bluuebunny/crossref_metadata_2025 huggingface dataset:
A study on the geometric effects of a concrete filling body in remaining roadways with fully mechanised caving
Authors: Zhang Minglei , Yang Yue , Gao Linsheng
Published: September 2021

To address the problem of the concrete filling body (CFB) force failing to reach test strength in remaining roadways, the weakening effects due to aspect ratio and dimensional parameters on the actual CFB strength were investigated in this study. The geometric effects of CFB (including hoop and size effects) as well as the geometric effect coefficient determination method were analysed. Through laboratory tests and PFC numerical simulations, the hoop and size effect coefficients of the CFB in the Gaohe Coal Mine were studied. Furthermore, the calculation equations of actual strength and bearing capacity of the CFB were derived. Regarding the filling body failure and coal deformation in the remaining roadway located at the No. W1319 working face, the actual bearing capacity of CFB and surrounding rock stability during secondary exploitation were theoretically studied. The investigation suggests the adoption of a grouting reinforcement scheme for surrounding rock. The field applications performed have demonstrated that the deformation control effect in the remaining-roadway surrounding rock was effectively improved during second mining and the filling body beside the roadway suffered no additional damage. Studying the geometric effect of CFB can provide some theoretical guidance and industrial significance to accurately identify the filling body strength and reduce the failure risk of surrounding rock in remaining roadways.
Simultaneously computing the 3D dip attributes for all the time samples of a seismic trace
Authors: Bai Bo , Yang Cun , Sun Wenbo
Published: September 2021

The seismic dip attribute is regularly used to aid structural interpretation and is commonly adopted as a compulsory input for computing other seismic geometric attributes. One disadvantage of current dip computation algorithms is that interpreters compute the dip attribute time sample by time sample and do not consider the relationship between dip values of nearby samples. The classic convolution theory suggests one formation boundary should have the corresponding seismic event. However, the seismic wavelet always has a certain time duration. As a result, one formation boundary has a corresponding seismic event that consists of several time samples. Ideally, the time samples, which belong to the same boundary, should have approximately the same dip attributes. In this research, a sample by sample computation procedure is treated as an independent optimisation procedure. Then, simultaneously computing the seismic dip of time samples of one seismic trace can be regarded as a multi-objective optimisation procedure. The proposed method is based on analysing features of seismic waveform within user-defined windows. Considering that nearby time samples should have continuous dip values, we the dynamic time warping to simultaneously compute seismic reflectors’ dip values of a seismic trace. We applied our method to a field seismic data to demonstrate its effectiveness.
Through the Eyes of Ulūpī: A Distinctive Snake Perspective in theMahābhārata
Authors: Black Brian
Published: September 2021

In this article, I will explore the role and significance of snakes in the Mahābhārata. Rather than offer a general account of how they are depicted across the text, I will focus my attention on one snake character in particular: Ulūpī, a vital, but often overlooked persona. Although she only participates in two episodes, in both cases she bursts into the narrative from underground to change the course of events decisively and with major consequences. By considering both of her appearances together, I will argue that Ulūpī plays a more central role in the unfolding of the narrative than has been previously realised. Throughout the article, I will reflect on Ulūpī’s identity as a snake. By looking at the terms used to describe her, how she relates to other prominent snake characters, and the relationship between her lineage and other snake lineages, I will show that her unique perspective brings out a nuanced and diverse understanding of snakes that can contribute to our wider appreciation of these complex characters in the Mahābhārata. Moreover, I will suggest that Ulūpī’s distinctive vantage point as a snake within the lineage of Airāvata sheds new light on two pivotal episodes: Janamejaya’s snake sacrifice and the burning of the Khāṇḍava Forest.
Frugivorous bats promote epizoochoric seed dispersal and seedling survival in a disturbed Neotropical forest
Authors: Villalobos-Chaves David , Rodríguez-Herrera Bernal
Published: September 2021

