bluuebunny/crossref_metadata_2025 huggingface dataset:
PARAMO: A Pipeline for Reconstructing Ancestral Anatomies Using Ontologies and Stochastic Mapping
Authors: Tarasov Sergei , Mikó István , Yoder Matthew Jon , Uyeda Josef C
Published: November 2019

Comparative phylogenetics has been largely lacking a method for reconstructing the evolution of phenotypic entities that consist of ensembles of multiple discrete traits—entire organismal anatomies or organismal body regions. In this study, we provide a new approach named PARAMO (PhylogeneticAncestralReconstruction ofAnatomy byMappingOntologies) that appropriately models anatomical dependencies and uses ontology-informed amalgamation of stochastic maps to reconstruct phenotypic evolution at different levels of anatomical hierarchy including entire phenotypes. This approach provides new opportunities for tracking phenotypic radiations and evolution of organismal anatomies.
Jumping and Grasping: Universal Locking Mechanisms in Insect Legs
Authors: Földvári Mihály , Mikó István , Ulmer Jonah M , dos Santos Rolo Tomy , Csősz Sándor , Pomiankowski Andrew , Baumbach Tilo , van de Kamp Thomas
Published: November 2019

Thickened femora of insects are correlated to enlarged muscle masses and serve two basic purposes: jumping/kicking and grasping/holding. Modifications on the ventral femoral wall and the tibial flexor tendon that are possibly involved in catch mechanisms have been described in multiple insect taxa with both jumping and grasping legs. Our comparative study aims to explore the functional and structural similarities of these modification in jumping and grasping leg types from Coleoptera, Hymenoptera, Diptera, and Orthoptera with the combination of cutting edge, noninvasive imaging methods, and classical dissections techniques. Our data indicate that locking mechanisms are present in the jumping and grasping legs of insects. We describe three femoro-tibial lock types based on the location of the interacting sclerites relative to the site of origin of the tibial flexor tendon. All of the three types can be found in jumping insect legs, whereas only one type is present in grasping legs. The locking mechanism might aid in keeping the femoro-tibial joint in a flexed position for an extended period of time. Our data indicate that morphologically similar modifications in the femoro-tibial joint are involved in energy-saving mechanisms both in jumping and grasping legs in insects.
Response to survey directed to patient portal members differs by age, race, and healthcare utilization
Authors: Peltz-Rauchman Cathryn D , Divine George , McLaren Daniel , Rubinfeld Ilan S , Conway William A , Allard David , Johnson Christine Cole
Published: November 2019

Health care systems are increasingly utilizing electronic medical record—associated patient portals to facilitate communication with patients and between providers and their patients. These patient portals are growing in recognition as potentially valuable research tools. While there is much information about the response rates and demographics of internet-based surveys as well as the demographics of patients who are portal members, not much is known about the response rate of internet-based surveys directed to a group of patient portal members or the demographics of which portal members respond to internet-based surveys issued within that specific population. The objective of these analyses was to determine the demographics of patient portal users who respond to an internet-based survey request. We hypothesized that respondents would more likely be: (1) older (65+), (2) European American, (3) married, (4) female, (5) college educated, (6) have higher medical care utilization, (7) have more comorbidities, and (8) have a private practice primary care physician (as opposed to a salaried group practice primary care physician). We found that our respondents tended to be older, of European geographic ancestry, and more frequent users of healthcare. While patient portal members are an easily identifiable and contactable group that are potentially valuable participants for research, it is important to understand that respondents to surveys solicited from this sampling frame may not be entirely representative. It will be important to develop strategies to more fully engage populations that represent the target population in order to increase overall and subgroup response rates.
Economical connections between several European countries based on TSP data
Authors: Crişan Gloria Cerasela , Pintea Camelia-M , Pop Petrică C , Matei Oliviu
Published: November 2019

