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Zhe Yang, Biao He, Zongji Lu, Shijiang Mi, Jianfeng Jiang, Zhongdi Liu, ,
Published: 22 September 2021
Abstract:
Currently Birnaviridae family contains four genera with all members identified from birds, fishes and insects only. The present study reports a novel birnavirus unexpectedly identified from classical swine fever virus (CSFV)-infected pigs by viral metagenomic analysis, therefore named as porcine birnavirus (PBRV). Follow-up RT-PCR screening of archived tissues of diseased pigs identified 16 PBRV strains from nine provinces/autonomous regions in China spanning 21 years (1998-2019), and the viral loads of PBRV in clinical samples were 105.°8-107.95 genome copies per 0.1 g tissue, showing the replication of PBRVs in the pigs. Genome-based sequence comparison showed that PBRVs are genetically distant from existing members within the Birnaviridae family with 45.8-61.6% and 46.2-63.2% nucleotide sequence similarities in segments A and B respectively, and the relatively closed viruses are avibirnavirus strains. In addition, indels of 57, 5, and 18 amino acid residues occurred in 16, 2, and 7 locations of the PBRV polyprotein, VP5, and VP1 proteins respectively as compared to the reference avibirnaviruses. Phylogenetic analysis showed that PBRVs formed an independent genotype separated from other 4 genera, which could be classified into 2 or 3 subgenotypes (PBRV-A1-2 and PBRV-B1-3) based on the nucleotide sequences of full preVP2 and VP1 genes respectively. All results showed that PBRV is a novel pig virus species, which constitutes the first mammalian birnavirus taxon, thereby naming as Mambirnavirus genus is proposed.
Noel Blanco-Touriñán, , , Rosa María Esquinas-Ariza, Francesca Resentini, , Cristian Carrasco-López, Claudio Novella-Rausell, Alberto Palacios-Abella, , et al.
Published: 22 September 2021
Abstract:
Plant Physiology, https://doi.org/10.1093/plphys/kiab348
Philosophia Mathematica; https://doi.org/10.1093/philmat/nkab021

Abstract:
J.E. Fenstad. Structures and Algorithms: Mathematics and the Nature of Knowledge. Logic, Argumentation & Reasoning; 15. Springer, 2018. Pp. x + 134. ISBN 978-3-319-72973-2 (hbk); 978-3-030-10294-4 (pbk); 978-3-319-72974-9 (e-book). doi.org/10.1007/978-3-319-72974-9.
European Heart Journal, Volume 42, pp 3581-3585; https://doi.org/10.1093/eurheartj/ehab627

Abstract:
For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts.
Kathryn Blethen, Samuel Sprowls, Tasneem Arsiwala, Ross Fladeland, Dhruvi Panchal, Neal Shah, Brooke Kielkowski, Weimin Gao, Paul Lockman
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.030

Abstract:
Lung cancer is the most prevalent malignancy to affect both men and women. Around 80% of all lung cancers are classified as non-small cell lung cancer (NSCLC). This subtype of lung cancer is also the most likely to metastasize to the brain. Clinically, the common treatment for NSCLC is epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), due to the high occurrence of EGFR mutations. However, the cancer cells quickly develop resistance to the EGFR TKIs. This resistance and the added difficulty of delivering drugs across the blood-tumor barrier in efficacious concentrations to treat brain lesions are important to consider when developing treatment strategies for lung cancer brain metastases. Our study utilizes a NSCLC cell line, PC-9-Br6, which was developed in our laboratory to preferentially metastasize to the brain. This cell line was demonstrated by our collaborator to express higher levels of Bcl-2 in comparison to the parental PC-9-P cell line. We hypothesized combining novel Bcl-2 inhibitors (ABT-199/ABT-263) with an EGFR inhibitor (gefitinib) would increase survival and decrease tumor burden in our clinically relevant mouse model of lung cancer brain metastases.
Andrew Sloan, Robin Buerki, Christopher Murphy
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.015

Abstract:
BACKGROUND Recurrent glioblastoma (rGBM) has poor response rate and survival. Laser Interstitial Thermotherapy (LITT), a minimally invasive approach, improves survival but is not curative alone. Previous studies of LITT suggested the possibility of an abscopal effect. Indeed, GBM are known to harbor elevated levels of immunosuppressive cells such as Treg, M2 macrophages and MDSC both in the tumor microenvironment as well as in the systemic circulation. Checkpoint inhibition (CPI) immunotherapy has proven highly effective for some solid tumors. CPI in newly diagnosed GBM demonstrated safety in phase I trials (NRG BN-002). Further, preclinical studies targeting PD-1 with concurrent RT appears to be synergistic and improve survival. We hypothesized that LITT would block tumor-induced immunosuppression and introduce tumor neoantigens. However, there was no data regarding safety of pembrolizumab combined with LITT. We thus conducted a phase I/II study of LITT + pembrolizumab starting at three times relative to LITT. METHODS This is a three armed Phase I/II study based on timing of pembrolizumab (200 mg q 21 days) relative to LITT at 35d or 14d post-op, or 7d pre-op, with an expansion cohort phase II arm conducted at the earliest tolerated time of CPI administration. Adults with proven supratentorial rGBM with KPS >=70 and <= 2mg/d of dexamethasone were eligible. RESULTS Arm 1-2 of the phase I trial demonstrated no SAEs grade II or greater, but limited evidence of response. Arm 3 (neoadjuvant) pembrolizumab appears to be equally safe and has been expanded to phase II, demonstrating at least two CR among the first 3 patients (66.6%) with >= 9 month follow-up and patients remain clinically stable at 10 and 15 months post-op. CONCLUSIONS Neoadjuvant pembrolizumab combined with LITT for rGBM appears to be safe in this phase I trial, and demonstrates early evidence of response. The phase II trial is ongoing.
Jason J Hayer, Dorit Nysar, Céline Heinemann, Caroline D Leubner,
Journal of Animal Science; https://doi.org/10.1093/jas/skab266

Abstract:
Consumers, industrial stakeholders, and the legislature demand a stronger focus on animal welfare of all livestock at the farm level by using suitable indicators in self-assessments. In order to deduce farms’ animal welfare status reliably, factors that influence indicators’ results need to be identified. Hence, this study aimed to apply possible animal welfare indicators for unweaned dairy calves on conventional dairy farms with early cow-calf separation and evaluate influencing factors such as age and sex of calves or climatic conditions on the applied indicators’ results. An animal welfare assessment using seven resource-based and 14 animal-based indicators was conducted at 42 typical Western German dairy farms (844 calves) in 2018 and 2019 by two observers. The effect of influencing factors was calculated by binary and ordinal logistic regressions and expressed as odds ratios. Although every unweaned calf was assessed during the farm visits, most farms had relatively few unweaned calves (average number of calves ± standard deviation = 20.1 ± 6.7 calves), with six farms having not more than ten calves. The small sample sizes question the usage of those indicators to compare between farms and to set thresholds at farm level. Only one assessed indicator (cleanliness core body) was not statistically affected by the evaluated influencing factors. Calf age was identified as the most decisive factor, as it affected 16 of 21 evaluated indicators and calf age distribution on-farm varied greatly. Climatic conditions (ambient temperature and rainfall) influenced resource-based indicators such as access to concentrate and water or the cleanliness of feeding implements and bedding as well as animal-based cleanliness indicators and the occurrence of health-related impairments such as coughing and diarrhea. The authors found differences between calves on farms assessed by the different observers in resource-based hygiene indicators but also in animal-based indicators like hyperthermia or hypothermia, highlighting the need for further evaluation of quality criteria in dairy calf welfare assessments. Nevertheless, animal welfare assessments by farmers themselves could be useful tools to sensitize farmers to animal welfare and thereby improve calves’ welfare.
, Samantha Steelman, Marco Martinez
Translational Animal Science; https://doi.org/10.1093/tas/txab160

Abstract:
This review will give a brief description of β-mannans, abundance in feedstuffs, utility of supplemental feed β-mannanase and subsequent animal responses. Soybean products and co-products of processing palm, coconut and guar seeds are the major sources of β-mannans in poultry and livestock feed. β-mannans are linear polymers of mannose residues linked by β-1,4 glycosidic bonds and their ingestion elicit undesirable and metabolically costly responses. Web of Science was searched to retrieve published studies for meta-analyses of the impact of supplemental β-mannanase on performance and digestibility in pigs and poultry. The mean difference (MD) between ß-mannanase and control on average daily gain (ADG, g/d) was +0.23 (P=0.013; 95% CI 0.05; 0.41), +10.8 g/d (P=0.0005; 95% CI of 6.6; 15.0 g/day) and +20.68 (P<0.000; 95% CI of 17.15; 24.20 g/day) for broiler chickens, nursery pigs and grow-finish pigs, respectively. The MD on β-mannanase improvement on FCR was -0.02 (P<0.0001) with 95% CI (-0.03; -0.02) suggesting a 2-to-3-point FCR improvement in broiler chickens. ß-mannanase improvement on gain to feed (G:F) was +13.8 g/kg (P=0.027; 2.1; 25.4 g/kg) and +8.77 g/kg (6.32; 11.23 g/kg) in nursery and grow-finish pigs, respectively. β-mannanase improved AMEn by 47 kcal/kg (P=0.0004) with 95% CI (28.8; 65.7 kcal/kg) in broiler chickens. The improvement of gross energy digestibility in pigs was 1.08 percentage unit with 95% CI (0.90; 1.26) translating to the release of between 30.6 and 42.8 kcal/kg of digestible energy. Although data was limited, β-mannanase improved egg production but had no impact on egg quality in laying hens. Turkeys may be more adversely affected by ß-mannans because of the high protein/ amino acids requirements necessitating higher dietary inclusion of soybean meal. However, growth performance and feed efficiency responses of turkeys fed diets supplemented with β-mannanase was variable. In summary, ß-mannanase supplementation improved performance linked to energy and nutrient utilization. However, the magnitude of response was variable within and between species indicating further application refinement is warranted to achieve consistent efficacy, including an improved understanding of the functional contribution of β-mannans hydrolysis products.
Ruchika Verma, Yasmeen Rauf, Ipsa Yadav, Volodymyr Statsevych, Jonathan Chen, Wendi Evanoff, Manmeet Ahluwalia, Pallavi Tiwari
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.022