Animal-dispersed plants usually rely upon multiple dispersers. In many ecosystems, most of these interactions have yet to be explored; thus, documenting the extent of contribution of each animal partner to the reproduction and survival of plant species is key to understanding the ecology and evolution of animal–plant mutualism, as well as the potential responses of the ecological networks to biodiversity loss through defaunation. Here, by characterizing the outcomes and differences of the epizoochoric seed dispersal carried out by two species of frugivorous bats (Artibeus phaeotis and Uroderma convexum) in a Neotropical forest, we tested the prediction that, through their feeding activity, both bat species disperse and influence the subsequent seedling survival of multiple seed species. By direct sampling on bats’ dispersing sites and surrounding areas, we found evidence of the dispersal of 2,310 seeds of eight plant species, of which 118 survived to become seedlings. The total density of seeds and the seedling survival were significantly higher in areas directly influenced by the bats (i.e., feeding roosts) than in peripheral areas. Positive density-dependent effects nevertheless were detected in both sampling areas (feeding roosts and peripheral areas). Interspecific comparisons showed that despite both bat species having similar dispersal outcomes, seedlings in peripheral areas related to A. phaeotis have better survival rates. Our results demonstrate that both bat species primarily disperse by epizoochoric means seeds of various tree species at several localities in the study site. This result, together with the positive density-dependent effects, suggests that bats are moving seeds away from maternal trees and depositing them in locations where some of the seeds can germinate, establish, and survive, thereby highlighting the positive contribution of these bat species to the reproductive success of trees inhabiting Neotropical habitats. Our results contribute to the growing knowledge of frugivorous interactions on hyperdiverse forests and the role of small vertebrates on seed dispersal mutualisms.
Maternal Mental Health Disorders Following Very Preterm Birth at 5 Years Post-Birth
Authors: Yates Rosemary , Anderson Peter J , Lee Katherine J , Doyle Lex W , Cheong Jeanie L Y , Pace Carmen C , Spittle Alicia J , Spencer-Smith Megan , Treyvaud Karli
Published: September 2021

Objective

Mothers of children born very preterm (VP) are at increased risk of developing postnatal depression, anxiety, and post-traumatic stress symptoms. However, mental health disorder rates are rarely assessed in this population compared with full-term peers, and it is unclear if postnatal distress symptoms precede higher rates of maternal mental health disorders at 5 years post-birth in both birth groups.

Methods

Mothers of children born VP (n = 65; mean [SD] age at birth, 33.9 [5.0]; 72.1% tertiary educated) and full-term (n = 90; mean [SD] age at birth, 33.4 [4.0]; 88.2% tertiary educated) completed questionnaires assessing symptoms of depression, anxiety, and trauma within 4 weeks of birth. At 5 years post-birth, they participated in a structured diagnostic interview assessing mood, anxiety, and trauma-related mental health disorders, both current and over the lifetime.

Results

There was little evidence for differences between mothers in the VP and full-term groups in rates of any mental health disorder at 5 years (VP = 14%, full-term = 14%) or lifetime (VP = 41%, full-term = 37%). In mothers of children born VP, elevated postnatal post-traumatic stress symptoms were associated with higher rates of mental health disorders at 5 years (odds ratio = 21.5, 95% confidence interval = 1.35–342).

Conclusions

Findings suggest that preterm birth may not lead to increased odds of later developing maternal mental health disorders, despite known risks of elevated postnatal distress following a VP birth. However, those with post-traumatic stress symptoms following a VP birth could be more vulnerable, and assessment and monitoring is recommended.
Cerebrospinal fluid leak post COVID-19 nasopharyngeal swab for a patient with idiopathic intracranial hypertension: a case report
Authors: Asiri Mohammed , Alhedaithy Riyadh , Alnazer Zainab
Published: September 2021

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 is an infectious disease that led to a global pandemic. In this article, we reported a case of a young women who is known to have idiopathic intracranial hypertension, with iatrogenic skull base injury from a nasopharyngeal swab. Her case was complicated by meningitis.
Relationships Between Circulating Tenascin-C Levels and Gonadal Hormones in Male Patients with Depressive Disorder: A Retrospective, Cross-Sectional Study
Authors: Peng Rui , Li Di , Li Yan
Published: September 2021

Objective

Tenascin-C (TNC) is an extracellular matrix glycoprotein closely associated with the progression of psychiatric disorders. The present study was performed to investigate the possible association between serum gonadal hormones and TNC levels in male patients with depressive disorder.

