bluuebunny/crossref_metadata_2025 huggingface dataset:
NIMG-101. COMPARISON OF PRE-SURGICAL MRI FINDINGS FROM LONG-TERM (≥ 3 YRS) VERSUS SHORT-TERM (< 3 YRS) GLIOBLASTOMA SURVIVORS: A BLINDED, CASE-CONTROL REVIEW
Authors: Komlodi-Pasztor Edina , Briceno Nicole , Vera Elizabeth , Choi Anna , Christ Alexa , Grajkowska Ewa , Leeper Heather , Lindsley Matthew , Wall Kathleen , Evans Karen , Kunst Tricia , Mentges Kelly , Reyes Jennifer , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Wu Jing , Polskin Lily , Armstrong Terri , Gilbert Mark , Smirniotopoulos James
Published: November 2022

BACKGROUND

The median overall survival of patients with glioblastoma (GBM) is 10-12 months and the five-year survival ranges from 5-10%. Favorable clinical and molecular prognostic markers have been described in the literature, although an individual patient’s prognosis cannot easily be predetermined on these features as shown in the NOB-LTS project by Briceno et al. (SNO 2021). Until now, no radiologic characteristics have been correlated with better patient outcomes. We reviewed eighteen MRI features to determine if these could aid the identification of long-term survivors (LTS).

METHODS

From the NOB-LTS cohort of our Natural History Study, 16 long-term survivals (LTS; ≥ 3 years survival post-diagnosis) were matched based on sex, age, and extent of resection to 32 control (STS, < 3 years survival post-diagnosis) patients with NGS-confirmed IDH-wt glioblastoma. Pre-surgical MRIs (T1, T1 post-contrast, T2, T2/FLAIR, DWI, ADC) were reviewed by three blinded reviewers and analyzed based on pre-set criteria.

RESULTS

T1 hypointensity occurred commonly in the LTS (71%) vs STS (29%) while central heterogeneous signal occurred commonly in the STS (73%) vs LTS (50%) patients. Restricted diffusion was seen in 82% of STS and 70% of LTS cases. No difference was seen in irregular enhancement, peripheral and grey matter enhancement on T1 post-contrast images. Evaluation of T2/FLAIR images showed no difference in the number of lobes involved, presence of mass effect, heterogeneity of the signal or the perilesional signal abnormality or involvement of grey matter.

CONCLUSION

Our results suggest that pre-surgical MRI might be a useful prognostic tool as T1 hypointensity more frequently, and T1 central heterogeneity less commonly seen in the LTS group. These imaging findings may provide additional insights regarding the differences in tumor biology between LTS and STS. Further validation and correlation with histological/molecular characteristics are planned to better predict patient outcomes with newly diagnosed glioblastoma.
NCMP-01. CEREBRAL ANGIOSARCOMA AND DISTANT RADIATION THERAPY
Authors: Frontario Ariana , Bazer Danielle , Kowalska Agnieszka
Published: November 2022

Angiosarcoma is a rare malignant tumor originating from vascular endothelial cells. Typically, the diagnosis of angiosarcomas carry poor prognosis. Radiation exposure is one of the most common risk factors for angiosarcomas. Due to the rarity of angiosarcoma, there is sparse literature, hence it is mostly seen in case reports. We describe a case of cerebral angiosarcoma with an unknown primary malignancy in a patient with distant history of non-Hodgkin’s lymphoma treated with chemotherapy and radiation therapy to the thorax. A 54 year old male with a history of Non-Hodgkin’s Lymphoma was treated with ABVD chemotherapy and thoracic radiation therapy in 1995,presented for bilateral vision loss. Neurologic examination revealed a left homonymous hemianopia .Further investigation with brain Magnetic Resonance Imaging revealed hemorrhagic lesions in the bilateral frontal and in the right parietal-occipital lobes. Computed tomography of the chest, abdomen, and pelvis was negative for malignancy. The patient underwent a right occipital craniotomy with resection of right parietal occipital lesion. Histopathology revealed metastatic angiosarcoma. It has been acknowledged that exposure to external beam radiotherapy puts patients at risk for angiosarcoma in the future. It is believed that radiation may induce the development of AS by several mechanisms. One mechanism is the direct oncogenic effect of ionizing radiation, which can damage DNA, leading to genome instability and mutation of cancer-related genes. A prior literature review noted twenty cases of angiosarcoma developing following therapeutic irradiation. Our particular patient’s prior exposure to irridation did not include a brain radiation field, so it is unlikely this patient had radiation induced angiosarcoma.Furthermore, it does not appear that his prior radiation exposure explains the location of his angiosarcoma as his radiation field was localized to chest. Although angiosarcoma is rare, it deserves further investigation to increase the knowledge base on etiology of metastasis.
NCMP-06. VENOUS THROMBOEMBOLISM INCIDENCE AND THE IMPACT OF PRE-DISEASED ANTICOAGULATION THERAPY IN GLIOBLASTOMA PATIENTS
Authors: Sloan Anthony , Elder Theresa , Desai Ansh , Wu Anna , Choi Serah , Sloan Andrew
Published: November 2022