Abstract:
PURPOSE The use of immunotherapy in glioblastoma management is under active investigation. Glioblastomas are “cold” tumors, meaning that they have inactivated or fewer tumor infiltrative lymphocytes in addition to substantial tumor necrosis, attributing to their poor response to immunotherapy. A significant challenge is the apriori identification of Glioblastoma patients who will respond favorably to immunotherapy. In this work, we evaluated the ability of computerized MRI-based quantitative features (radiomics) extracted from the lesion habitat (including enhancing lesion, necrosis, and peritumoral hyperintensities) to predict response and progression-free survival (PFS) in recurrent GBM patients treated with combination of Nivolumab and Bevacizumab. METHODS Immunotherapy response assessment in neuro-oncology (iRANO) criteria along with PFS were used to analyze n=50 patients enrolled in a randomized clinical trial where patients received Nivolumab with either standard or low dose Bevacizumab. These patients were assessed to see if they had complete response, partial response, stable disease (i.e. responders, n=31), or disease progression (i.e. non-responders, n=19). Lesion habitat constituting necrotic core, enhancing tumor, and edema were delineated by expert radiologist on Gd-T1w, T2w and FLAIR MRI scans. COLIAGE radiomic features from each of the delineated regions were selected using minimum redundancy maximum relevance (mRMR) via cross-validation, to segregate non-responder patients from responders. A multivariable cox proportional hazard model was used to predict survival (PFS). RESULTS CoLlAGe correlation, sum average, and sum variance features (capture local heterogeneity) from the lesion habitat, were found to segregate non-responder patients from responders with an accuracy of 86%, followed by 80% using features from peritumoral hyperintensities and 78% from enhancing tumor. In our survival analysis, C-index of 0.688 was obtained using features from the entire lesion habitat, followed by peritumoral hyperintensities (0.675) and enhancing tumor (0.656). CONCLUSION Radiomic features from the lesion habitat may predict response to combination of Nivolumab and Bevacizumab in recurrent Glioblastomas.
Tobias Weiss, Teresa Hemmerle, Patrick Roth, Dario Neri, Michael Weller
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.031

Abstract:
Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. We previously demonstrated encouraging anti-tumor activity with the targeted delivery of tumor necrosis factor a (TNF) in preclinical orthotopic glioma models. TNF- a is a potent pro-inflammatory cytokine which may trigger strong anti-tumor immunity. However, its systemic administration at therapeutically active doses is hampered by toxic side effects. L19TNF is a fully human antibody-cytokine fusion protein, comprising TNF- a fused to the antibody L19 that binds a tumor-specific epitope of the extracellular matrix protein fibronectin. This allows a targeted delivery of therapeutically relevant doses of TNF to the tumor site upon intravenous administration while sparing healthy tissues. In this phase I/II open label, non-randomized, monocentric study, we investigated the safety and preliminary activity of L19TNF for patients with isocitrate dehydrogenase (IDH) wildtype World Health Organization (WHO) grade III / IV glioma at first relapse. Twenty patients were enrolled from 2019-2020 and treated with intravenous infusions of L19TNF. In the phase I part of the study, 6 patients were assigned to two different dose levels of L19TNF and a dose of 13 µg/kg was established as the recommended dose. In the phase II part 14 patients were treated at the recommended dose. No dose-limiting toxicities were observed and survival follow-up is ongoing. In almost all patients, we observed treatment-associated emerging tumor necrosis. For patients that had re-surgery at progression on or after treatment with L19TNF, we demonstrated increased numbers of tumor-infiltrating lymphocytes compared to the tumor tissue obtained at primary diagnosis. Translational studies to better understand the effects of L19TNF on a molecular and immunophenotypic level are ongoing. ClinicalTrials.gov Identifier: NCT 03779230
Ruthanna Davi, Antara Majumdar, Martin Bexon, Nicholas Butowski, Chandtip Chandhasin, Melissa Coello, Sunit Das, Fahar Merchant, Nina Merchant, David Reardon, et al.
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.008

Abstract:
BACKGROUND Drug development in recurrent glioblastoma multiforme (rGBM) is challenging. For randomized controlled trials (RCTs) short survival horizons and limited life-prolonging treatment options may delay accrual and introduce bias through differential dropout of control patients. Comparing results of a single-arm Phase 2b trial of intratumoral delivery of MDNA55 (an interleukin-4 receptor targeted fusion protein) to an external control arm, we sought early efficacy insights and consideration by the FDA of incorporating an ECA in a Phase 3 registrational trial. METHODS Using propensity score weighting, we compared rGBM patients from the Phase 2b trial (NCT02858895) (2017-2019) to patients from rGBM registries who had received standard of care therapies (2011-2019) and met eligibility requirements. Propensity scores were estimated using a logistic regression model with 11 covariates. We compared the propensity score weighted groups according to demographic and disease attributes before and after weighting and compared overall survival between the two groups. RESULTS Through propensity score weighting, 43 (98%, 43/44) MDNA55 patients and 40.80 weighted ECA patients (from 62 unweighted registry patients) were identified for comparison. MDNA55 and ECA patients were balanced on all baseline characteristics (i.e., standardized mean difference ≤ 0.15). Compared to ECA patients, MDNA55 patients had a 37% lower hazard of death (hazard ratio 0.63, 95% confidence interval: 0.39,1.02). CONCLUSION In advance of a Phase 3 trial, comparison of Phase 2b trial results to an ECA suggests that MDNA55 may be efficacious in rGBM. In view of the known challenges associated with drug development for rGBM, these results provided a proof-of-concept for the design of a novel hybrid Phase 3 trial. This planned Phase 3 trial incorporates propensity score weighting to create a composite hybrid randomized and external control arm, an approach preferred by the FDA over full replacement of a randomized control with an external control.
Jana Ivanidze, Sean Kim, Michelle Roytman, Rohan Ramakrishna, Susan Pannullo, Theodore Schwartz, Joseph Osborne, Rajiv Magge, Eaton Lin, Jonathan Knisely
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.026

Abstract:
PURPOSE Postoperative PET/MRI with [68Ga]-DOTATATE can differentiate residual meningioma from postsurgical change, aid in target delineation, and portend a more favorable dosimetry with decreased PTV and organ-at-risk dose. Our purpose was to demonstrate utility of DOTATATE PET/MR for radiosurgical treatment (RT) response assessment in meningiomas. METHODS Patients underwent postoperative radiation treatment planning using DOTATATE PET/MRI as part of our IRB-approved prospective trial. Both DOTATATE PET and gadolinium-enhanced T1 weighted MR imaging were incorporated in RT-planning. All patients underwent follow-up DOTATATE PET/MRI at 6-12 months following completion of radiosurgery. Maximum absolute standardized uptake value (SUV) and SUV ratio (SUVR) of lesion/ superior sagittal sinus SUV were obtained. RANO criteria were applied to determine significance of change in size. Statistical analyses were performed using paired t-tests. RESULTS 13 patients (15% WHO-I, 54% WHO-II, 23% WHO-III, 8% WHO grade unknown) were followed postoperatively with pre- and post-RT DOTATATE PET/MRI. 29 meningiomas were treated. 46% (6/13) of subjects received SBRT and 54% (7/13) received SRS. Post-RT DOTATATE PET/MRI demonstrated a 46.4% SUV decrease (p-value = 0.0001) and a 60.8% SUVR decrease (p-value < 0.0001). Of 21 measurable lesions, the size product decreased by 21%; while this decrease was statistically significant (p-value = 0.0008), it was below the 25% decrease defined as clinically significant by RANO guidelines. To date, all patients remain stable radiographically without evidence of recurrence (mean follow-up post RT: 14 months; range: 6-24 months). CONCLUSIONS DOTATATE PET SUV and SUVR demonstrated marked, significant decrease post radiosurgery. Lesion size decrease was statistically significant but not clinically significant by RANO criteria. DOTATATE PET/MR thus represents a promising approach to aid in response assessment for radiosurgically treated meningiomas. Longer-term follow-up is needed to determine the correlation between the degree of post-RT SUV and/or SUVR decrease and progression-free-survival.
Gaetano Finocchiaro, Marica Eoli, Bernhard Gentner, Alessia Capotondo, Elena Anghileri, Gabriele Antonarelli, Matteo Barcella, Maria Grazia Bruzzone, Matteo Carrabba, Valeria Cuccarini, et al.
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.014