Materials and Methods

We measured serum TNC levels by enzyme-linked immunosorbent assay. In addition, we investigated the influence of testosterone (T) and estradiol (E2) on TNC levels in primary neuronal cultures.

Results

Patients with depression had lower levels of T, free tri-iodothyronine (FT3), thyroid-stimulating hormone (TSH), and the T/E2 ratio than healthy control patients. Levels of TNC and high-sensitivity C-reactive protein were significantly higher in patients than in healthy volunteers. Serum TNC concentrations were negatively associated with levels of E2 and T and with the T/E2 ratio. Levels of TNC, TSH, and FT3 and the T/E2 ratio were predictors of depression. Among men with depression, TNC was negatively associated with T levels and with the T/E2 ratio. Incubating pheochromocytoma 12 cells with the combination of T and E2 greatly decreased TNC levels in the culture medium.

Conclusion

Increased TNC levels may predict imbalance between T and E2 in patients with depression, and gonadal hormones may modulate TNC expression in vivo.
Bride Price in the Patriarchal South Sudanese Society: A Legal Perspective
Authors: Deng Mark A W
Published: September 2021

This article discusses bride price and numerous problems associated with it from a legal perspective. Two such problems, indeed, the most serious of all, are: (i) bride price objectifies and commodifies women, and this lowers women’s status in society; and (ii) bride price violates a woman’s freedom to choose who to marry as all but young girls, that is, those under the age of 18, are forced into marriage by their families for bride-wealth. Young girls who dare to resist can be tortured severely, or even put to death. These practices violate the Transitional Constitution of South Sudan 2011 and the Child Act 2008 under which ‘customs’ and ‘traditions’ that are harmful to women and children are explicitly prohibited. They are equally in conflict with regional and international human rights conventions that proscribe similar practices. In light of all these issues, the article recommends bride price to be abolished through legislative measures—i.e. for the Government of South Sudan to enact a law to criminalise bride price. While this suggestion is likely to be met with resistance, given how deeply culturally ingrained this practice is, what should be compelling for the government is securing women and children’s rights and freedoms.
Observations of compact sources in galaxy clusters using MUSTANG2
Authors: Dicker Simon R , Battistelli Elia S , Bhandarkar Tanay , Devlin Mark J , Duff Shannon M , Hilton Gene , Hilton Matt , Hincks Adam D , Hubmayr Johannes , Huffenberger Kevin , Hughes John P , Di Mascolo Luca , Mason Brian S , Mates J A B , McMahon Jeff , Mroczkowski Tony , Naess Sigurd , Orlowski-Scherer John , Partridge Bruce , Radiconi Federico , Romero Charles , Sarazin Craig L , Sehgal Neelima , Sievers Jonathan , Sifón Cristóbal , Ullom Joel , Vale Leila R , Vissers Michael R , Xu Zhilei
Published: September 2021

Compact sources can cause scatter in the scaling relationships between the amplitude of the thermal Sunyaev–Zel’dovich Effect (tSZE) in galaxy clusters and cluster mass. Estimates of the importance of this scatter vary – largely due to limited data on sources in clusters at the frequencies at which tSZE cluster surveys operate. In this paper, we present 90 GHz compact source measurements from a sample of 30 clusters observed using the MUSTANG2 instrument on the Green Bank Telescope. We present simulations of how a source’s flux density, spectral index, and angular separation from the cluster’s centre affect the measured tSZE in clusters detected by the Atacama Cosmology Telescope (ACT). By comparing the MUSTANG2 measurements with these simulations we calibrate an empirical relationship between 1.4 GHz flux densities from radio surveys and source contamination in ACT tSZE measurements. We find 3 per cent of the ACT clusters have more than a 20 per cent decrease in Compton-y but another 3 per cent have a 10 per cent increase in the Compton-y due to the matched filters used to find clusters. As sources affect the measured tSZE signal and hence the likelihood that a cluster will be detected, testing the level of source contamination in the tSZE signal using a tSZE-selected catalogue is inherently biased. We confirm this by comparing the ACT tSZE catalogue with optically and X-ray-selected cluster catalogues. There is a strong case for a large, high-resolution survey of clusters to better characterize their source population.
Gas-phase laboratory study on PAH/amino-acid cluster cations
Authors: Yang Yuanyuan , Zhang Congcong , Hu Xiaoyi , Zhang Deping , Chen Yang , Zhen Junfeng , Qin Liping
Published: September 2021