A fluent economical collaboration between countries is a major need. European flows of trade and people are supported by efficient connections between main localities from a geographic region, in many cases overriding national borders. This paper introduces three traveling salesmen problem instances based on freely available geographic coordinates of the main cities of France, Portugal and Spain. These instances are unified, generating other four larger instances: three with all pairs of countries and one instance with the settlements from all the three countries. The study includes an analysis of quality of solutions for a version of branch & cut algorithm and some hybrid heuristics including the Lin–Kernighan algorithm. $Bor\mathring{u}vka$, Quick$Bor\mathring{u}vka$ and Greedy algorithms are also used in the hybrid approaches in order to obtain a potential beneficent initial solution for the Lin–Kernighan algorithm. Concorde solver, nowadays state-of-the-art exact software, together with the already mentioned algorithms, is used to test and furthermore analyze the new TSP instances. Some results are represented using online services such as Google Maps, showing the potential integration of the Concorde’s optimum results into commercial routing applications. The very good results provided by the Lin–Kernighan method allow its usage for real medium-sized routing instances.
Lithium iron phosphate power cell fault detection system based on hybrid intelligent system
Authors: Luis Casteleiro-Roca José , Quintián Héctor , Luis Calvo-Rolle José , Méndez-Pérez Juan-Albino , Javier Perez-Castelo Francisco , Corchado Emilio
Published: November 2019

Nowadays, batteries play an important role in a lot of different applications like energy storage, electro-mobility, consumer electronic and so on. All the battery types have a common factor that is their complexity, independently of its nature. Usually, the batteries have an electrochemical nature. Several different test are accomplished to check the batteries performance, and commonly, it is predictable how they work depending of their technology. The present research describes the hybrid intelligent system created to accomplish fault detection over a Lithium Iron Phosphate—LiFePO4 power cell type, commonly used in electro-mobility applications. The approach is based on the cell temperatures behaviour for voltage and current specific values. Taken into account the operating range of a real system based on a LiFePO4 cell, a large set of points of operation have been used to achieve the dataset. The different behaviour zones have been obtained by clustering as a first step. Then, different regression techniques have been used over each cluster. Polynomial regression, artificial neural networks and support vector regression were the combined techniques to develop the hybrid intelligent model proposed. The intelligent system gives very good results over the operating range, detecting all the faults tested during the validation.
A case of sigmoid colon perforation presenting with pneumomediastinum
Authors: Kuroda Yukihito , Hisakura Katsuji , Akashi Yoshimasa , Enomoto Tsuyoshi , Oda Tatsuya
Published: November 2019

A 62-year-old woman had developed polymyositis 12 years previously and had taken oral steroids. Chest and abdominal computed tomography showed pneumomediastinum and free air in the abdominal cavity. Although a colon perforation was suspected, the perforation site could not be identified on the image. In addition, a diagnosis of oesophageal rupture could not be excluded from the findings of pneumomediastinum. After general anaesthesia, an upper gastrointestinal endoscopy was performed before surgery. Because there was no obvious perforation in the oesophagus, a laparotomy approach was used. A perforation was found on the mesentery side of the sigmoid colon, and a perforation of the sigmoid colon’s diverticulum towards the mesentery was diagnosed. A Hartmann’s procedure was performed. Colon perforations are rarely associated with pneumomediastinum. Preoperative endoscopy is useful to help diagnose and determine the surgical procedure if an obvious perforation cannot be identified.
Pseudo-BCI algebras with derivations
Authors: Corina Ciungu Lavinia
Published: November 2019

In this paper we define two types of implicative derivations on pseudo-BCI algebras, we investigate their properties and we give a characterization of regular implicative derivations of type II. We also define the notion of a $d$-invariant deductive system of a pseudo-BCI algebra $A$ proving that $d$ is a regular derivation of type II if and only if every deductive system on $A$ is $d$-invariant. It is proved that a pseudo-BCI algebra is $p$-semisimple if and only if the only regular derivation of type II is the identity map. Another main result consists of proving that the set of all implicative derivations of a $p$-semisimple pseudo-BCI algebra forms a commutative monoid with respect to function composition. Two types of symmetric derivations on pseudo-BCI algebras are also introduced and it is proved that in the case of $p$-semisimple pseudo-BCI algebras the sets of type II implicative derivations and type II symmetric derivations are equal.
Efficacy of a Temporary Hemostatic Device in a Swine Model of Closed, Lethal Liver Injury
Authors: Qin Hao , Yang Lei , Liu Daocheng , Chen Sixu , Lyu Mingrui , Bao Quanwei , Lai Xinan , Liu Huayu , Chen Qiang , Zong Zhaowen
Published: November 2019

Introduction

Solid abdominal organ hemorrhage remains one of the leading causes of death both on the battlefield of modern warfare and in the civilian setting. A novel, temporary hemostatic device combining CELOX and direct intra-abdominal physical compression was invented to control closed SAOH during transport to a medical treatment facility.