Abstract:
Temferon is a macrophage-based treatment relying on ex-vivo transduction of autologous HSPCs to express immune-payloads within the TME. Temferon targets the immune-modulatory molecule IFN-a, to a subset of tumor infiltrating macrophages known as Tie-2 expressing macrophages (TEMs) due to the Tie2 promoter and a post-transcriptional regulation layer represented by miRNA-126 target sequences. As of 31st May 2021, 15-patients received Temferon (D+0) with follow-up of 3 – 693 days. After conditioning neutrophil and platelet engraftment occurred at D+13 and D+13.5, respectively. Temferon-derived differentiated cells, as determined be the number of vector copy per genome, were found within 14 days post treatment and persisted albeit at lower levels up to 18-months. Very low concentrations of IFN-a in the plasma (8.7 pg/ml-D+30) and in the CSF (1.6 pg/ml-D+30) were detected, suggesting tight regulation of transgene expression. Five-deaths occurred at D+322, +340, +402, +478 and +646 due to PD, and one at D+60 due to complications following the conditioning regimen. Eight-patients had progressive disease (range: D-11 to +239) as expected for this tumor type. SAEs include GGT elevation (possibly related to Temferon) and infections, venous thromboembolism, brain abscess, hemiparesis, seizures, anemia and general physical condition deterioration, compatible with ASCT, concomitant medications and PD. Four-patients underwent 2ndsurgery. Recurrent tumors had gene-marked cells and increased expression of ISGs compared to first surgery, indicative of local IFNa release by TEMs. In one patient, a stable lesion had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased ISGs than in the progressing lesion, detected in the same patient. Tumor-associated clones expanded in the periphery. TME characterization by scRNA and TCR-sequencing is ongoing. To date, Temferon is well tolerated, with no DLTs identified. The results provide initial evidence of Temferon potential to activate the immune system of GBM patients, as predicted by preclinical studies.
Kristen Batich, Gary Archer, Pamela Norberg, David Ashley, John Sampson, Mustafa Khasraw
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.020

Abstract:
INTRODUCTION Targeting tumor-associated antigens (TAAs) via peptide vaccination has been tested against malignant glioma with minimal success. Poor responses are attributed to relatively low antigen level expression of the TAA and insufficient CD8+ T cell responses. Including a universal class II epitope that provides CD4+ T cell help towards CD8+ responses has been tested with the immunogenic tetanus toxoid epitope P30, but P30 has been employed as a separate peptide in this regard. The current study will employ targeting of three major glioma TAAs: EphA2, pp65 from Cytomegalovirus, and survivin. The ability to induce more potent TAA-specific immune responses will be tested using two novel strategies: P30-linked TAA peptides and a combinatorial vaccination of the linked peptides (P30-EPS). HYPOTHESES In Evaluation of Tumor Associated P30-Peptide Antigen I (ETAPA-I), P30-EPS is anticipated to have an acceptable toxicity profile. Multi-peptide vaccination is thought to bypass tumor heterogeneity and selection of antigen-negative clones, known as antigen escape. Moreover, the administration of EPS covalently linked to P30 is anticipated to increase the magnitude of antigen-specific immune responses and elicit both CD4- and CD8-mediated immune recognition. TRIAL DESIGN/OBJECTIVES A maximum of 24 patients with newly diagnosed, unmethylated WHO grade IV glioma will be treated. Following resection and standard of care chemoradiation, patients will be vaccinated serially during the priming phase (Day 1-22) and booster phase (Day 84 and 140). All P30-EPS vaccines during priming and boosting phases are co-administered with the adjuvant Hiltonol (Oncovir, poly-ICLC), and patients self-administer Hiltonol throughout the booster phase. The primary endpoint will evaluate the safety profile of P30-EPS. Secondary objectives include polyfunctional T-cell responses specific to EphA2, pp65 and survivin, TCR diversity, and survival. CONCLUSION We describe a study that employs known TAA targets of malignant glioma with the novel strategy of combinatorial class II-linked peptide vaccination.
Timothy Brown, Christina Zoccoli, Alireza Mansouri, Michael Glantz
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.027

Abstract:
BACKGROUND Despite an American Academy of Neurology Practice Guideline and ASCO/SNO endorsement against the routine use of anticonvulsant prophylaxis in patients with primary and metastatic brain tumors, there remains widespread variation in practice and several unanswered questions. METHODS Exhaustive evidence-based literature searches were conducted, and patient-level data from randomized controlled trials (RCTs) were analyzed to answer three questions: does anticonvulsant prophylaxis reduce the risk of first seizures in patients with primary and metastatic brain tumors; does prophylaxis improve one-year overall survival in patients with primary and metastatic brain tumors; and what effect have practice guidelines had on practice patterns. RESULTS Five RCTs (n=441 patients) addressed anticonvulsant prophylaxis in patients with brain tumors. Overall, anticonvulsant prophylaxis did not reduce the risk of a first seizure in patients with any brain tumor (RR= 0.95 [0.58-1.55], p= 0.85, anticonvulsant prophylaxis vs. placebo), brain metastasis (RR = 0.96 [0.73-1.25], p=0.77, 5 RCTs) or primary brain tumors (RR= 1.03 [0.19-5.72], p=0.97, 4 RCTs). Eleven RCTs of anticonvulsant prophylaxis (n=3767 patients with CNS tumors) provided data for survival analysis and demonstrated a lower RR of death at one year compared to those who did not receive prophylaxis (0.88 [0.81-0.94] p = 0.0006). Physician-reported practice of prescribing anticonvulsant prophylaxis diminished only negligibly after initial guideline publication (54.9% [1 study] vs. 51.6%, [3 studies] p<0.014). CONCLUSION Prophylactic anticonvulsants in patients without a history of seizures does not reduce the risk of first seizures in patients with primary or metastatic brain tumors. Despite this, anticonvulsant prophylaxis provides a small survival benefit at one year, although, this finding may be driven by confounded studies. Rates of anticonvulsant prophylaxis prescription have decreased only minimally and remain very high despite strong evidence against this practice and guideline publication. Evidence-based medicine requires additional mechanisms for encouraging practice change.
Sarah Blitz, Christine Dominas, Michael J Pannell, E Antonio Chiocca, Patrick Y Wen, Oliver Jonas, Pierpaolo Peruzzi
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.004

Abstract:
Genomic studies of tumor specimens are becoming standard of care in patients with gliomas to characterize druggable molecular features. Unfortunately, with the exception of IDH1-R132 mutation and MGMT promoter methylation, molecular markers have failed to predict clinical responses to drugs, and the impact of targeted therapies remains minimal. There is a need for a high-throughput, patient-specific, and significantly predictive method to inform a most effective personalized therapy. This pilot trial tests the safety and feasibility of drug-releasing microdevices which are temporarily implanted into the tumor during a standard craniotomy. They release microdoses of up to 20 drugs or drug combinations into surrounding tissue in a controlled spatial distribution. The devices, together with a cuff of surrounding tumor tissue, are removed at the end of surgery, and the tissue is analyzed for biological and molecular response markers allowing for in situ characterization of the drug efficacy. Four patients have been enrolled to date, out of a total planned of six. Two microdevices were implanted into each tumor (8 total devices). Average indwelling time in tumor tissue was 139 minutes. Eight devices (100%) were successfully retrieved, and all surgeries were completed without immediate (<24 hours) or delayed (<30 days) complications. Seven (87%) specimens were of adequate quality, allowing for planned histological and molecular studies. For all analyzed specimens, the intraoperative incubation time was sufficient to observe: 1) Drug concentration gradients; 2) Differential molecular signs of cell toxicity (DNA damage and Caspase 3 activation); 3) Whole genome transcriptional changes; 4) Tumor microenvironment composition; and 5) Preliminary evidence of concordance between the biological readout obtained from microdevice analysis and clinical response. Drug-releasing microdevices were well tolerated, seamlessly integrated in standard craniotomy workflow, and allowed for collection of a significant amount of data related to the differential efficacy of multiple drugs in a personalized manner.
Yoshihiro Muragaki, Eiichi Ishikawa, Masayuki Nitta, Manabu Tamura, Tadao Ohno, Taiichi Saito, Shunichi Tsuzuki, Atsushi Fukui, Takakazu Kawamata
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.016