Glioblastoma (GBM) patients have a 24-30% risk of developing venous thromboembolism (VTE), including deep vein thrombosis or pulmonary embolism, over the course of their diagnosis. However, very little data exists regarding the impact of VTE on survival in GBM patients, with or without anticoagulation. This study aimed to investigate 1) the demographic factors associated with VTE incidence in GBM patients, 2) any correlation between VTE incidence and length of survival and, and 3) the impact of pre-diagnosis antiplatelet/anticoagulation therapy on VTE development and survival. A total of 150 GBM patients treated at University Hospital Seidman Cancer Center were included and retrospectively analyzed. Information was collected regarding history of aspirin, clopidogrel, DOAC, heparin, and/or warfarin use. The diagnosis of VTE both prior to GBM diagnosis and at various time points following diagnosis was determined followed by calculating overall survival and progression free survival (PFS). Of the 150 GBM patients, 53 (35.3%) developed a VTE overall. VTE incidence correlated with a lower KPS at presentation (r = -.225, p =.027) and a decrease in overall survival among GBM patients (r = -.191, p =.041). Antiplatelet/anticoagulation therapy prior to GBM diagnosis correlated with decreased VTE formation overall, as well as longer PFS among non-VTE patients (r =.261, p = .026) but not among patients who later developed VTE (r = .165, p = .302). Our findings demonstrate that patients with lower KPS are at a higher risk for developing VTE. Among GBM patients who did not develop VTEs, those on antiplatelet/anticoagulation therapy prior to diagnosis had longer PFS compared to those who were not on anticoagulants. These preliminary studies highlight the need for better VTE prophylaxis and therapy among GBM patients. These results further suggest the potential benefit of anticoagulation therapy in GBM patients irrespective of VTE formation.
NCOG-03. IMPACT OF THE RATE OF RADIOGRAPHIC RESPONSE (RR) OF BRAIN METASTASES (BM) TO WHOLE BRAIN RADIATION THERAPY (WBRT) ON NEUROCOGNITIVE FUNCTION (NCF) ON NRG-CC001
Authors: Devisetty Kiran , Pugh Stephanie , Brown Paul , Gondi Vinai , Wefel Jeffrey , Solanki Abhishek , Kalapparambath Tomy , Harmon Grant , Saripalli Anjali , Chou Brian , Venkatesulu Bhanu Prasad , Boike Thomas , Kundapur Vijayananda , Roberge David , Bovi Joseph , McGee Mackenzie , Kruser Tim , Baschnagel Andrew , Usuki Kenneth , Mehta Minesh , Kachnic Lisa
Published: November 2022

BACKGROUND

The assessment of BM response to WBRT and its impact on NCF in clinical trials has been limited by lack of standardized imaging protocols. NRG-CC001 is a randomized clinical trial requiring pre-specified MRI protocols at baseline and 6-months, providing a uniform dataset to investigate if RR correlates with NCF changes.

METHODS

NRG-CC001 randomized patients with BM to hippocampal avoidance WBRT (HA-WBRT) or WBRT. NCF was analyzed using 6-month standardized change scores and deterioration, defined using the reliable change index. Chi-square and t-tests were used for pretreatment characteristic comparisons. Inter-rater reliability between central and institutional assessment of RR was assessed with weighted kappa, κ. Linear regression was used to test trends in NCF change scores across types of response and multivariable logistic regression was used to test the association of RR to NCF deterioration.

RESULTS

149 and 135 patients were evaluable for RR and NCF assessment, respectively. Pretreatment characteristics were well-balanced, except for post-high school education (70.6% HA-WBRT vs. 52.5% WBRT, p=0.023). Inter-rater reliability between central and institutional assessment of RR was fair (κ=0.36). There was no difference between arms in RR (p=0.41) with overall rates of 14.1% CR, 42.2% PR, 17% SD, and 26.7% PD. Patients with CR had improved 6-month NCF change as measured by HVLT-R Total Recall (p=0.0005), HVLT-R Delayed Recall (p=0.0003), HVLT-R Delayed Recognition (p=0.011), TMT-B (p=0.033), COWA (p=0.016), and Clinical Trial Battery Composite score (p=0.0011). Multivariable analysis demonstrated less deterioration in HVLT-R Delayed Recall for CR (p=0.019) and PR (p=0.0086) vs. SD/PD and HVLT-R Recognition for PR (p=0.031) vs. SD/PD.

CONCLUSIONS

HA-WBRT and WBRT result in similar RR at 6-months. CR or PR is associated with better NCF preservation. This suggests investigation into treatment escalation for patients with SD/PD may provide further NCF benefit along with HA-WBRT and memantine.Grant support from NCI-UG1CA189867 and U24CA180803.
NCOG-07. SURVIVAL BENEFIT OF RADIOTHERAPY AND SURGERY IN PATIENTS WITH LUNG CANCER BRAIN METASTASES WITH POOR PROGNOSIS FACTORS: A SINGLE-CENTER, RETROSPECTIVE, PROPENSITY SCORE MATCHING ANALYSIS
Authors: Liang Lun , Wang Zhenning , Duan Hao , Lu Jie , Jiang Xiaobing , Cui Run , Li Chang , Zhong Sheng , Guo Xiaoyu , Hu Hongrong , He Zhenqiang , Chen Likun , Mou Yonggao
Published: November 2022

PURPOSE

To investigate the effect of radiotherapy and surgery in patients with lung cancer brain metastases (BMs) with poor prognosis factors.

METHODS

We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model.

RESULTS

Age ≥ 65 years, Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy led to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥ 65 years and pretreatment KPS score ≤ 70 before and after PSM. Before PSM,whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in non-surgery patients. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy.

CONCLUSIONS

Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy.
NCOG-45. DIFFERENTIAL AND DOSE-DEPENDENT EFFECTS OF CRANIAL IRRADIATION ON BRAIN STRUCTURES AND NEUROPSYCHOLOGICAL OUTCOMES IN CHILDREN WITH POSTERIOR FOSSA BRAIN TUMORS TREATED WITH DIFFERENT MODALITIES
Authors: Dhanani Sofia , O'Neil Sharon , Cho Scarlet , Shin Brandon , Nelson Marvin , Wong Kenneth , Olch Arthur , Tanedo Jeffrey , Biele Oliver , Rodman Jack , Lepore Natasha , Nelson Mary
Published: November 2022

BACKGROUND

Studies investigating dose-dependent effects of cranial irradiation (CRT) in children with posterior fossa brain tumors are limited by examining combined effects of surgery, chemotherapy, and radiation. We aimed to determine alterations in brain volume and microstructure, and neuropsychological outcomes in children with posterior fossa tumors treated with surgery alone, surgery and chemotherapy, and surgery, chemotherapy, and CRT combined. We explored the relationship of radiation dose to the thalamus, putamen, and hippocampus to outcomes of intelligence, processing speed, executive functions, memory, and social/emotional functioning.