As an important class of carbon reservoirs in the interstellar medium (ISM), polycyclic aromatic hydrocarbon (PAH) molecules play an important role in the evolutionary network of prebiotic molecules. Here, the experimental evidence of astronomically relevant amino-acid derivatives – PAH/amino-acid clusters – is provided, and we study their ion–molecular collision reactions in the gas phase. With the initial molecular precursors dicoronylene (DC, C48H20)/alanine (Ala, C3H7NO2) and DC/isoleucine (Ile, C6H13NO2), the experiments indicate that PAH–amino-acid cluster cations (e.g. (Ala)C48H$_{(0-19)}\, ^+$ and (Ile)C48H$_{(0-19)}\, ^+$) and graphene–amino-acid cluster cations (e.g. (Ala)nC$_{48}\, ^+$ and (Ile)nC$_{48}\, ^+$, n = 1, 2, 3, 4) are efficiently formed in a strong interstellar radiation field. In addition, the structure of clusters and the binding energy of their formation pathways are studied by a quantum chemistry calculation method: gas-phase reactions (ion–molecule reactions) between PAH cations with amino acids readily occur (exothermic energy around 2.0–4.7 eV), and these newly formed clusters have a complex molecular configuration (C–O and C–N bond type). These laboratory studies provide a cluster growth pathway (through an ion–molecule reaction) towards the formation of amino-acid derivatives in a bottom-up process and insight into their chemical-evolution behaviour, opening up aromatic-based chemistry that is available to the species (dehydrogenated PAHs or graphene molecules) that formed from the photofragmentation process of PAHs in interstellar environments. When conditions are suitable (e.g. have similar molecular abundance spatial distributions in the ISM), amino-acid derivatives can form efficiently, and newly built large PAH/amino-acid clusters may be widespread in space.
Identification of novel OCRL isoforms associated with phenotypic differences between Dent disease-2 and Lowe syndrome
Authors: Sakakibara Nana , Ijuin Takeshi , Horinouchi Tomoko , Yamamura Tomohiko , Nagano China , Okada Eri , Ishiko Shinya , Aoto Yuya , Rossanti Rini , Ninchoji Takeshi , Awano Hiroyuki , Nagase Hiroaki , Minamikawa Shogo , Tanaka Ryojiro , Matsuyama Takeshi , Nagatani Koji , Kamei Koichi , Jinnouchi Kumiko , Ohtsuka Yasufumi , Oka Masafumi , Araki Yoshinori , Tanaka Toju , Harada Mari S , Igarashi Toru , Kitahara Hikaru , Morisada Naoya , Nakamura Shun-ichi , Okada Taro , Iijima Kazumoto , Nozu Kandai
Published: September 2021

Background

Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1–7 lead to Dent disease-2, whereas those in exons 8–24 lead to Lowe syndrome. Herein we identified the mechanism underlying the action of novel OCRL protein isoforms.

Methods

Messenger RNA samples extracted from cultured urine-derived cells from a healthy control and a Dent disease-2 patient were examined to detect the 5′ end of the OCRL isoform. For protein expression and functional analysis, vectors containing the full-length OCRL transcripts, the isoform transcripts and transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells.

Results

We successfully cloned the novel isoform transcripts from OCRL exons 6–24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained >50% enzyme activity, whereas the Lowe syndrome variants retained <20% activity.

Conclusions

We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.
CLRM-01. MACHINE LEARNING TO UNCOVER SIGNATURES OF VULNERABILITY IN GLIOBLASTOMA UMBRELLA SIGNATURE TRIAL (GUST)
Authors: Peng Sen , Lee Matthew , Tang Nanyun , Ahluwalia Manmeet , Fonkem Ekokobe , Fink Karen , Raizer Jeffrey , Walker Christopher , Dhruv Harshil , Berens Michael
Published: September 2021

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.
CLRM-02. TRIAL IN PROGRESS: A PROSPECTIVE, MULTICENTER PHASE 2B STUDY TO ESTABLISH IMAGE INTERPRETATION CRITERIA FOR 18F-FLUCICLOVINE PET IN DETECTING RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY (PURSUE)
Authors: Kotecha Rupesh , Chaglassian Alain , Tainer Nancy , Teoh Eugene J
Published: September 2021