Abstract:
INTRODUCTION The development of novel treatments for glioblastoma is desired and immunotherapy is theoretically expected for highly invasive glioblastoma. An autologous formalin-fixed vaccine (AFTV) derived from resected tumor tissue is stable, contains multiple tumor peptides, and could induce specific immunity. We have conducted three clinical trials in patients with glioblastoma, and the most recent trial was a double-blind, multicenter, phase IIb trial with 63 case enrollments. Although this Phase IIb study revealed no vaccine effects in the whole cohort (mOS: 25.6 months of AFTV group, 31.5 months of the placebo group), the 3-year PFS for patients with total tumor removal was 81% in the AFTV group versus 46% in the placebo group (P=0.067). AFTV vaccine (Cellm-001) may have an effect on certain patient subgroups, and a Phase III study has started in November 2021 (jRCT2031200153). Based on Phase IIb, the enrolled patients were those who could be completely resected on MRI. Cellm-001 administration to a patient in the placebo group at recurrence (crossover) was prohibited. In addition, photodynamic therapy (PDT) was added as a stratification factor because our retrospective study showed a good prognosis of 19 patients who underwent both PDT and AFTV (mOS 47.7 months). PATIENTS AND METHODS Trial design: double-blind (1: 1), phase III multicenter, registration 4 years, observation 2 years. ESTIMATED ENROLLMENT: 112 patients with primary glioblastoma (18-75 years old) whose contrast-enhanced lesion could be completely removed on the image and who received standard local radiotherapy and temozolomide chemotherapy. STRATIFICATION FACTORS: presence or absence of PDT, age, KPS. ADMINISTRATION METHOD: Intradermal administration 3 times before radiochemotherapy and 6 times in parallel with maintenance chemotherapy after completion. PRIMARY ENDPOINT: OS, secondary endpoints: PFS and adverse events. https://jrct.niph.go.jp/en-latest-detail/jRCT2031200153. CONCLUSION An investigator-initiated phase III trial will investigate the efficacy and safety of unique AFTV immunotherapy.
Sen Peng, Matthew Lee, Nanyun Tang, Manmeet Ahluwalia, Ekokobe Fonkem, Karen Fink, Jeffrey Raizer, Christopher Walker, Harshil Dhruv, Michael Berens
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.000

Abstract:
Glioblastoma is characterized by intra- and inter-tumoral heterogeneity. A glioblastoma umbrella signature trial (GUST) posits multiple investigational treatment arms based on corresponding biomarker signatures. A contingency of an efficient umbrella trial is a suite of orthogonal signatures to classify patients into the likely-most-beneficial arm. Assigning optimal thresholds of vulnerability signatures to classify patients as “most-likely responders” for each specific treatment arm is a crucial task. We utilized semi-supervised machine learning, Entropy-Regularized Logistic Regression, to predict vulnerability classification. By applying semi-supervised algorithms to the TCGA GBM cohort, we were able to transform the samples with the highest certainty of predicted response into a self-labeled dataset and thus augment the training data. In this case, we developed a predictive model with a larger sample size and potential better performance. Our GUST design currently includes four treatment arms for GBM patients: Arsenic Trioxide, Methoxyamine, Selinexor and Pevonedistat. Each treatment arm manifests its own signature developed by the customized machine learning pipelines based on selected gene mutation status and whole transcriptome data. In order to increase the robustness and scalability, we also developed a multi-class/label classification ensemble model that’s capable of predicting a probability of “fitness” of each novel therapeutic agent for each patient. Such a multi-class model would also enable us to rank each arm and provide sequential treatment planning. By expansion to four independent treatment arms within a single umbrella trial, a “mock” stratification of TCGA GBM patients labeled 56% of all cases into at least one “high likelihood of response” arm. Predicted vulnerability using genomic data from preclinical PDX models correctly placed 4 out of 6 models into the “responder” group. Our utilization of multiple vulnerability signatures in a GUST trial demonstrates how a precision medicine model can support an efficient clinical trial for heterogeneous diseases such as GBM.
Daniel Barboriak, Katy Peters, Allan Friedman, Henry Friedman, Annick Desjardins
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.024

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BACKGROUND Approximately 50% of patients with newly diagnosed high-grade glioma (HGG) develop progressive enhancement between their post-operative MRI scan and 12 weeks after radiation and temozolomide. Inter-reader variability on the assessment of progressive enhancement in this patient group is a significant barrier in designing multi-center biomarker trials to distinguish true progression from pseudoprogression. Although enhancement segmentation algorithms have become more widely available, more automated and reproducible techniques to identify patients who develop progressive enhancement are needed to facilitate acquisition of non-standard of care biomarkers when this occurs. We explored the feasibility of using a feature-based algorithm in tandem with freely available / open source automated segmentation algorithms to identify this subset of patients. METHODS An automated algorithm using subtraction of registered segmentations to detect new areas of localized thickness of enhancement was developed. Criteria for feasibility (50% within 95% CI of percent patients identified, and sensitivity of >85% of patients assessed as progressed [P+] identified) were determined prospectively. The algorithm was implemented across five different automated enhancement segmentation techniques, then evaluated using a retrospective dataset of 73 patients with newly diagnosed HGG (age 50.8±13.2 years, 37 men, 36 women, 50 GBM, 23 Grade III). Standardized post-baseline brain tumor imaging protocol MR acquisitions were obtained on 1.5T and 3T scanners (GE and Siemens). On chart review, 53% of patients were assessed by neuroradiologists and/or neuro-oncologists as P+ (progression vs. pseudoprogression). RESULTS 50% was within the 95% CI of percent of patients identified for all five segmentation algorithms. Sensitivity was over 85% for three segmentation algorithms, with the MIC-DKFZ algorithm having highest sensitivity of 92%. For this algorithm, specificity was 77%, PPV was 81% and NPV was 90%. CONCLUSION A feature-based algorithm in tandem with open source segmentation algorithms showed preliminary feasibility for automated identification of patients with progressive enhancement.
Aditya Mohan, Katherine Peters, Kelly Hotchkiss, Kristen Batich, Kendra Congdon, Gordana Vlahovic, Gary Archer, Pamela Norberg, Weihua Xie, James Herndon, et al.
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.019

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INTRODUCTION While primary GBM is largely heterogeneous and devoid of homogeneously expressed neoantigens, mutant IDH1 (R132H) is a uniformly expressed hallmark in >70% of low grade gliomas. As such, IDH1 mutations represent a potentially valuable vaccination target. METHODS Here, we report an update on the immunogenicity results of the mutant IDH1 peptide vaccine alone and in combination with temozolomide (TMZ). In the phase I RESIST clinical trial (NCT02193347), patients with recurrent and resectable IDH1 R132H mutant grade 2 glioma received peptide vaccinations composed of 500 µg of mutant IDH1 peptide and 150 µg of GM-CSF mixed 1:1 with Montanide adjuvant prior to surgical resection. Vaccines 1, 2, and 3 were given 15 (+/-) 3 days apart. 7-12 days after vaccine 3, patients underwent standard of care tumor (SOC) resection. After resection, patients with grade 2 gliomas were given up to 15 doses of peptide vaccine in combination with TMZ regimens while patients with transformed grade 3 gliomas were given up to 15 doses of peptide vaccine in combination with SOC radiation therapy + TMZ regimens. T cell responses against the mutant peptide were measured after vaccine 3 using IFN-γ ELISPOT and intracellular flow cytometry for IL-2, TNFα,and IFNγ. RESULTS 3/20 patients were taken off the study before completion of study related activities. 1/20 patients progressed before completion of all vaccines. Out of 134 total doses of vaccine delivered, only one dose generated a grade 2 or higher injection site reaction according to the CTCAE guidelines. Vaccination with the mutant peptide led to an overall increase in IFN-γ+ spot-forming splenocytes specific to the mutant peptide (p=0.0408). CONCLUSION Administering the mutant IDH1 peptide vaccine in patients with recurrent IDH-mutant gliomas was able to induce anti-IDH1 R132H immune responses in this initial phase I study.
Kate Traynor
American Journal of Health-System Pharmacy; https://doi.org/10.1093/ajhp/zxab359

Abstract:
Sidney Paul Phillips, administrative director of pharmacy at Memorial Hermann TMC in Houston, TX, died unexpectedly July 2. He was 46 years old.
Cecile Riviere-Cazaux, Terry Burns
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.012

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INTRODUCTION Gliomas present a formidable challenge for translational progress. Heterogeneity within and between tumors may demand empirically individualized and adaptive paradigms requiring rapid mechanistic feedback. We asked if tumor-associated metabolic biomarkers from glioma extracellular fluid could impart mechanistic “intelligence” reflecting intra- and inter-tumoral heterogeneity. METHODS Five live human gliomas (2 oligos; 2 IDH-WT GBMs; 1 IDH-mutant GBM), were evaluated in situ with high molecular weight (100kDA) intraoperative microdialysis using 3 disparately placed catheters. Isotonic 3% dextran perfusate was collected in 20 min (40mL) aliquots. CSF samples (n=21) were additionally evaluated from these and other patients with diverse brain tumors. The IDH-mutant glioma-associated oncometabolite D2-hydroxyglutarate (D2-HG) was quantified with targeted Liquid Chromotography-Mass Spectrometry (LC-MS). Over 200 metabolites were further evaluated via untargeted LC-MS using the Metabolon platform. Correlation, clustering, ROC and enrichment analyses were employed to identify correlations within and between patient samples. RESULTS CSF samples from patients with IDH-mutant gliomas contained over twenty-fold higher levels of D2-HG (median 4.1 mM, range 1.6-13.2, n=7) compared to those from IDH-wild type tumors (median 0.19 mM; range 0.89-0.35, n=14). Microdialysate from IDH-mutant gliomas contained 10-953mM D2-HG, 9-63x higher than paired CSF samples. Interestingly, IDH status failed to predict the global metabolic signature of microdialysate. Microdialysate samples clustered into 2 major metabolic phenotype clusters with IDH-WT and IDH-mutant gliomas in each cluster. A superimposed metabolic signature distinguishing enhancing from non-enhancing tumor, was conserved in both patient clusters. Amino acid and carnitine metabolism predominated in microdialysate signatures. TCA cycle and Warburg-associated metabolites were differentially enriched in CSF samples after prior therapy independent of tumor burden. CONCLUSIONS Intra-operative micro-dialysis may complement currently available “intelligence” regarding the phenotype, burden, and metabolism of live human gliomas and is feasible within standard-of-care surgical procedures. Future work will evaluate utility for pharmacodynamic feedback following novel early phase candidate therapies.
Daniel Barboriak, Jon Steingrimsson, Constantine Gatsonis, David Schiff, Lawrence Kleinberg
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.006