Materials and Methods

A swine model of closed, lethal liver injury was established to determine hemostasis. The animals were randomly divided into group A (extra-abdominal compression), group B (gauze packing), group C (intra-abdominal compression), group D (CELOX coverage), and group E (intra-abdominal compression and CELOX coverage) with six swines per group. Survival time (ST), blood loss (BL), vital signs, pathologic examination, and CT-scan were monitored to further observe the effectiveness of the device.

Results

Group E had an average 30-minute extension in ST (74.3 ± 15.4 minutes versus 44.0 ± 13.8 minutes, p = 0.026) with less BL (46.0 ± 13.0 versus 70.8 ± 8.2 g/kg, p = 0.018), and maintained mean arterial pressure≥70 mmHg and cardiac output ≥ 3.5 L/minute for a longer time. No significant differences were observed in ST and BL of groups B and E, and there were no marked differences in ST and BL of groups A, C, and D. No CELOX clots were noted in the spleen, pancreas, lungs, heart, kidneys, or the adjacent large vessels in groups D and E. Compared to group A, the CT-scan showed better hepatic hemorrhage control in group E.

Conclusions

The device, which combined 20 g of CELOX particles and 20 pieces of CELOX (8 g) sponge tablets with 50-mmHg intra-abdominal compression for 10 minutes, prolonged the ST by an average of 30 minutes with less BL. It was not markedly different from the full four quadrants gauze packing of liver in hemostatic effect, with no CELOX clot formation in other organs.
Optical intensity interferometry observations using the MAGIC imaging atmospheric Cherenkov telescopes
Authors: Acciari V A , Bernardos M I , Colombo E , Contreras J L , Cortina J , Delgado C , Díaz C , Fink D , Mariotti M , Mangano S , Mirzoyan R , Polo M , Schweizer T , Will M
Published: November 2019

Imaging Atmospheric Cherenkov Telescopes (IACTs) currently in operation feature large mirrors and order of 1 ns time response to signals of a few photo-electrons produced by optical photons. This means that they are ideally suited for optical interferometry observations. Thanks to their sensitivity to visible wavelengths and long baselines optical intensity interferometry with IACTs allows reaching angular resolutions of tens to microarcsec. We have installed a simple optical setup on top of the cameras of the two 17 m diameter MAGIC IACTs and observed coherent fluctuations in the photon intensity measured at the two telescopes for three different stars. The sensitivity is roughly 10 times better than that achieved in the 1970’s with the Narrabri interferometer.
Xenbase: deep integration of GEO & SRA RNA-seq and ChIP-seq data in a model organism database
Authors: Fortriede Joshua D , Pells Troy J , Chu Stanley , Chaturvedi Praneet , Wang DongZhuo , Fisher Malcom E , James-Zorn Christina , Wang Ying , Nenni Mardi J , Burns Kevin A , Lotay Vaneet S , Ponferrada Virgilio G , Karimi Kamran , Zorn Aaron M , Vize Peter D
Published: November 2019

Xenbase (www.xenbase.org) is a knowledge base for researchers and biomedical scientists that employ the amphibian Xenopus as a model organism in biomedical research to gain a deeper understanding of developmental and disease processes. Through expert curation and automated data provisioning from various sources Xenbase strives to integrate the body of knowledge on Xenopus genomics and biology together with the visualization of biologically significant interactions. Most current studies utilize next generation sequencing (NGS) but until now the results of different experiments were difficult to compare and not integrated with other Xenbase content. Xenbase has developed a suite of tools, interfaces and data processing pipelines that transforms NCBI Gene Expression Omnibus (GEO) NGS content into deeply integrated gene expression and chromatin data, mapping all aligned reads to the most recent genome builds. This content can be queried and visualized via multiple tools and also provides the basis for future automated ‘gene expression as a phenotype’ and gene regulatory network analyses.
SyntDB: defining orthologues of human long noncoding RNAs across primates
Authors: Bryzghalov Oleksii , Szcześniak Michał Wojciech , Makałowska Izabela
Published: November 2019