METHODS

Forty-seven children with treated posterior fossa tumors (17 with surgery; 11 with surgery and chemotherapy; 19 with surgery, chemotherapy, and CRT) underwent neuroimaging and neuropsychological assessment a mean of 4.8 years after treatment, along with 17 healthy sibling controls (n=64). The putamen, thalamus and hippocampus were manually segmented on MRI, and structural mean radiation doses were calculated. Differences in demographics and medical history were evaluated using χ2 and t-tests. Linear regression examined differences in neuropsychological performance, structural volumes, and diffusion indices. Pearson correlation explored relationships of structural radiation doses to diffusion indices and neuropsychological outcomes.

RESULTS

All patients scored lower on Block Design than controls (p=0.01), and the surgery and chemotherapy group scored the lowest. There was no significant difference in mean fractional anisotropy (FA) values in the thalamus, hippocampus and putamen between the three patient groups and controls. Hippocampal volume and mean radiation dose approached significant correlation (r= -0.49; p=0.07). Right putamen FA correlated with mean radiation dose (r=0.56; p=0.02). When controlling for age, thalamic volume was lowest in the irradiated group (p=0.02).

CONCLUSIONS

Treatment of pediatric posterior fossa brain tumors with surgery, chemotherapy, and CRT impacts thalamic volume and may have a dose-dependent effect on the microstructure of the putamen compared to treatment with surgery/chemotherapy.
EXTH-32. SEQUENTIAL SUNITINIB AND AURANOFIN TREATMENT INDUCEDCYTOTOXICITY THROUGH ROS-MEDIATED MECHANISM IN GLIOBLASTOMA
Authors: Bagchi Monisha , Jamali Fatemeh , Martinez-jaramillo Elvis , Sabri Siham , Abdulkarim Bassam
Published: November 2022

Glioblastoma (GBM) displays aberrant expression of several receptor tyrosine kinases (RTKs) leading to worse prognosis. Despite aggressive treatment including surgery, radiation and the alkylating agent temozolomide (TMZ), GBM tumors counteract deleterious effects of treatment-induced reactive oxygen species (ROS) leading to resistance to standard treatment. Likewise, expression of the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) plays a key role in resistance to TMZ.We previously reported a potential link between MGMT expression and decreased angiogenesis in GBM. The differential expression of MGMT affected response to sunitinib, a multitargeted RTK inhibitor with anti-angiogenic properties FDA-approved in different cancer types. Notably, TMZ-resistant GBM MGMT-positive cells were more vulnerable to sunitinib treatment compared to isogenic MGMT-negative cells. We further provided evidence for a positive relationship between MGMT and the antioxidant enzyme, thioredoxin reductase 1 (TrxR1) in GBM. The TrxR1-targeting drug Auranofin, FDA-approved for rheumatoid arthritis generated ROS and induced more cytotoxic effects in GBM cells displaying low expression of MGMT and TrXR1. We hypothesized that sunitinib-induced anti-proliferative effects might sensitize GBM cells to Auranofin. We showed that MGMT-negative GBM cells, which displayed lower levels of TrxR1, were more vulnerable to Auranofin than MGMT-positive cells. The ROS scavenger N-acetylcysteine (NAC) reverted the cytotoxicity of Auranofin suggesting ROS-mediated cytotoxic effects. Conversely, Sunitinib exhibited ROS-independent anti-proliferative effects in MGMT-positive cells. Remarkably, sequential treatment using sunitinib pre-treatment (2 hours) followed by Auranofin (24 hours) significantly decreased cell viability, clonogenicity, increased ROS, decreased TrXR1 and MGMT expression and sensitized MGMT-positive GBM cells resistant to Auranofin. NAC reverted these synergistic effects, suggesting ROS-mediated mechanism. Our study provides new insights into the modulation of the cellular redox homeostasis using sequential sunitinib and Auranofin. This will enable repurposing Auranofin and sunitinib, two drugs with a known safety profile for an effective therapeutic strategy for GBM patients.
EXTH-34. ANTI-RETROVIRAL REPURPOSING FOR TREATMENT OF GLIOBLASTOMA
Authors: Rivas Sarah , Govindarajan Vaidya , Valdez Mynor Mendez , Heiss John , Shah Ashish
Published: November 2022