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Validated biomarkers that more accurately predict prognosis and/or measure disease burden in patients with high-grade gliomas would help triage which treatment strategies are most promising for evaluation in Phase III multicenter trials. Multicenter trials to evaluate imaging biomarkers in this group face particular challenges; these trials have historically been slow to accrue and have not recently succeeded in validating new imaging biomarkers useful in treatment development. Due to variability in image acquisition protocols, scanner hardware, image analysis, and interpretive schemes, promising results obtained in single centers are poor predictors of success in the multicenter setting. Multicenter preliminary data to support further evaluation of imaging biomarkers is rarely available. The need for more efficient trial designs that bring multicenter data earlier into the process of biomarker development has become increasingly clear. In this presentation, the planning process within ECOG-ACRIN’s Brain Tumor Working Group for a platform multicenter trial called GABLE (Glioblastoma Accelerated Biomarker Learning Environment trial) designed to evaluate biomarkers for distinguishing pseudoprogression from true progression in patients with newly diagnosed GBM is described. In our planning process, it was determined that efficiencies can be gained from evaluating multiple biomarker types in parallel rather than serially; in the context of the proposed trial, not only conventional imaging biomarkers but plasma biomarkers and radiomic biomarkers can be evaluated simultaneously. Patient tolerance limits the feasibility of evaluating multiple non-standard-of-care imaging biomarkers in parallel. For this group of biomarkers, a “fast-switching” serial evaluation strategy using multiple interim analyses was developed to triage out biomarkers unlikely to succeed in identifying patient groups with clinically significant differences in median survival. For biomarker triage, an endpoint of event-free survival (events of either death or NANO progression) was proposed. Simulations were used to evaluate alpha and beta error using this evaluation strategy.
Timothy Brown, Alireza Mansouri, Samer Zammar, Michael Glantz
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.010

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INTRODUCTION The basic science research endeavor has been abundantly and astonishingly successful in the last three decades in elucidating the mechanisms of neuro-oncologic disease and in suggesting therapeutic strategies. Clinical successes have lagged behind, and translation of promising laboratory findings into clinical practice is rare. We hypothesize that one important reason for this discordance is the use of different paradigms for designing laboratory and clinical trials, and that utilizing clinically relevant procedures could improve laboratory study impact. METHODS We identified all pre-clinical neuro-oncology therapeutic trials published in four high-impact journals between 11/2018 and 4/2019 and assigned a level of evidence (LOE) to each study using the American Academy of Neurology evidence classification system. We then identified all phase III trials of therapeutics for COVID and performed the same analysis on all preclinical studies preceding the trials. RESULTS Of the 26 neuro-oncology articles identified, 85% had a LOE of IV and 15% were class III. An analysis of successful human trials showed significantly more high quality laboratory studies supporting “successful” compared to “unsuccessful” trials (p=0.048). This same pattern was identified in phase III trials of COVID. Twenty antiviral studies failed to meet the primary endpoint; all were preceded by class III or IV LOE preclinical studies. Eight evaluable phase three studies of COVID vaccines were identified, all of which met their primary endpoints. These were supported with a mix of Class I/II (n=4) and III/IV (n=4) preclinical studies. Higher LOE by AAN criteria is associated with successful COVID therapeutic trials (p=0.0034). CONCLUSIONS Despite rigorous, elegant, and enlightening laboratory experiments, successful translation to human therapeutics remains rare. Envisioning basic science research through the lens of clinical therapeutics represents a challenging but surmountable paradigm shift that may reverse this pattern and create a more successful research enterprise in neuro-oncology and beyond.
Kelly Hotchkiss, Kirit Singh, Kristen Batich, Gerald Archer, Pamela Norberg, Annick Desjardins, Henry Friedman, Margaret Johnson, Katherine Peters, Mustafa Khasraw, et al.
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.017

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INTRODUCTION Cytomegalovirus (CMV) antigens are excellent anti-tumor immunotherapeutic targets in glioblastoma (GBM). The PERFORMANCE trial (IRB-pro34208, IND-15846) assessed the feasibility, safety and optimal adjuvant temozolomide (TMZ) regimen to be used with PEP-CMV vaccination in adults with newly-diagnosed GBM. METHODS Seropositive CMV patients (n=16) were randomized into two arms and treated with standard of care RT-TMZ (SOC) (150-200 mg/m2/day on days 1-5 per 28-day cycle) or dose-intensive TMZ (DI) (75-100 mg/m2/day on days 1-21 per 28-day cycle). Patients received intradermal PEP-CMV vaccines (500μg of CMVpp65 synthetic long peptide (SLP) mixed with Montanide ISA-51) on days 23, 37 and 51 following TMZ. All patients received tetanus/diphtheria toxoid (Td) preconditioning at the vaccination site on day 22. Serum cytokine levels were measured pre-vaccination, 1-hour and 2-hours post vaccination. PEP-CMV specific circulating PBMCs were quantified at baseline and after each vaccine. RESULTS Of the 16 trial patients, 7 experienced site-reactions, 4 had grade-II Immune Related Adverse Events (IRAEs), and 4 experienced flu-like grade-III IRAEs. Inflammatory cytokines (IL-2, IFNγ, MIP-1a, IL-8, TNFα, and IL-10) were elevated in patients with grade-III responses 2-hours post vaccine 1. Td p2/p30 specific PBMC levels were similar between IRAEs. However, pp65 responsive PBMCs were elevated at baseline in patients with grade-III reactions compared to site-reaction suggesting pre-existing peptide specific responses may lead to increased vaccine immunogenicity. PBMCs specific for pp65 increased with number of consecutive vaccines. No difference in progression free survival (PFS) or overall survival (OS) was observed between TMZ regimens. CONCLUSION PEP-CMV vaccination with Td preconditioning is feasible and generates immune responses specific to pp65 in patients with newly diagnosed GBM. Importantly, IRAEs were associated with antitumor efficacy. The mild IRAEs in PERFORMANCE are likely indicative of vaccine potency and can be managed through standard premedication as has been used in other trials with similar IRAEs.
Asher Marks, Ranjit Bindra
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.002

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DESCRIPTION The lack of enrollment of AYA patients on clinical trials is well documented and multivariant. Here we present the basic science, examination of its relevance to the AYA population specifically, and the parallel deployment of two international clinical trials via a pediatric neuro-oncology and adult brain tumor consortium. DISCUSSION In February of 2017, the laboratory of Ranjit Bindra, MD, PhD, published a manuscript describing the finding that tumors with IDH1/2 mutations induce a BRCAness state leading to PARP inhibitor (PARPi) sensitivity and synergistic interactions with temozolomide chemotherapy [2]. Despite IDH1/2 mutations being rare in the pediatric high-grade glioma population, three independent groups confirmed that the incidence is significantly increased to ~30% in the adolescent and young adult (AYA) population. Upon discovery of a high blood-brain-barrier penetrant, high potency PARPi by BeiGene Pharmaceuticals, an international trial was launched through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) [3] to test this drug in an AYA specific trial recruiting patients ages 13 to 25, with a concurrent trial being run for patients older than 25 years of age through the Adult Brain Tumor Consortium (ABTC) [4]. While most trials that enroll AYA patients are forced to assess them as a unique cohort in post-analysis, if at all, the PNOC trial mentioned above was designed from the ground up with the AYA population in mind. It has allowed us to base initial dosing, recruitment strategies, psychosocial assessments, and outcomes, specifically on the AYA population. Ultimately, we expect their distinctive biology to yield unique results when compared to the ABTC trial. We propose that this is a model that could potentially be replicated in other disease processes and early phase drugs with the buy-in of the pharmaceutical industry and early phase consortiums. Acknowledgements: BeiGene Pharmaceuticals, PNOC, ABTC, CureSearch, Gateway Foundation
Sébastien Perreault, Valérie Larouche, Uri Tabori, Cynthia Hawkins, Sarah Lippé, Benjamin Ellezam, Jean-Claude Decarie, Luis H Ospina, Yves Theoret, Leandra Desjardins, et al.
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.032

