IV [WAIS] Coding subtests evaluated PS. Cerebellar regions of interest (ROIs) were autosegmented, including cortex and white matter (WM). Supratentorial cortical and WM structures subserving the above cognitive domains were also autosegmented. Supratentorial PS-associated ROIs included the posterior, mid-posterior, central, mid-anterior, and anterior corpus callosum along with the bilateral intrahemispheric WM. Volume (cm3) was measured in all ROIs at each timepoint. Diffusion biomarkers (fractional anisotropy [FA] and mean diffusivity [MD]) were measured in all WM structures at each timepoint. Linear mixed-effects models assessed cerebellar biomarkers as predictors of neurocognitive scores. If found to be associated, cerebellar biomarkers were subsequently evaluated as predictors of cognitive scores controlling for domain-specific supratentorial ROI biomarkers.

RESULTS

Left (p=0.04) and right (p< 0.001) cerebellar WM volume declined over time. Cerebellar biomarkers were not associated with memory, executive function, or language. Left cerebellar cortex atrophy correlated with worse DKEFS-TM Number (p=0.01) and Letter (p=0.01) Sequencing scores. Right cerebellar cortex atrophy correlated with worse DKEFS-TM Visual Scanning (p=0.02) and Number (p=0.03) and Letter (p=0.02) Sequencing scores. Greater right cerebellar WM MD correlated with worse DKFS-TM Visual Scanning performance (p=0.03). These associations remained significant after controlling for corpus callosum and intrahemispheric WM injury biomarkers.

CONCLUSION

Biomarkers of cerebellar injury correlated with worse post-RT PS, independent of corpus callosum and intrahemispheric WM damage. Cerebellar dose avoidance may preserve PS.
NCOG-42. THE IMPACT OF PER2 POLYMORPHISMS ON THE EXPRESSION OF SLEEP AND ACTIVITY IN A NOVEL MOUSE MODEL OF CRANIAL-IRRADIATION-INDUCED HYPERSOMNOLENCE (C-RIH)
Authors: Adegbesan Kendra , Ardori Francesco Tomassoni , Yanpallewar Sudhirkumar , Briceno Nicole , King Amanda , Tessarollo Lino , Gilbert Mark , Smart DeeDee , Armstrong Terri , Shuboni-Mulligan Dorela
Published: November 2022

Chronic daytime sleepiness, or hypersomnolence, is one of the most common and disruptive side effects of cranial radiotherapy and is associated with disturbances in mood and cognition in primary brain tumor patients. Our laboratory previously found that increased minor allele presence of the PERIOD2 (PER2) polymorphism (rs934945, G-E mutation) correlated with a decreased likelihood of hypersomnolence in PBT patients. PER2, a key molecular component of the circadian clock, assists in the generation and maintenance of daily sleep/wake rhythms. We aim to understand the effects of this PER2 polymorphism on radiation sensitivity within our previously established mouse model of cranial-irradiation-induced hypersomnolence (C-RIH). Five cohorts of male/female transgenic mice were generated using CRISPR-Cas9, replacing the endogenous mouse CRY binding domain with one of two polymorphic variants within the human genome (G-E and conventional Per2h23). General activity and sleep were monitored continuously over 10 days before and after therapeutic irradiation (whole brain, 15Gy, single fraction). Independent samples t-tests compared knock-in groups and species variants. During the active phase, G-E knock-in mice showed less radiation-induced suppression of activity (-7% males; -20% females) relative to Per2h23 knock-ins (-18% males; -36% females). For rest, both male and female G-E mice (+4% males; +16.4% females) expressed less radiation induced sleep during their active phase than Per2h23 mice (+7% males; +27.7% females). However, this pattern did not rise to significance. Current experiments will expand the numbers of mice used in each group to further explore these initial patterns. Understanding the genetic markers that predict radiation sensitivity could help generate more patient specific methods to mitigate these negative behavioral outcomes. Our mouse models provide a platform to introduce polymorphisms and test their impact on treatment-related symptoms.
NCOG-46. PERSONALIZED, PARCEL-GUIDED RTMS FOR NEURO-REHABILITATION AFTER TUMOR NEUROSURGERY: SAFETY AND PROOF OF CONCEPT
Authors: Yeung Jacky , Tang Jessica , Holle Jonas , Teo Charles , Sughrue Michael
Published: November 2022