SyntDB (http://syntdb.amu.edu.pl/) is a collection of data on long noncoding RNAs (lncRNAs) and their evolutionary relationships in twelve primate species, including humans. This is the first database dedicated to primate lncRNAs, thousands of which are uniquely stored in SyntDB. The lncRNAs were predicted with our computational pipeline using publicly available RNA-Seq data spanning diverse tissues and organs. Most of the species included in SyntDB still lack lncRNA annotations in public resources. In addition to providing users with unique sets of lncRNAs and their characteristics, SyntDB provides data on orthology relationships between the lncRNAs of humans and other primates, which are not available on this scale elsewhere. Keeping in mind that only a small fraction of currently known human lncRNAs have been functionally characterized and that lncRNA conservation is frequently used to identify the most relevant lncRNAs for functional studies, we believe that SyntDB will contribute to ongoing research aimed at deciphering the biological roles of lncRNAs.
Renal physiology of glucose handling and therapeutic implications
Authors: Cherney David Z , Kanbay Mehmet , Lovshin Julie A
Published: November 2019

The rationale for using sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D) has evolved over the last decade. Due to the effects on glucosuria and body weight loss, SGLT2 inhibitors were originally approved for glycemic control in T2D. Since glucosuria is attenuated in chronic kidney disease (CKD) Stages 3–5, initial regulatory approval for SGLT2 inhibitor use was limited to patients with T2D and preserved estimated glomerular filtration rate. Over time, however, it has become increasingly apparent that these therapies have a variety of important pharmacodynamic and clinical effects beyond glycemic lowering, including antihypertensive and antialbuminuric properties, and the ability to reduce glomerular hypertension. Importantly, these sodium-related effects are preserved across CKD stages, despite attenuated glycemic effects, which are lost at CKD Stage 4. With the completion of cardiovascular (CV) outcome safety trials—EMPA-REG OUTCOME, CANVAS Program and DECLARE TIMI-58—in addition to reductions in CV events, SGLT2 inhibition consistently reduces hard renal endpoints. Importantly, these CV and renal effects are independent of glycemic control. Subsequent data from the recent CREDENCE trial—the first dedicated renal protection trial with SGLT-2 inhibition—demonstrated renal and CV benefits in albuminuric T2D patients, pivotal results that have expanded the clinical importance of these therapies. Ongoing trials will ultimately determine whether SGLT2 inhibition will have a role in renal protection in other clinical settings, including nondiabetic CKD and type 1 diabetes.
ATIM-14. RESULTS OF PHASE II CLINICAL TRIAL OF ONCOLYTIC HERPES VIRUS G47Δ IN PATIENTS WITH GLIOBLASTOMA
Authors: Todo Tomoki
Published: November 2019

Genetically engineered, conditionally replicating herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for cancer. We have developed a triple-mutated, third-generation oncolytic HSV-1, G47∆, that exhibits enhanced replication capability in a variety of cancer, efficient induction of specific antitumor immunity, and high safety features. G47∆ also kills cancer stem cells very efficiently. The first-in-man, phase I-IIa study of G47∆ in recurrent glioblastoma patients was performed from 2009 to 2014 at the University of Tokyo, followed by phase II investigator-initiated clinical trial in patients with recurrent or residual glioblastoma from 2015 to test the efficacy. In this phase II, each patient received stereotactic injections with G47∆ into the tumor, repeatedly, but into different coordinates, every 4 weeks, for the maximum 6 times. A set dose of 1 x 10E9 pfu/dose was used. In most patients, G47∆ was given in addition to the maintenance chemotherapy using temozolomide. The primary endpoint was a 1-year survival rate. The repeated stereotactic injections were well tolerated. The interim analysis showed that the 1-year survival rate of 13 patients was 92.3%, which was significantly higher than 15%, the preset control value based on meta-analysis of historical data. The statistical significance was above the criteria of early termination, so this trial was terminated early and considered as the pivotal study for new drug application. Severe adverse events related to G47∆ were experienced by 2 patients only, both of which were grade 2 fever. Because G47∆ was designated as a ‘Sakigake’ breakthrough therapy drug by the Japanese government, and further as an orphan drug for malignant glioma, a fast-track drug approval is expected. G47∆ has proven safe even when injected repeatedly 6 times into the brain. The use of G47∆ may become a preferred treatment that potentially leads to a cure of malignant glioma in the near future.
ATIM-16. VALIDATION OF RESPONSE TO NEOADJUVANT ANTI-PD-1 IMMUNOTHERAPY IN RECURRENT GLIOBLASTOMA
Authors: Chow Frances , Mochizuki Aaron , Lee Alexander , Galvez Mildred , Orpilla Joey , Everson Richard , Liau Linda , Cloughesy Timothy , Prins Robert
Published: November 2019