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BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This ongoing multicenter phase II trial includes three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). The primary objective was to evaluate the overall response rate based on RANO criteria after daily oral trametinib administration for 18 cycles, lasting 28 days each. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and quality of life evaluation during treatment. RESULTS As of February 12 2021, 50 patients have been enrolled (NF1: n=10; KIAA1549-BRAF fusion: n=31; other: n=9 including 5 patients with FGFR1 alterations). Median age is 8.8 years (range 2.4-25.5). Median follow-up is 17.5 months (range 4.7-28.5). Forty-three patients are evaluable. The overall response includes: 4 partial response (PR) (9%), 18 minor response (MR) (42%), 17 stable disease (40%), 4 progressive disease (9%). Median time to response is 5.5 months (range 2.4-13.8). Median duration of response is 6.1 months (range 0.6-26.5). Progression free survival at 12 months is 79.9% (95% CI 68.5-93.6%) and median progression free survival has not yet been reached. Treatment was discontinued for 30 patients: 16 after completing 18 cycles as planned, 5 for progressive disease, 5 for adverse events, 4 for other reasons. A total of 8 patients progressed after discontinuation of treatment including 6 patients (37.5%) that completed 18 cycles. Five of these patients had achieved minor response prior to discontinuation. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Treatment was overall well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.
Fred Lam
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.003

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Standard of care for patients with glioblastoma (GBM) includes resection with concurrent temozolomide (TMZ) and radiotherapy, with inevitable disease recurrence. Upon recurrence, tumors are often resistant to first-line therapies and/or have infiltrated eloquent or deep brain regions, precluding repeat resection. There is currently no standard of care for recurrent GBM and patients succumb to their disease burden within 12- 15 months of their initial diagnosis of recurrence, exposing an unmet need to find novel therapies to treat recurrent disease. Bromodomain and extraterminal (BET) proteins are chromatin readers that affect transcription of genes. The oral BET inhibitor (BETi) OTX-015 has shown promise in a dose-escalation, phase I study in patients with acute leukemia and other BET inhibitors are currently in phase I studies for the treatment of primary brain tumors. We have recently shown that BET inhibition increases DNA damage and mitotic catastrophe in oncogenic cells by increasing transcription-replication conflicts and downregulating expression of key DNA damage checkpoint proteins, and have also shown its efficacy in decreasing tumor burden and improving survival when combined with TMZ in intracranial mouse models of glioma. We have also demonstrated that BETi's synergize with Olaparib by downregulating expression of the BRCA-driven DNA damage repair pathway and further leverages additive effects when triply combined with other DNA damaging agents such as Lomustine to decrease tumor burden and improve survival in patient-derived mouse models of GBM and medulloblastoma. We therefore hypothesize that the synergistic and additive effects of this triple combination seen in our preclinical studies will achieve therapeutic benefits in patients with recurrent GBM.
Rupesh Kotecha, Alain Chaglassian, Nancy Tainer, Eugene J Teoh
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.001

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BACKGROUND Brain metastases represent the most common intracranial tumor in adults, occurring in 10-40% of cancer patients. Most patients undergo multimodal treatment approaches and post-treatment follow-up with conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) of the brain is performed to monitor for disease recurrence. However, owing to the similar appearance of treatment-related changes like radiation necrosis with that of true recurrence, conventional MRI alone suffers from low specificity. Given the high mortality of patients with brain metastases and the considerable treatment-associated morbidity, a need remains for an imaging modality that accurately differentiates recurrence from treatment-related changes. Accurate imaging is key to preventing unnecessary surgery or changes in effective therapy in patients mistaken for disease progression as well as prevent continuation of ineffective therapy if radiation necrosis is incorrectly diagnosed. To this end, 18F-fluciclovine is a synthetic amino acid-based PET imaging agent that has potential to evaluate primary and metastatic brain cancers owing to its low normal background uptake in the brain and increased uptake in brain tumors. METHODS NCT04410367 is a prospective, open-label, single-arm, single-dose (185 MBq ± 20%) study with a primary objective to establish visual image interpretation criteria for 18F-fluciclovine PET studies of recurrent brain metastases. Forty subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled across ~8 US sites if they have a reference lesion considered equivocal on MRI for recurrent disease and are planned for craniotomy. Subjects will undergo 18F-fluciclovine PET <42 days after the MRI and 1–21 days before planned craniotomy. Outcome measures comprise the diagnostic performance of 18F-fluciclovine PET at different thresholds of 18F-fluciclovine uptake compared with histopathology, subject- and lesion-level diagnostic performance based on established image interpretation criteria, and safety evaluations. Enrolment began in August 2020 and the trial is open at the time of submission.
Zhong-Ping Chen, Cheng-Cheng Guo, Qun-Ying Yang, Jia-Wei Li, Shao-Xiong Wu, Jeffrey Bacha, Greg Johnson, John Langlands, Claire Kwan, Sarath Kanekal, et al.
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.033

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VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemo-resistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. Pharmacokinetics (Cmax and AUC) of VAL-083 were broadly linear with respect to dose, and drug half-life was 0.8 hrs. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. The median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Eighteen (18/29; 62.1%) patients have died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. These results support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.
Mame Daro Faye, Siham Sabri, Paula De Robles, Raman Agnihotram, Alexander Torres-Vasquez, Jacob Easaw, Bassam Abdulkarim
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.036

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INTRODUCTION Despite advances in treatment modalities, the overall prognosis of GBM remains dismal, particularly for patients with unmethylated MGMT promoter. Thus, alternative treatment strategies are warranted. Our group has previously shown that addition of Sunitinib (SU11248) to standard therapy significantly improved the response of unmethylated MGMT cells through decreased angiogenicity and tumorigenicity. In this phase II trial, we tested for the first time the combination of Sunitinib with RT and Temozolomide in newly diagnosed MGMT unmethylated GBM patients. METHODS Patients with histologically confirmed WHO Grade IV GBM and MS-PCR confirmed unmethylated MGMT promoter, age 18-70, KPS ≥70, life expectancy ≥6 months were eligible. 41 patients treated between 2012 and 2017 were screened, 37 of which were eligible. Patients received 12.5 mg of daily Sunitinib for 7 days, followed by concurrent RT, Temozolomide and 12.5 mg Sunitinib for 6 weeks, then adjuvant Temozolomide x6 cycles. RT and Temozolomide doses were as per standard of care. Primary objective was PFS as assessed by RANO criteria, secondary objectives were OS and safety. RESULTS Median follow-up time was 15 months. Median PFS was 7 months (95%CI, 6.7-7.2) and 6-month PFS was 59.3%. Median OS was 13 months (95%CI, 12.62-13.37) and 2-year OS was 17.8%. Two patients had OS >50 months, with one surviving 71 months. Having received >3 cycles of adjuvant Temozolomide, surgery at progression or age ≤65 significantly predicted for better OS, with hazard ratios of 0.184 (p=0.001), 0.402 (p=0.026) and 10.017 (for age >65, p=0.002) respectively. Grade ≥3 thrombocytopenia occurred in 18.9% of patients, grade ≥3 neutropenia in 10.8% and grade ≥3 thromboembolic events in 13.5%. There were no grade 5 evens. CONCLUSION Addition of Sunitinib to RT and Temozolomide was well tolerated and survival outcomes compared favorably to the current standard of care for GBM patients with unmethylated MGMT promoter status.
, , Lindsay P Campbell, , Fred Aboagye-Antwi, Luis Arturo Ibarra-Juárez,
Journal of Medical Entomology; https://doi.org/10.1093/jme/tjab161

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Mosquito-borne diseases account for human morbidity and mortality worldwide, caused by the parasites (e.g., malaria) or viruses (e.g., dengue, Zika) transmitted through bites of infected female mosquitoes. Globally, billions of people are at risk of infection, imposing significant economic and public health burdens. As such, efficient methods to monitor mosquito populations and prevent the spread of these diseases are at a premium. One proposed technique is to apply acoustic monitoring to the challenge of identifying wingbeats of individual mosquitoes. Although researchers have successfully used wingbeats to survey mosquito populations, implementation of these techniques in areas most affected by mosquito-borne diseases remains challenging. Here, methods utilizing easily accessible equipment and encouraging community-scientist participation are more likely to provide sufficient monitoring. We present a practical, community-science-based method of monitoring mosquito populations using smartphones. We applied deep-learning algorithms (TensorFlow Inception v3) to spectrogram images generated from smartphone recordings associated with six mosquito species to develop a multiclass mosquito identification system, and flag potential invasive vectors not present in our sound reference library. Though TensorFlow did not flag potential invasive species with high accuracy, it was able to identify species present in the reference library at an 85% correct identification rate, an identification rate markedly higher than similar studies employing expensive recording devices. Given that we used smartphone recordings with limited sample sizes, these results are promising. With further optimization, we propose this novel technique as a way to accurately and efficiently monitor mosquito populations in areas where doing so is most critical.
Yun Ji, Shuting Fang, Ying Yang,
Journal of Animal Science; https://doi.org/10.1093/jas/skab268