Glioblastoma (GBM) is a WHO grade IV glioma whose heterogeneous nature and stem-like features contribute to resistance to conventional chemotherapeutics. Previously, antiretrovirals have been proposed as anti-neoplastic agents, but their clinical efficacy is limited. With the advent of modern anti-retroviral and combinatorial therapy, we sought to repurpose FDA-approved anti-retroviral drugs for glioblastoma. Here, we performed an unbiased screen of 16 antiretrovirals in 40 glioma cell lines using DEPMap for drug repositioning. We identified six potential antiretrovirals among several drug classes with significant anti-glioma activity: abacavir (ABC), lamivudine (LMV), raltegravir (RLT), darunavir (DAR), indinavir (IND), and etravirine (ETV). We validated the effects of six antiretrovirals on patient-derived GBM neurospheres (GBM28 and GBM43) and established glioma cell line (A172). The non-nucleoside reverse transcriptase inhibitor (ETV) had the lowest effective IC50 in chemoresistant PDX GBM neurospheres (15uM) and A172 cells (2.7uM). Synergy assessment of ETV with standard of care temozolomide (TMZ) demonstrated that these drugs work independently of one another (Bliss score of -0.39 and -0.83 in GBM 28 and GBM 43, respectively). In addition, we investigated ETV effect on stemness features and human endogenous retroviral elements. Western blot, immunofluorescence and qPCR showed a decrease in the stemness markers, OCT-4, and HERV-K env expression. Reverse transcriptase levels decreased significantly after sublethal ETV treatment (5uM) for 48 hours in the stem-like GBMNS but not in adherent A172 cells. Overall, several antiretroviral drugs could be repositioned for glioblastoma therapy. Given its ideal therapeutic index and ability to penetrate the blood-brain barrier, ETV may be a promising candidate for future clinical trials in neuro-oncology.
EXTH-60. ONCR-GBM, A NOVEL ARMED ONCOLYTIC HSV-1 VECTOR ENGINEERED FOR EFFICACY AND SAFETY IN GLIOBLASTOMA
Authors: Strathdee Craig , Giovannoni Federico , Molgora Martina , Kong Lingxin , Floyd Michael , Teng Jian , Gyulakian Yulia , Grzesik Peter , Farkaly Terry , Denslow Agnieszka , Feau Sonia , Jacques Judith , Kennedy Edward , Lerner Lorena , Quéva Christophe , Colonna Marco , Quintana Francisco
Published: November 2022

Glioblastoma (GBM) is the most common type of primary brain tumor in adults, with a 5-year overall survival of only 7%. Oncolytic viruses are a promising and active area of research in GBM with the recent approval of an oncolytic HSV-1 vector, teserpaturev (Delytact, also known as G47Δ, Daiichi Sankyo) for recurrent GBM based on an overall survival of 92% at 1 year. G207, an HSV-1 vector more attenuated than teserpaturev, recently reported acceptable tolerability with evidence of responses in children with recurrent or progressive high-grade glioma. These vectors are not expressing any cDNA transgene that may enhance and prolong antitumor activity. We report here the development of ONCR-GBM, an oncolytic HSV-1 vector specifically engineered for safety using a microRNA attenuation strategy to limit viral replication in healthy cell type of the CNS. ONCR-GBM has been developed from a novel potently oncolytic strain of HSV-1 and optimized for infection of GBM tumor cells. Antitumor efficacy has been further enhanced through the expression of multiple payloads designed to modify the immunosuppressive tumor microenvironment of GBM. We previously reported that a vector expressing IL-12 and a PD-1 antagonist nanobody achieved > 90% survival after a single injection in the GL261-Nectin1 orthotopic model. This vector promoted immune cell recruitment and activation in tumors and protected surviving animals from a subsequent tumor rechallenge. Additional payloads selected for interfering with the immune suppressive stroma in GBM have been evaluated for potentiating the response of IL-12 and anti PD-1 expressing HSV-1. We will present the outcome of the in vivo screen, and the selection of the optimal combination of payloads featured in ONCR-GBM clinical candidate.
EXTH-69. ASTROCYTOMA CELLS HARBORING MUTANT IDH1 ARE UNIQUELY SENSITIVE TO INHIBITION OF OXIDATIVE PHOSPHORYLATION
Authors: Gurjar Anagha , Colman Howard , Holmen Sheri
Published: November 2022

BACKGROUND

Diffuse gliomas are the most common primary brain tumor in adults, affecting ~20,000 people in the United States each year. Current treatment modalities, which include surgery, radiation, and chemotherapy, are relatively ineffective against these tumors and the prognosis is poor. Although most cancer cells rely on glycolysis to generate ATP, IDH1 mutant gliomas show enhanced dependence on oxidative phosphorylation. Thus, we evaluated the effect of IACS-010759, a potent and selective inhibitor of complex I that interferes with cellular respiration, in multiple patient-derived glioma cells.

METHODS

In the present study, we used six different patient-derived glioma cell cultures including four that are IDH1 wild type (wt) (GSC 20, GSC 23, LN 18 and SF 268) and two that are IDH1R132H mutant (BT142 & 21238-IDH1R132H). All cells were cultured as neurospheres to maintain glioma stem cell (GSC) culture conditions. The toxicity of IACS-010759 was also evaluated in immortal non-transformed mouse astrocytes. Neurospheres and astrocytes were treated with IACS-010759 (0.1 µM-100 µM) and cell viability was evaluated after 72 hours using CellTiter-Glo.

RESULTS

Inhibition of oxidative phosphorylation significantly reduced cell proliferation in all glioma cells evaluated. The IC50 of IACS-010759 ranged from 0.7 nM-100 µM but was lowest in IDH1R132H astrocytoma cells, supporting the hypothesis that IDH1 mutant astrocytoma cells have enhanced dependence on oxidative phosphorylation. Importantly, immortal, non-transformed astrocytes were relatively resistant to IACS-010759 suggesting that this strategy may have an effective therapeutic window in this disease.

CONCLUSION

In summary, IACS-010759-induced inhibition of oxidative phosphorylation elicited pronounced anti-neoplastic responses in vitro, especially in astrocytomas expressing mutant IDH1. IACS-010759 may be a promising therapy for both IDH1 wt and mutant gliomas, and we are currently evaluating the efficacy of this strategy in glioma mouse models.
EXTH-86. BH3 PROFILING IDENTIFIES ONC201/TIC10 AS A PROMISING PARTNER OF ABT-263 IN MEDULLOBLASTOMA IN VITRO
Authors: Spilz Antonia , Hajosch Annika , Seyfried Felix , Peraud Aurelia , Prabhu Varun V , Allen Joshua E , Westhoff Mike-Andrew , Siegelin Markus , Wirtz Christian Rainer , Karpel-Massler Georg
Published: November 2022

OBJECTIVE

Medulloblastoma represents one of the most common brain tumors in children. In this study, we identified by BH3 profiling that ONC201/TIC10 sensitizes for Bcl-xL/Bcl-2 inhibition in medulloblastoma and performed a preclinical testing of a combined treatment with ONC201/TIC10 and the Bcl-xL/Bcl-2 inhibitor ABT-263.