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.
CLRM-04. PHASE I/II SAFETY AND EFFICACY STUDY OF BET BROMODOMAIN INHIBITOR OTX-015 WITH OLAPARIB AND LOMUSTINE IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Lam Fred
Published: September 2021

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.
CLRM-05. DRUG-RELEASING MICRODEVICES TO PREDICT RESPONSES TO TARGETED THERAPIES IN PATIENTS WITH GLIOMAS
Authors: Blitz Sarah , Dominas Christine , Pannell Michael J , Chiocca E Antonio , Wen Patrick Y , Jonas Oliver , Peruzzi Pierpaolo
Published: September 2021

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.
IMMU-03. MULTICENTER RANDOMIZED PLACEBO CONTROLLED PHASE III TRIAL OF AN AUTOLOGOUS FORMALINFIXED TUMOR VACCINE (CELLM-001) FOR NEWLY DIAGNOSED GLIOBLASTOMAS
Authors: Muragaki Yoshihiro , Ishikawa Eiichi , Nitta Masayuki , Tamura Manabu , Ohno Tadao , Saito Taiichi , Tsuzuki Shunichi , Fukui Atsushi , Kawamata Takakazu
Published: September 2021

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.
IMMU-05. A PHASE I STUDY IN PROGRESS OF HEGFRVIII-CD3 BI-SCFV (BRITE) IN PATIENTS WITH WHO GRADE IV MALIGNANT GLIOMA
Authors: Singh Kirit , Hotchkiss Kelly , Gedeon Patrick , Schaller Teilo , Herndon James , Archer Gary , Sampson John , Khasraw Mustafa
Published: September 2021

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.
IMMU-06. TARGETING IDH1 MUTANT GRADE II RECURRENT GLIOMAS USING A PEPTIDE VACCINATION STRATEGY
Authors: Mohan Aditya , Peters Katherine , Hotchkiss Kelly , Batich Kristen , Congdon Kendra , Vlahovic Gordana , Archer Gary , Norberg Pamela , Xie Weihua , Herndon James , Jaggers Denise , Landi Daniel , Johnson Margaret , Desjardins Annick , Friedman Henry , Yan Hai , Ashley David , Khasraw Mustafa , Reap Elizabeth , Sampson John
Published: September 2021

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.
IMMU-08. PHASE II TRIAL OF PEMBROLIZUMAB AND LENVATINIB FOR LEPTOMENINGEAL METASTASES
Authors: Wang Nancy , Cahill Daniel , Oh Kevin , Cahill Jennifer , Gerstner Elizabeth , Brastianos Priscilla
Published: September 2021

Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.
NEIM-03. FEASIBILITY OF AUTOMATED ASSESSMENT OF PROGRESSIVE ENHANCEMENT ON MRI IN PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA USING A FEATURE-BASED ALGORITHM
Authors: Barboriak Daniel , Peters Katy , Friedman Allan , Friedman Henry , Desjardins Annick
Published: September 2021

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.
SCSS-02. INVOLVEMENT OF SUPPORTIVE CARE TEAM AND SOCIAL WORK IN NEUROONCOLOGY IN A TERTIARY CARE HOSPITAL
Authors: Puri Sushant , Huber Michael , Tuite Jason , Arzbaecher Jean , Nicholas Martin , Maraka Stefania
Published: September 2021

BACKGROUND/OBJECTIVES

Supportive Care and Social Work services are underutilized in Neurooncology. ASCO Quality Oncology Program Initiative (QOPI) includes emotional assessment by second and advance care planning (ACP) by third oncologic visit in solid malignancies. We looked (1) reason, location, and the duration from diagnosis for the involvement of supportive care teams and (2) what are the determining factors for advanced care planning in glioblastoma.

METHODS

After obtaining an IRB approval for the study, we performed a retrospective chart review of glioblastoma patients seen at University of Illinois Chicago 2015-2020 using the ICD Code C71.9 for malignant gliomas. Patients who had a pathologic diagnosis of glioblastoma, age > 18 years, and had their entire neurooncologic care at UIC were included in the study. Demographic features, socioeconomic determinants, tumor characteristics, and treatment history were noted. Supportive Care Teams and Social Work notes were reviewed.