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High oxalate consumption has been recognized as a risk factor for renal calcium oxalate stones in companion animals (dogs and cats). However, the cellular signaling involved in oxalate-induced dysfunction in renal tubular epithelial cells remains not fully elucidated. In this study, Mardin-Darby canine kidney (MDCK) cells, an epithelial cell line derived from canine kidney tubule, were tested for cell proliferation activity and barrier function after being exposed to sodium oxalate (NaOx). Further, the involvement of Wnt/β-catenin in NaOx-induced renal epithelial barrier dysfunction was evaluated. MDCK cells treated with NaOx exhibited reduction in cell proliferation and migration. Besides, NaOx exposure led to a decrease in transepithelial electrical resistance (TEER) and an increase in paracellular permeability. The deleterious effects of NaOx on epithelial barrier function were related to the suppressed abundance of tight junction proteins including zonula occludens (ZOs), occludin, and claudin-1. Of note, protein levels of β-catenin and p-β-catenin (Ser552) in MDCK cells were repressed by NaOx, indicating inhibitory effects on Wnt/β-catenin signaling. An inhibition of GSK-3β enhanced the abundance of β-catenin and p-β-catenin (Ser552), and protected against epithelial barrier dysfunction in NaOx-treated MDCK cells. The results revealed a critical role of Wnt/β-catenin signaling in the epithelial barrier function of MDCK cells. Activation of Wnt/β-catenin signaling might be a potentially therapeutic target for the treatment of oxalate-linked renal stones.
Jose Pablo Leone, Nabihah Tayob, Alyssa Pereslete, Jennifer Ligibel, Heather Parsons, Wenya Bi, Jean Zhao, Eric Winer, Nancy Lin
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.034

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BACKGROUND The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. Paxalisib is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS This is a single-center, phase II study to evaluate the efficacy of the combination of paxalisib with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive paxalisib (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to paxalisib/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha <10%. Cohort B will enroll 10 patients. The trial opened in February, 2019 and 8 patients have been enrolled. NCT03765983.
Masamichi Takahashi, Yohei Chiba, Kazuki Sudo, Yuki Kojima, Hitomi Okuma, Shinji Kohsaka, Masahiko Ichimura, Natsuko Okita, Kenichi Nakamura, Ryunosuke Machida, et al.
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.029

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Background Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, in press), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043)
, Takayuki Shijo, Masako Okada, Sinji Hasegawa
European Heart Journal - Case Reports; https://doi.org/10.1093/ehjcr/ytab374

Abstract:
Background Acute papillary muscle rupture due to infective involvement has been recognized as a complication of infective endocarditis. However, there is very limited literature describing the rupture of the posteromedial papillary muscle in primary aortic valve endocarditis without aortic root abscess. This report highlights the etiology of the papillary muscle rupture in the setting of primary aortic valve endocarditis and the importance of a multidisciplinary approach. Case summary An 81-year-old man without any heart failure symptoms presented with fever and loss of vision in his left eye. Initial echocardiography revealed moderate aortic valve regurgitation due to a perforated right coronary cusp without aortic root abscess, and his blood cultures were positive for Group G Streptococci. During adequate antibiotic therapy, he developed acute severe mitral regurgitation secondary to posteromedial papillary muscle rupture. Following emergent aortic and mitral valve replacement using bioprosthetic valves, he made excellent progress on a 6-week course of intravenous antibiotics. Discussion The echocardiography and the histological findings suggested that the main cause of papillary muscle rupture was most likely a metastatic focus of infection from the aortic valve via a regurgitant jet. Successful treatment of this fatal complication includes early diagnosis and prompt surgical intervention by a multidisciplinary approach.
Susumu Odajima, Kensuke Matsumoto, Eriko Hisamatsu, Kenji Okada, Ken-Ichi Hirata
European Heart Journal - Case Reports; https://doi.org/10.1093/ehjcr/ytab376

Abstract:
Short summary A 51-year-old man presented with decompensated heart failure due to acute aortic regurgitation; he also showed “mid-diastolic mitral regurgitation”, presumably originating from pressure crossover between the left ventricle and atrium.
Mahmood AminiLari, Li Wang, Samuel Neumark, Taranah Adli, Rachel J Couban, Aidan Giangregorio, Colleen E Carney,
Published: 21 September 2021
Abstract:
Study Objectives We conducted a systematic review to explore the effectiveness of medical cannabis for impaired sleep. Methods We searched MEDLINE, EMBASE, CENTRAL and PsychINFO to January 2021 for randomized trials of medical cannabis or cannabinoids for impaired sleep vs. any non-cannabis control. When possible, we pooled effect estimates for all patient-important sleep-related outcomes and used the GRADE approach to appraise the certainty of evidence. Results Thirty-nine trials (5,100 patients) were eligible for review, of which 38 evaluated oral cannabinoids and 1 administered inhaled cannabis. The median follow-up was 35 days, and most trials (33 of 39) enrolled patients living with chronic cancer or noncancer chronic pain. Among patients with chronic pain, moderate certainty evidence found that medical cannabis probably results in a small improvement in sleep quality versus placebo (modeled risk difference [RD] for achieving the minimally important difference [MID], 8% [95% CI, 3 to 12]). Moderate to high certainty evidence shows that medical cannabis vs. placebo results in a small improvement in sleep disturbance for chronic non-cancer pain (modeled RD for achieving the MID, 19% [95% CI, 11 to 28]) and a very small improvement in sleep disturbance for chronic cancer pain (WMD of -0.19cm [95%CI, -0.36 to -0.03cm]; interaction p=0.03). Moderate to high certainty evidence shows medical cannabis, versus placebo, results in a substantial increase in the risk of dizziness (RD 29% [95%CI, 16 to 50], for trials with ≥3 months follow-up), and a small increase in the risk of somnolence, dry mouth, fatigue, and nausea (RDs ranged from 6% to 10%). Conclusion Medical cannabis and cannabinoids may improve impaired sleep among people living with chronic pain, but the magnitude of benefit is likely small.
Mei-Yin Polley, Daniel Schwartz, James Dignam
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.011

Abstract:
While recent Phase 3 glioblastoma (GBM) trials have failed to establish novel therapies, they potentially provide a high-quality source of external control patients treated with temozolomide. We consider hybrid two-stage adaptive designs that leverage these external controls to safely accelerate Phase 3 GBM trials. The basic strategy is that first patients are randomized 1:1 between the control and experimental arms, then an interim check measures similarity between the trial's control patients and potential external controls, and finally if this interim similarity is high the randomization ratio is changed accordingly and the external controls are used in the final analysis. An extensive simulation study is conducted to assess operating characteristics and we discuss when these hybrid designs can accelerate GBM therapy development while maintaining strict error control.
Samuel T Chao, Alain Chaglassian, Nancy Tainer, Eugene J Teoh
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.023

Abstract:
BACKGROUND Brain metastases occur in up to 40% of patients with cancer and are associated with poor prognosis and considerable levels of recurrence. Consequently, close follow-up with serial brain MRI is performed post-treatment to monitor for recurrent disease. Although conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) is the recommended follow-up modality, it has poor specificity with limited ability to differentiate between true disease recurrence and treatment-related changes such as radiation necrosis. Therefore, alternative imaging options are sought in order to help physicians confidently diagnose treatment-related changes and thus reliably stratify the risk of continuation of a therapeutic regimen, especially given the morbidity associated with current treatments. Amino acid PET imaging agent, 18F-fluciclovine, has increased uptake in brain tumors relative to normal tissue and may be useful for detecting recurrent brain metastases. METHODS NCT04410133 is a prospective, open-label, single-arm, single-dose (185 MBq ±20%) study with a primary objective to confirm the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for detection of recurrent brain metastases where MRI is equivocal. Approximately 150 subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled in this multicenter trial (~18 US sites) if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures such as biopsy/neurosurgical intervention or clinical follow-up. Subjects will undergo 18F-fluciclovine PET <42 days after the equivocal MRI and 1–21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Secondary objectives include evaluation of subject- and lesion-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity, respectively) for recurrent brain metastases, inter-reader and intra-reader agreement, and safety evaluations. Enrolment began in October 2020 and the trial is open at the time of submission.
Holly Roberts, Karthik Ravi, Allison Schepers, Bernard Marini, Cassie Kline, Sabine Mueller, Carl Koschmann, Andrea Franson
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.005

Abstract:
Genetic sequencing of diffuse intrinsic pontine gliomas (DIPG) has revealed genomic heterogeneity, fueling an interest in individualized targeted therapies. A feasibility study, PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), was completed within the Pacific Pediatric Neuro-Oncology Consortium in which a multidisciplinary tumor board reviewed molecular and genomic profiling of each participant’s tumor to make targeted therapy recommendations. Separately, our team developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to derive numeric scores for anticancer agents to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that agents highly-scored by CNS-TAP would overlap with agents recommended by the PNOC003 tumor board. For each study participant, we retrospectively utilized the genomic profiling report to identify actionable alterations and incorporated these data into CNS-TAP to find the highest-scoring agents. We compared these CNS-TAP-recommended agents with recommendations from the tumor board for each of the 28 PNOC003 participants. Overall, 93% of patients (26/28) had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% of all agents (36/95) chosen by the tumor board were also selected by CNS-TAP. When only molecularly targeted anticancer agents were included in a sub-analysis, 60% of agents (34/57) were recommended by both methods. At present, we are prospectively evaluating the CNS-TAP tool within PNOC008: A Pilot Trial Testing the Clinical Benefit of Using Molecular Profiling to Determine an Individualized Treatment Plan in Children and Young Adults with High-Grade Glioma (NCT03739372). The CNS-TAP tool recommendations are shared during the PNOC008 molecular tumor board meetings once a consensus treatment recommendation has been reached. Subsequent analyses will focus on any adjustments in therapy decisions within the tumor board that result from the CNS-TAP tool output.
Kirit Singh, Kelly Hotchkiss, Patrick Gedeon, Teilo Schaller, James Herndon, Gary Archer, John Sampson, Mustafa Khasraw
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.018