METHODS

BH3 profiling was performed to examine ONC201/TIC10-mediated dependencies on anti-apoptotic Bcl-2 family proteins. The combination treatment with ONC201/TIC10 and ABT-263 was tested in different medulloblastoma cells using MTT assays. Isobolograms were calculated to characterize the drug-drug interaction. Tumor spheroid and chorioallantoic membrane assays were used to examine the effects of the combination therapy in a 3D setting. Annexin V/PI staining and flowcytometry were used to detect pro-apoptotic effects. Western blot analyses and knockdown experiments with siRNA were performed for molecular analysis. Extracellular flux analyses served at examining effects on the tumor cell metabolism.

RESULTS

BH3 profiling showed that ONC201/TIC10 sensitizes medulloblastoma cells to Bcl-xL/Bcl-2 inhibition. In line with this finding, combined treatment with ONC201/TIC10 and ABT-263 led to a predominantly synergistic inhibitory effect on the cell viability of established (D425, D458, DAOY, HD-MB03), primary cultured (PC322) and stem-like (SC322) medulloblastoma cells in 2D and 3D models. The response towards the combination therapy was independent of baseline c-myc expression. On the molecular level, treatment with ONC201/TIC10 led to a dose-dependent decrease of Mcl-1. Moreover, the combination caused enhanced cleavage of caspases 9 and 3. On the metabolic level, the combination therapy led to a reduction in both, oxidative phosphorylation and the glycolytic rate and a reduced expression of respiratory chain proteins.

CONCLUSION

Combined treatment with ONC201/TIC10 and ABT-263 had a predominantly synergistic inhibitory effect on the cell viability of medulloblastoma cells. This effect was associated with downregulation of Mcl-1. Moreover, the combination treatment resulted in a metabolic reprogramming which likely creates a state of energy deprivation.
QLTI-08. SURVEY OF CANADIAN NEURO-ONCOLOGY CLINICIANS ABOUT THE TREATMENT OF ADULT MEDULLOBLASTOMA
Authors: Climans Seth , Cacciotti Chantel , Lim-Fat Mary Jane
Published: November 2022

BACKGROUND

Given the rarity of medulloblastoma in adults (fewer than 50 incident cases annually across Canada), the optimal chemotherapy strategy in this population is unknown. The management of adult medulloblastomas is thought to vary from institution to institution. Guidelines often omit suggestions for specific chemotherapy regimens, reflecting the lack of high quality evidence in this population. We sought to understand Canadian adult medulloblastoma practice patterns, hoping to inform future quality metrics and guidelines.

METHODS

In March 2022 a 30-question survey was sent out to 71 adult neuro-oncology clinicians on the Canadian Adolescent and Young Adult national rounds mailing list. Snowball sampling was permitted.

RESULTS

There were 25 responses (up to 35% response rate). Radiation oncologists (11), neuro-oncologists (8), medical oncologists (4), and neurosurgeons (2) responded from 6/10 Canadian provinces. They each treated on average 1.6 medulloblastoma patients per year. Most (61% of respondents) said that medulloblastoma molecular subgrouping was always done at their centre. Half (50%) indicated that cerebrospinal fluid testing was always done at diagnosis. The most common (64%) radiation regimen was 36 Gy (in 20 fractions) craniospinal irradiation + 18 Gy (in 10 fractions) boost. Concomitant chemotherapy was rarely given (75% of respondents included chemotherapy less than half of the time). Adjuvant chemotherapy was frequently administered (79% of respondents give it more than half of the time). The most common adjuvant chemotherapy was Cisplatin/Lomustine/Vincristine (57%), but other regimens included Cisplatin/Lomustine/Vincristine alternating with Cyclophosphamide/Vincristine (21%), Cisplatin/Cyclophosphamide/Vincristine (14%), and carboplatin-based regimens (14%). Respondents noted challenges prescribing chemotherapy in this population: drug toxicities, limited resources, and clinical uncertainty. There was support for standard of care adult medulloblastoma guidelines in 92% of respondents.

CONCLUSIONS

There is significant practice variation among Canadian neuro-oncology centres treating adult medulloblastoma. This variation can serve as an opportunity for quality improvement and clinical research.
QLTI-26. INTEGRATION OF NEURO-ONCOLOGY CLINICAL PATHWAYS IN PROVIDENCE SOUTHERN CALIFORNIA CLINICAL RESEARCH NETWORK
Authors: Bott Thomas , Bozoyan Nanor , Babcock Trisha , Cushman Kristen , Sharma Akanksha , Wagle Naveed , Carrillo Jose , Juarez Tiffany , Kesari Santosh
Published: November 2022

INTRODUCTION

ClinicalPath is an evidence-based oncology decision support and analytics tool for cancer care. ClinicalPath’s treatment recommendations are prioritized based on efficacy, toxicity, and cost by a nationwide committee of oncologists. The pathways are updated quarterly and are expected to speed the integration of new treatments into practice, standardize therapy, improve quality, and decrease cost. The pathway system also allows for local clinical trial mapping to promote clinical trial awareness and increase enrollment. ClinicalPath provides clinical pathways delivering personalized, evidence-based oncology guidance at the point of care. ClinicalPath’s network in North America serves more than 2,000 cancer physicians, within 54 practices in 31 states (15 academic medical centers, 29 hospital systems, and 9 community practices). Population: Our population is derived from multiple hospitals in Southern California within the Providence Health System. Methodology: Medical oncologists and Advanced Practice Providers received training on ClinicalPath before go-live. ClinicalPath was integrated into the Epic EHR in multiple Southern CA hospitals in a single month.