Deficits in neurological and psychocognitive function are common for patients who have undergone surgical removal of primary tumors. Repetitive Transcranial Magnetic Stimulation (rTMS) is an emerging non-invasive tool used for the treatment of neuropsychiatric disorders. We present a retrospective review of individualized, targeted rTMS in thirteen patients who presented with post-operative neurological deficits following craniotomy for tumor resection. Multiple cortical targets were selected based on the patient’s neurological disorder, the networks associated with the deficit, and anomalies in the functional connectivity of the patient’s brain as determined by machine-learning. TMS treatment was performed for 5 consecutive days. EuroQol quality of life (EQ-5D), functional extremity scales, and neuropsychiatric questionnaires related to the patient’s deficit were assessed prior to rTMS treatment, after treatment, and during follow-up. Five patients (38.5%) had glioblastomas; four patients (30.8%) had oligodendrogliomas; two patients (15.4%) had astrocytoma; one patient (7.7%) had ganglioglioma; and one patient (7.7%) had a pineal cyst. All thirteen patients reported significantly improved quality of life after rTMS treatment (p = 0.0065) and during follow-up (p = 0.0038) as compared to baseline. For patients with functional deficits, lower extremity functional scale (LEFS) was significantly improved one week after rTMS treatment (p = 0.0205). Upper extremity function scale (UEFS) showed non-significant trend in improvement after rTMS treatment (p = 0.0777). In the two patients who developed post-craniotomy depression, they showed a 26% and 88% reduction in depressive symptoms based on the Beck’s Depression Inventory (BDI) at two-month follow-up. These results suggest that the personalized, functional connectivity approach to rTMS target and treatment may be effective for patients with post-craniotomy functional impairments and neuropsychiatric disorders. This method of post-operative interventional neuro-rehabilitation is safe, noninvasive, and allows for the simultaneous treatment of multiple symptoms.
EXTH-03. HSP90 INHIBITION OVERCOMES RESISTANCE TO MOLECULAR TARGETED THERAPY IN BRAFV600E MUTANT HIGH-GRADE GLIOMA
Authors: Tateishi Kensuke , Sasame Jo , Naoki Ikegaya , Natsumeda Manabu , Kawazu Masahito , Wakimoto Hiroaki , Cahill Daniel , Yamamoto Tetsuya
Published: November 2022

INTRODUCTION

Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E mutant high-grade gliomas (HGGs); however, the therapeutic effect is limited by the emergence of drug resistance.

METHODS

We established multiple paired BRAFV600E mutant HGG patient-derived xenograft (PDX) models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo.

RESULTS

We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the re-activation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3β (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular-targeted therapy.

CONCLUSIONS

The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E mutant HGG.
EXTH-04. PATIENT-DERIVED CELLS FOR EX VIVO DRUG SCREENING STUDIES OF GLIOMAS
Authors: El-Heliebi Amin , Urbanic-Purkart Tadeja , Mahdy-Ali Kariem , Skofler Christina , Gerlitz Lisa , Stanzer Stefanie , Franz Joakim , Harbusch Nora , Madl Tobias , Widhalm Georg , Rössler Karl , Tomberger Martina , Mattersdorfer Karin , Kroneis Thomas , Oberhuber Monika , Pieber Thomas , Prietl Barbara
Published: November 2022