Abstract:
INTRODUCTION Approximately 30% of glioblastomas harbor the tumor specific EGFRvIII mutation. hEGFRvIII-CD3 bi-scFv (Brain Bi-Specific T Cell Engager - BRiTE) is a novel bispecific antibody construct which can redirect a patient’s entire repertoire of T cells (TCR-agnostic) to specifically lyse EGFRvIII-positive tumor cells. Compared to CAR-T therapy, it offers a highly potent yet off-the-shelf approach for glioblastoma. BRiTE is now entering Phase I clinical trials (NCT04903795) and will be trialed as a monotherapy or with autologous T cell infusion. Migration of T cell binding macromolecules across the blood-brain barrier may be facilitated by activated T cells which adhere to the microvascular endothelium and enter the brain parenchyma. Concurrent administration of activated T cells could therefore enhance trafficking of BRiTE and other antibody-based macromolecules into the intracerebral compartment. HYPOTHESIS We hypothesize that treatment of EGFRvIII-positive WHO grade IV malignant glioma with BRiTE alone or with peripheral T-cell infusion is safe and can induce objective tumor shrinkage at tolerable doses. TRIAL DESIGN/OBJECTIVES A maximum of 18 patients with newly diagnosed or recurrent WHO grade IV malignant EGFRvIII+ glioma will be enrolled after undergoing standard of care treatment. The primary objective will be evaluating the safety of BRiTE alone and with autologous T cell infusion. Patients will receive a single BRiTE infusion, followed 14 days later by an infusion of activated autologous T cells and a second bolus BRiTE infusion. Dose escalation and de-escalation will be managed using a Bayesian optimal interval design. Secondary objectives will be to describe clinical benefit as determined by objective response rate per mRANO criteria, and to evaluate BRiTE pharmacokinetics in serum. CONCLUSION We describe a first-in-human trial of bispecific T cell engager therapy for glioblastoma. We also describe our novel approach for enhancing intracranial penetration of BRiTE using autologous T cell infusion.
Nancy U Lin, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Emma Oscroft, Shawn Anand, Graham Walker, Nadia Harbeck
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.013

Abstract:
BACKGROUND Despite treatment advances, up to 50% of patients with advanced HER2+ BC develop BM (Zimmer. Cancer Rep. 2020). Patients with HER2+ BC with BM have a worse prognosis than patients without BM. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a subgroup with stable BM, with a confirmed objective response rate (ORR) of 61.4% and an extracranial confirmed ORR by independent central review (ICR) of 58.3%, median progression-free survival (PFS) of 19.4 and 18.1 mo, and median duration of response (DOR) of 20.8 and 16.9 mo (Modi. Cancer Res. 2021; Jerusalem. Ann Oncol. 2020). Here we describe a trial evaluating T-DXd in patients with previously treated advanced/metastatic HER2+ BC ±BM. DESIGN DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (86 sites in the US, Europe, Australia, and Japan), phase 3b/4 study assessing T-DXd 5.4 mg/kg q3w efficacy and safety in patients with previously treated advanced/metastatic HER2+ BC ±BM that progressed with ≥1 prior anti-HER2–based regimen and received ≤2 lines of therapy in the metastatic setting (excluding patients with prior tucatinib). Patients (n=250/cohort) will be enrolled in cohort 1 (−BM at baseline) or 2 (+BM at baseline). BM must be untreated and not needing immediate local therapy or previously treated and stable or progressing. Primary endpoints are ORR (cohort 1) and PFS (cohort 2) (both by RECIST version 1.1 per ICR). Secondary endpoints are OS, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and QOL in both cohorts; incidence of new symptomatic CNS metastasis (CNSM) in cohort 1; and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNSM in cohort 2. This is an encore; the original presentation will be at The European Society for Medical Oncology 2021.
Hui-Kuo Shu, Karen Xu, Karthik Ramesh, Vicki Huang, Saumya Gurbani, Eduard Schreibmann, Brent Weinberg, Soma Sengupta, Alfredo Voloschin, Matthias Holdhoff, et al.
Neuro-Oncology Advances, Volume 3; https://doi.org/10.1093/noajnl/vdab112.035

Abstract:
PURPOSE Glioblastomas (GBMs) are highly aggressive brain tumors with poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability, anti-GBM activity, and potential to enhance chemoradiation. This clinical trial sought to determine a tolerable dose of concurrent belinostat and assess the clinical efficacy of combining this drug with standard-of-care therapy. METHODS 13 patients each were enrolled in control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750mg/m2 1x/day x 5 days) every 3 weeks (weeks 0, 3, and 6 of RT). All patients received standard temozolomide and radiation therapy (RT). Patient outcomes included progression-free survival, overall survival (OS), and analysis of recurrence pattern of the recurrent gross tumor volume (rGTV). RESULTS Belinostat at 750 mg/m2 produce dose-limiting toxicities (DLTs) in 2 of 3 patients while belinostat at 500 mg/m2 did not result in DLTs. Median OS was 18.5 months for the belinostat cohort and 15.8 months for the control cohort (p=0.53). The rGTVs in the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients that experienced out-of-field recurrences, tumors were detectable by spectroscopic MRI (sMRI) before RT. In particular, one belinostat patient had an IDH-mutant GBM that had an extraordinary response to therapy with significant shrinkage of enhancing tumor much greater than expected. CONCLUSION Belinostat given concurrently at 500 mg/m2 is well-tolerated. While median OS was not significantly increased for the belinostat cohort, recurrence analysis suggests better in-field control with belinostat, suggesting a radio-sensitizing effect. This study suggests that belinostat can act as a synergistic therapeutic agent for GBMs that may be further enhanced by sMRI-guided RT and may be particularly effective against IDH mutant tumors. A trial is currently in development using belinostat with sMRI-guided RT for IDH-mutant high-grade gliomas.
, Paul M Brennan, Michael T C Poon, ,
Neuro-Oncology Advances; https://doi.org/10.1093/noajnl/vdab136

Abstract:
Background Patients with central nervous system (CNS) tumours may be at risk of dying from cardiovascular disease (CVD). We examined CVD mortality risk in patients with different histological subtypes of CNS tumours. Methods We analysed UK(Wales)-based Secure Anonymised Information Linkage (SAIL) for 8,743 CNS tumours patients diagnosed in 2000-2015, and US-based National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) for 163,183 patients in 2005-2015. We calculated age-, sex-, and calendar-year- adjusted standardised mortality ratios (SMRs) for CVD comparing CNS tumour patients to Wales and US residents. We used Cox regression models to examine factors associated with CVD mortality among CNS tumour patients. Results CVD was the second leading cause of death for CNS tumour patients in SAIL (UK) and SEER (US). Patients with CNS tumours had higher CVD mortality than the general population (SAIL SMR=2.64, 95% CI=2.39-2.90, SEER SMR=1.38, 95% CI=1.35-1.42). Malignant CNS tumour patients had over 2-fold higher mortality risk in US and UK cohorts. SMRs for non-malignant tumours were almost 2-fold higher in SAIL than in SEER. CVD mortality risk particularly cerebrovascular disease was substantially greater in patients diagnosed at age younger than 50 years, and within the first year after their cancer diagnosis (SAIL SMR=2.98, 95% CI=2.39-3.66, SEER SMR=2.14 95% CI=2.03-2.25). Age, sex, race/ethnicity in USA, deprivation in UK and no surgery were associated with CVD mortality. Conclusions Patients with CNS tumours had higher risk for CVD mortality, particularly from cerebrovascular disease compared to the general population, supporting further research to improve mortality outcomes.
Published: 21 September 2021
Abstract:
The striatum integrates sensorimotor and motivational signals, likely playing a key role in reward-based learning of goal-directed behavior. However, cell type-specific mechanisms underlying reinforcement learning remain to be precisely determined. Here, we investigated changes in membrane potential dynamics of dorsolateral striatal neurons comparing naïve mice and expert mice trained to lick a reward spout in response to whisker deflection. We recorded from three distinct cell types: i) direct pathway striatonigral neurons, which express type 1 dopamine receptors; ii) indirect pathway striatopallidal neurons, which express type 2 dopamine receptors; and iii) tonically active, putative cholinergic, striatal neurons. Task learning was accompanied by cell type-specific changes in the membrane potential dynamics evoked by the whisker deflection and licking in successfully-performed trials. Both striatonigral and striatopallidal types of striatal projection neurons showed enhanced task-related depolarization across learning. Striatonigral neurons showed a prominent increase in a short latency sensory-evoked depolarization in expert compared to naïve mice. In contrast, the putative cholinergic striatal neurons developed a hyperpolarizing response across learning, driving a pause in their firing. Our results reveal cell type-specific changes in striatal membrane potential dynamics across the learning of a simple goal-directed sensorimotor transformation, helpful for furthering the understanding of the various potential roles of different basal ganglia circuits.
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