RESULTS

After 3 months of utilization within our Southern California region, 342 treatment decisions were made across all cancers, and 85.1% of cancer patients were treated on pathway. Of which, 7 treatment decisions were made within the neuro-oncology specialty, and 85.7% of those cancer patients were treated on pathway.

CONCLUSION

We successfully integrated and initiated ClinicalPath in a multiple hospital-affiliated community oncology clinical trial network. We are actively working across our Southern California Region to map locally available clinical trials to promote awareness and increase enrollment. Provider utilization and patient on-pathway rates are actively monitored and will be updated.
SURG-22. STAGED LASER INTERSTITIAL THERAPY (LITT) FOR THE SURGICAL TREATMENT OF INSULAR GLIOMA: A CASE SERIES WITH A NOVEL TREATMENT PARADIGM
Authors: Fadel Hassan , Pawloski Jacob , Haider Sameah , Robin Adam , Lee Ian
Published: November 2022

BACKGROUND

Insular gliomas pose a significant surgical challenge due to the insula’s delicate surrounding functional and vascular anatomy. Insular gliomas are conventionally treated with open surgical resection augmented by several surgical adjuvants. Despite advancements in technology and surgical techniques, surgical resection of insular gliomas has been associated with frequent and potentially severe morbidity. Laser interstitial thermal therapy (LITT) is a novel, cytoreductive, and less-invasive treatment option for glioma.

OBJECTIVE

We describe the first-ever series of patients with insular glioma treated with staged LITT with or without subsequent craniotomy.

METHODS

A retrospective institutional database identified patients with insular glioma who underwent staged LITT treatments. Clinical, histopathological, and volumetric lesional characteristics were obtained. Procedural characteristics, morbidity, overall survival (OS), and progression-free survival (PFS) were determined.

RESULTS

Between 2019-2022, 11 patients with insular glioma were treated in stages with a total of 21 LITT procedures with or without subsequent craniotomy. Four patients had Diffuse Astrocytoma (IDHmt/TP53+), one Gemistocytic Astrocytoma (IDHmt/TP53+), three Anaplastic Astrocytoma (IDHmt/TP53+), one Anaplastic Oligodendroglioma (IDHmt/1p19q codel), one secondary GBM (IDHmt/TP53+), and one GBM (IDHwt/TP53-). Six patients were treated with LITT alone, while five patients were treated with LITT followed by a craniotomy for complete resection. Patients had a median tumor volume of 31.5 cm3 (9.58, 97) and a mean extent of ablation±resection of 97.68% (S.D. 5.4). At a median follow-up of 12.59 months, patients had a median PFS of 12.88 months and an OS of 14.46 months. No patients had a change in KPS following LITT. Two patients had a decrease in KPS following surgery.

CONCLUSION

We present the first-ever reported series of insular glioma treated with staged LITT with/without subsequent resection. We found that staged treatment of insular gliomas with LITT is safe, effective, and a minimally invasive option that avoids the potentially significant morbidity associated with conventional surgery.
Intensive care unit requirements in patients treated with immune checkpoint inhibitors
Authors: Cooksley Tim , Weaver Jamie M J , Haji-Michael Phil
Published: November 2022

Objective

To determine the proportion of emergency patients treated with immune checkpoint inhibitors (ICIs) that require critical care admission and their requirements.

Design

Prospective case series.

Methods

Analysis of acutely unwell patients treated with ICIs attending a tertiary UK cancer hospital between May 2018 and May 2022. The primary outcome measure was the percentage of patients treated with ICI therapy requiring ICU admission. The secondary outcome measure was whether this need was driven by an immune-mediated toxicity.

Results

Eighteen (1.2%) patients of the 1561 acutely admitted patients treated with ICI therapy required an admission to ICU. Ten (55.5%) patients were admitted due to an immune-mediated toxicity; four due to pneumonitis and four due to myasthenia gravis. Seven of 10 survived their ICU admission with 6 surviving at least 6-month post-ICU discharge.

Conclusions

Only a small minority of emergency admissions in patients treated with ICIs require admission to ICU. This series adds further evidence that patients with organ failure due to immune-mediated toxicity may achieve good outcomes from ICU admission.
ESTIMATION OF FETAL AND PEDIATRIC DOSES FROM CHEST CT EXAMINATIONS USING VIRTUALDOSE SOFTWARE
Authors: Ye Zirui , Qi Miao , Zhao Yingming , Wei Wei , Xu X George
Published: November 2022

Pregnant women and children sometimes had to undergo chest computed tomography (CT) scans during the Corona Virus Disease 2019 (COVID-19) pandemic. This study estimated the fetal and pediatric doses from chest CT scans. Organ doses and effective doses were calculated using the VirtualDose-CT software. Two groups of computational human phantoms, pregnant females and pediatric patients were used in this study. The results of doses normalized to volumetric CT Dose Index (CTDIvol) can be used universally for other dosimetry studies. Based on our calculations and international survey data of CTDIvol, fetal absorbed doses from COVID-19-related chest CT were found to be 0.04–0.36, 0.05–0.44 and 0.07–0.61 mGy for 3, 6 and 9 months of pregnancy, respectively. When the scan range is extended to the abdominal region, fetal doses increase by almost 4-fold. Effective doses for COVID-19-related chest CT were 1.62–13.77, 1.58–13.46, 1.57–13.33 and 1.29–10.98 mSv for the newborn, 1-, 5- and 10-y-old children, respectively. In addition, the effects of specific axial scan ranges exceeding the thorax region were evaluated. Although doses from chest CT scans are small, such data allow radiologists and patients to be informed of the dose levels and ways to avoid unnecessary radiation.
Biological properties of different extracts of the Kalanchoe daigremontiana (‘Mother of thousands’): a review
Authors: Carreiro Faustino Denise , das Chagas Lima Naiara Nascimento , James Allahdadi Kyan , Cedraz Pinto Laise
Published: November 2022