BACKGROUND

In precision oncology ex vivo drug screening systems have the potential to improve clinical outcomes. Traditionally, cancer drugs are tested on cancer cell line models, but these cannot represent an individual patient and are biologically too distinct. Drug screening systems usually rely on viability assays and correlations to genomic alterations. Beside genomic alterations, the cellular metabolism is significantly altered which may lead to drug resistance. Here we aim to establish a drug screening platform using tumor cells derived directly from the individual patient glial tumor tissue, create patient derived tumor cells (PDCs) and combine the outcomes from standardized viability- and genetic-assays with a new developed metabolomics platform. Materials and

METHODS

Fresh native tissue from patients harbouring low- and high-grade glioma are collected (n=46). Tumor tissue used for NMR-based metabolomic analyses and targeted sequencing analyses as well as PDC isolation. To preserve the original tumor similarity, tissue is short term cultured for two weeks, and PDCs are seeded and treated with a panel of clinical- and preclinical drugs followed by viability assessment, sequencing and metabolomic profiling.

RESULTS

Culturing of PDCs is successful in ≥ 85% of patient cases, provided that at least 2 g of tumor tissue is available. The automatized high throughput ex vivo drug response identifies drug candidates, which might become relevant for therapeutic approaches in future. It is possible to distinguish between IDH1-wild-type and IDH1-mutant tumors based on the metabolomic profile, which is confirmed by immunohistochemical staining and molecular analysis of IDH1 R132H-mutation. Strong metabolomic variations have been identified, including GABA, lactate, and myo-inositol levels between tumor and healthy tissue.

CONCLUSION

Entangling drug screening and genetic assays with metabolomic profiling of glial tumors enriches the information about cellular drug response and paves the way for future clinical studies and better understanding of underlying drug resistance mechanisms in gliomas.
EXTH-06. PRE-INFUSION METABOLIC MODULATION OF CAR-T CELLS PROMOTES THE RESISTANCE TO THE SUPPRESSIVE EFFECTS OF HYPOXIA AND ENHANCES ANTI-TUMOR EFFECTS AGAINST INTRACEREBRAL GLIOMAS
Authors: Hatae Ryusuke , Kyewalabye Keith , Yamamichi Akane , Chen Tiffany , Chuntova Pavlina , Okada Hideho
Published: November 2022

Effective immunotherapy for glioma has not yet been established. We have found the energy metabolic status of immune cells within the tumor microenvironment is remarkably different between intracerebral and extracranial tumors. In mice bearing intracerebral SB28-EGFRvIII gliomas with intravenous infusion of EGFR vIII-targeting CAR-T cells, we found that mitochondrial markers in tumor-infiltrating T cells were down-regulated compared to those in splenic T cells. Therefore, we hypothesized that the treatment of CAR-T cells with a metabolic regulator that activates mitochondria before infusion would improve the therapeutic effect of CAR-T cells. Using a hypoxic incubator to mimic the tumor microenvironment of brain tumors, we screened drugs that would improve the metabolic state of CAR-T cells and sustain their anti-tumor effect. We have found that, although the mammalian target of rapamycin (mTOR) inhibitor rapamycin and AMP-activated protein kinase (AMPK) activator metformin are ineffective when administered as single drugs, the combined use of these drugs (met+rap) prolongs the anti-glioma effect of CAR-T cells under hypoxic conditions. A single intravenous infusion of CAR-T cells that were pre-treated with met+rap significantly prolonged the survival of mice bearing intracerebral SB28-EGRFvIII tumors compared with CAR-T cells without the pre-infusion treatment. Met+rap-treated CAR-T cells infiltrated the intracerebral tumor more effectively and maintained their functions better than the control CAR-T cells, suggesting that the met+rap treatment conferred CAR-T cells with abilities to traffick and function in the severe microenvironment of brain tumors. Importantly, because the CAR-T cells were pre-treated with the drugs during the in vitro expansion only but without drug administrations in vivo, this strategy would circumvent any toxicity associated with in vivo treatments with the same drugs. These data suggest that the treatment of CAR-T cells during the in vitro expansion with the two drugs may improve the efficacy of CAR-T cell therapy for brain tumors.