RESULTS

Out of the total 403 patients, there were 78 glioblastoma patients. A total 33 met the inclusion criteria. 10 out of 33 had been seen by the supportive care team. Patients in both groups were equally matched for demographics, socioeconomic determinants, and tumor characteristics. ACP were significantly better documented in the supportive care group (p = 0.035). Supportive Care teams were consulted much later after the disease diagnosis, usually in the inpatient setting mostly consulted for goals of care discussion and hospice enrollment. There was a significant positive correlation between the involvement of Supportive Care team and Social Work.

DISCUSSION

A multidisciplinary clinic including an inbuilt palliative and social work teams can improve the Quality of Life (QoL) in glioblastoma patients and their caregivers. ICD code 99497 for a dedicated ACP discussion by the neurooncologist can be used. An ongoing phase III RCT EPCOG aims to assess (QoL) in patients with glioblastoma receiving early palliative intervention.
SYST-07. PILOT STUDY UTILIZING THE HDAC INHIBITOR BELINOSTAT WITH CHEMORADIATION FOR NEWLY-DIAGNOSED GLIOBLASTOMA
Authors: Shu Hui-Kuo , Xu Karen , Ramesh Karthik , Huang Vicki , Gurbani Saumya , Schreibmann Eduard , Weinberg Brent , Sengupta Soma , Voloschin Alfredo , Holdhoff Matthias , Barker Peter , Kleinberg Lawrence , Olson Jeffrey , Shim Hyunsuk
Published: September 2021

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.
Sexual Orientations and Identities Among Sexual Minority Emerging Adults
Authors: Svensson Marc E. D. , Frost David M.
Published: September 2021

This chapter focuses on the development of sexual orientations and identities among sexual minority emerging adults, such as lesbian, gay, bisexual, queer, pansexual, and other non-heterosexual sexual identities. The importance of sociohistorical context when examining sexual orientations and identity development is considered in explaining why emerging adults increasingly question binary constructs of both sexuality and gender, and more often adopt fluid and shifting identities, compared to older generations. New psychological frameworks accounting for these more diverse ways of approaching sexual identity and gender identity are reviewed. Nevertheless, health disparities among sexual minority emerging adults still prevail, and the minority stress framework is utilized to explain and understand the underlying reasons. The chapter concludes with suggestions on directions for future research on sexual orientations and identities in emerging adulthood.
Generation Disaster
Authors: Vermeulen Karla
Published: September 2021

Generation Disaster: Coming of Age Post-9/11 is an in-depth examination of the multiple stressors that shaped the developmental environment for today’s emerging adults in their youth and as they now take on adult responsibilities in an unprecedentedly complex world. Those stressors include all of the societal changes that occurred in the United States after the attacks of September 11, 2001, as well as other threats like the increase in school shootings and other human-caused disasters, worsening natural disasters and concerns about the future due to climate change, and the global pandemic. The omnipresence of social media amplifies these issues and heightens political divisiveness, while the difficult job market, growing wealth gap between rich and poor, and burden of student debt make many emerging adults doubt they’ll ever find a satisfying career, be able to start a family, or buy a home. As a result, many are stressed out and pessimistic about their futures, yet others are flourishing despite all of the challenges they face. Generation Disaster provides a detailed look into the many forces that are shaping this cohort of emerging adults, drawing on quantitative and qualitative research and including extensive quotations that allow its members to speak for themselves to counter the negative stereotypes older people often perpetuate about them.
Conclusion
Authors: Vermeulen Karla
Published: September 2021

The “Conclusion” chapter summarizes key points from the book, emphasizing how complex and unstable the world has always been for Generation Disaster. While every generation faces its own challenges, there has never been a combination of social and political stressors shaping daily life to the degree this cohort has experienced, yet many demonstrate remarkable resilience and optimism. I know it’s not realistic to encourage older adults to retire from their lucrative jobs or powerful political positions to make way for the next generation or to voluntarily redistribute their assets to narrow the wealth gap, but older adults are encouraged to stop judging Generation Disaster and instead to allow them to demonstrate what they’re capable of when simply given the opportunity.