Objectives

Kalanchoe daigremontiana (KD) is a succulent plant with widespread popular use as an anticancer and for the treatment of a variety of other diseases. The presence of bufadienolides (BFD), a cardiotoxic compound and other substances may justify some of its biological properties, however, clinical studies and toxicity and safety data are still scarce. The objective of this systematic review was to describe KD’s biological properties and mechanisms, as well as its toxicity. Searches were performed in four databases with the descriptors: ‘kalanchoe daigremontiana’ AND ‘cytotoxicity’, ‘antioxidant’ OR ‘anti-inflammatory’ OR ‘toxicity’. In total, 11 studies were included according to the PRISMA 2020 protocol.

Key findings

The aqueous and ethanolic extracts of KD showed important antioxidant and anti-inflammatory activity, associated with the presence of flavonoids and phenols in the extracts. The extracts from fractions that were rich in BFD or dichloromethane showed anticancer (related to inhibition of mitochondrial dehydrogenase activity and reduction of glutathione level) and anticoagulant actions (due to reduced fibrin clot formation and increased degradation).

More studies are still needed to demonstrate the concentration limits for beneficial effects and the toxic limitations of this species, until then, cautious use and consumption of KD is recommended.
The case for standalone micro-invasive glaucoma surgery: rethinking the role of surgery in the glaucoma treatment paradigm
Authors: Radcliffe Nathan
Published: November 2022

Purpose of review

To highlight progress in glaucoma therapy challenging the traditional medication-first approach and present evidence supporting early standalone surgery in the era of micro-invasive glaucoma surgery (MIGS).

Recent findings

Medical therapy is limited by well documented poor adherence that compromises the quality of intraocular pressure reduction. Results from modern clinical trials demonstrate advantages of selective laser trabeculoplasty and MIGS procedures in terms of both IOP control and progression risk.

The MIGS options for pseudophakic or precataractous patients are limited by regulatory rules that require the performance of some procedures only at the time of cataract surgery. These include the iStent/iStent Inject and the Hydrus implants. Nonbleb-forming procedures currently available for standalone use in eyes with mild–moderate primary open-angle glaucoma include gonioscopy-assisted transluminal trabeculotomy (which lowers IOP by 28-61% and medication use by 38–73% in various studies), trabecular ablation with the Trabectome (23–39% and 21–43%, respectively), excisional goniotomy with the Kahook Dual Blade (15–36% and 15–40%, respectively), ab interno canaloplasty (35% and 57%, respectively), and combined canaloplasty and trabeculotomy using the OMNI system (39–40% and 64–73%, respectively). For patients who would benefit from early standalone surgery, these procedures offer meaningful reductions in both IOP and medication burden.
Risk Factors for 30-Day Mortality in Neonates With Carbapenem-resistant A. baumannii Sepsis
Authors: Phatigomet Manapat , Thatrimontrichai Anucha , Maneenil Gunlawadee , Dissaneevate Supaporn , Janjindamai Waricha
Published: November 2022

Background:

Carbapenem-resistant Acinetobacter baumannii (CRAB) sepsis is becoming an extreme threat caused by high-case fatality rates and poor prevention and control in ICUs worldwide. However, the risk of mortality among neonatal CRAB sepsis is still unclear.

Methods:

A retrospective medical records review study, which aimed to identify the risk factors of mortality in neonates with CRAB sepsis (including both bacteremia and/or meningitis) in Thailand from 1996 to 2019. All cases featuring positive blood and cerebrospinal fluid cultures for CRAB were reviewed. A multivariable logistic regression model was analyzed for nonsurvivors and survivors of neonatal CRAB sepsis.

Results:

In a 24-year period, 47 of these were identified with CRAB sepsis. The median (interquartile range) gestational age and birth weight were 30 (28–35) weeks and 1500 (933–2482) g, respectively. The 30-day case fatality rate was 55% (26/47). In multivariable analysis, nonsurvivors of neonatal CRAB sepsis were associated with congenital heart disease (adjusted odds ratio [OR] = 1.33; 95% CI 1.06–1.66, P = 0.02), CRIB II score ≥9 (adjusted OR = 1.65; 95% CI: 1.20–2.27, P = 0.004), severe thrombocytopenia (adjusted OR = 1.45; 95% CI: 1.09–1.94, P = 0.02), and septic shock (adjusted OR = 1.62; 95% CI: 1.33–1.99, P <0.001).

Conclusion:

The risk factors of mortality in neonates with CRAB sepsis are associated with congenital heart disease, CRIB II score ≥9, shock, and severe thrombocytopenia.
Tolerability and efficacy of duloxetine for the prevention of persistent musculoskeletal pain after trauma and injury: a pilot three-group randomized controlled trial
Authors: Beaudoin Francesca L. , Gaither Rachel , DeLomba Weston C. , McLean Samuel A.
Published: November 2022

This study investigated the tolerability and preliminary efficacy of duloxetine as an alternative nonopioid therapeutic option for the prevention of persistent musculoskeletal pain (MSP) among adults presenting to the emergency department with acute MSP after trauma or injury. In this randomized, double-blind, placebo-controlled study, eligible participants (n = 78) were randomized to 2 weeks of a daily dose of one of the following: placebo (n = 27), 30 mg duloxetine (n = 24), or 60 mg duloxetine (n = 27). Tolerability, the primary outcome, was measured by dropout rate and adverse effects. Secondary outcomes assessed drug efficacy as measured by (1) the proportion of participants with moderate to severe pain (numerical rating scale ≥ 4) at 6 weeks (pain persistence); and (2) average pain by group over the six-week study period. We also explored treatment effects by type of trauma (motor vehicle collision [MVC] vs non-MVC). In both intervention groups, duloxetine was well tolerated and there were no serious adverse events. There was a statistically significant difference in pain over time for the 60 mg vs placebo group (P = 0.03) but not for the 30 mg vs placebo group (P = 0.51). In both types of analyses, the size of the effect of duloxetine was larger in MVC vs non-MVC injury. Consistent with the role of stress systems in the development of chronic pain after traumatic stress, our data indicate duloxetine may be a treatment option for reducing the transition from acute to persistent MSP. Larger randomized controlled trials are needed to confirm these promising results.
Association of female sex with increased risk of sleep disturbance in adult patients with moderate to severe psoriasis: a Chinese cross-sectional study
Authors: Tan Min-Jia , Luo Yan , Hu Jing-Jin , Wang Mi , Wang Qiao-Lin , Xu Li-Cong , Hu Kun , Li Xing-Yu , Yang Jing , Chen Jun-Chen , Kuang Ye-Hong , Zhu Wu
Published: November 2022

Objective:

Up to 85.3% of patients with psoriasis experience sleep disturbance (SD). However, SD has not been characterized in Chinese patients with psoriasis, and the factors that affect SD among adult patients with psoriasis remain unclear. This study was performed to examine the risk of SD in patients with psoriasis compared with a control group of healthy individuals and to identify factors contributing to SD in patients with psoriasis.

Methods:

This was a cross-sectional, questionnaire-based, case-control study involving 142 adult participants with psoriasis and 142 healthy controls. The Pittsburgh Sleep Quality Index (PSQI) was administered to assess SD. Mild psoriasis was defined by Psoriasis Area and Severity Index (PASI) and body surface area (BSA) cut-offs of <10, and mild to severe psoriasis was determined by PASI and BSA cut-offs of ≥10.

Results:

The prevalence of SD (PSQI score of ≥6) was 47.9% in adult patients with psoriasis. The mean PSQI score in patients with psoriasis was 6.1 ± 3.7, which was higher than that in the control group (4.9 ± 2.5, P < 0.001). The risk of SD in the psoriasis group was 1.669 times higher (adjusted odds ratio, 1.669; 95% confidence interval, 1.008–2.761; P = 0.046) than that in the healthy group. Female sex (adjusted odds ratio, 4.130; 95% confidence interval, 1.306–13.058; P = 0.016) was significantly associated with an increased risk of SD in patients with moderate to severe psoriasis, whereas there were no significant factors affecting the risk of SD in patients with mild psoriasis.

Conclusions:

Patients with psoriasis were more likely than healthy controls to develop SD. In patients with moderate to severe psoriasis, but not in those with mild psoriasis, female sex was associated with a higher likelihood of SD.
Right Ventricular Injury Increases Mortality in Patients with Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Analysis
Authors: Chad Thomas , Yusuff Hakeem , Zochios Vasileios , Pettenuzzo Tommaso , Fan Eddy , Schmidt Matthieu ,   for the Protecting the Right Ventricle network (PRORVnet)
Published: November 2022

Right ventricular injury (RVI) in the context of acute respiratory distress syndrome (ARDS) is well recognized as an important determinant risk factor of mortality. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is part of the algorithm for the management of patients with severe ARDS and severely impaired gas exchange. Although VV-ECMO may theoretically protect the RV it is uncertain to what degree RVI persists despite VV-ECMO support, and whether it continues to influence mortality after ECMO initiation. The aim of this systematic review and meta-analysis was to investigate the impact of RVI on mortality in this context, testing the hypothesis that RVI worsens mortality in this cohort. We performed a systematic search that identified seven studies commenting on RVI and mortality in patients with ARDS receiving VV-ECMO. The presence of RVI was associated with greater mortality overall (odds ratios [OR]: 2.72; 95% confidence intervals [CI]: 1.52–4.85; p < 0.00) and across three subgroups (RV dilatational measures: OR: 3.51; 95% CI: 1.51–8.14; p < 0.01, RV functional measures: OR: 1.84; 95% CI: 0.99–3.42; p = 0.05, RV measurements post-ECMO initiation: OR: 1.94; 95% CI: 1.01–3.72; p < 0.05). Prospective studies are needed to investigate the causal relationship between RVI and mortality in this patient group and the best management strategies to reduce mortality.
Updates in percutaneous tracheostomy and gastrostomy: should we strive for combined placement during one procedure?
Authors: DeMaio Andrew , Yarmus Lonny
Published: November 2022

Purpose of review

Percutaneous tracheostomy and gastrostomy are minimally invasive procedures among the most common performed in intensive care units. Practices across centres vary considerably, and questions remain about the optimal timing, performance and postoperative care related to these procedures.

Recent findings

The COVID-19 pandemic has triggered a reevaluation of the practice of percutaneous tracheostomy and gastrostomy in the ICU. Combined percutaneous tracheostomy and gastrostomy at the bedside has potential benefits, including improved nutrition, decreased exposure to anaesthetics, decreased patient transport and decreased hospital costs. Percutaneous ultrasound gastrostomy is a novel technique that eliminates the need for an endoscope that may allow intensivists to perform gastrostomy at the bedside.

Multidisciplinary care is essential to the follow up of critically ill patients receiving tracheostomy and gastrostomy. Combined tracheostomy and gastrostomy has numerous potential benefits to patients and hospital systems. Interventional pulmonologists are uniquely qualified to perform both procedures and serve on a tracheostomy and gastrostomy team.