BACKGROUND

Recurrent glioblastoma has a poor median overall survival despite multimodal treatment. The use of pembrolizumab, an anti-PD-1 monoclonal antibody, demonstrates promise, including improved overall survival and increased immune response, when used in the neoadjuvant setting.

METHODS

We evaluated 13 patients with surgically accessible recurrent glioblastoma who were treated at the University of California, Los Angeles with neoadjuvant checkpoint inhibition prior to tumor resection. Combining data with our previously published multi-center study, we followed this cohort prospectively, performing tumor gene expression to validate the immune response and improved survival following neoadjuvant therapy with pembrolizumab.

RESULTS

When combined with findings from our prior study, patients in the neoadjuvant group (n = 27) had an overall survival of 400 days, whereas those in the adjuvant-only group (n = 19) had a median overall survival of 228 days by Kaplan-Meier estimator (P = 0.029, log-rank test). Progression-free survival in the neoadjuvant group was 108 days, whereas in the adjuvant-only group it was 72.5 days (P = 0.017, log-rank test). In elastic net penalized Cox proportional hazards regression, neoadjuvant anti-PD-1 blockade continued to be associated with improved overall survival, with a hazard ratio of 0.11 (P=0.003, log-rank test). Bulk tumor gene expression corroborates our previously described pattern of increased T-cell- and IFN-g-related gene expression, decreased cell-cycle-related signatures and their association with clinical response. Additionally, epigenetic regulation inversely correlated with clinical response.

CONCLUSIONS

Our findings support the neoadjuvant timing of PD-1 blockade in enhancing local immune responses and prolonging overall- and progression-free-survival. Correlative biological studies suggest a potential role for cell-cycle-related gene expression as a biomarker to predict response to therapy. Continued data collection and the addition of patients to the neoadjuvant arm of the trial, will be crucial to determine the potential role of checkpoint inhibition in the treatment of this deadly disease.
ATIM-20. A RETROSPECTIVE STUDY EVALUATING THE SAFETY AND SURVIVAL OF THE COMBINATION OF PD-1 IMMUNE CHECKPOINT BLOCKADE AND BEVACIZUMAB IN RECURRENT GLIOBLASTOMA
Authors: Friedman Joshua , Hormigo Adilia
Published: November 2019

INTRODUCTION

Immune checkpoint inhibitors (ICI) have demonstrated clinical efficacy in a variety of cancers. It is known that cancer including glioblastoma (GBM) induces an immunosuppression. Bevacizumab by normalizing blood vessels in the tumor can facilitate immune surveillance and potentially improve the efficacy of ICI in GBM patients. We analyze GBM patients with recurrent disease treated with ICI and bevacizumab.

METHODS

We retrospectively review records of patients diagnosed with recurrent GBM treated at our institution with Pembrolizumab or Nivolumab and bevacizumab and evaluate for tolerance and outcomes.

RESULTS

Twenty-one patients, 12 men and 9 women with median age 62 (range 36–78) and KPS 70 (range 60–90) were treated with a median of 10 ICI cycles (range 4–29) and 5 of bevacizumab (range 0–21). A total of 8 patients (38%) had immune-related adverse events (IRAE): 3 grade 1, 3 grade 2 and 2 grade 3. A patient with pneumonitis required cessation of ICI. Median OS for the 21 patients was 22 months (range 6–41). The 7 patients that had MGMT detected in their tumors had a median OS of 27 months (range 23–41) compared to a survival of 21 months (range 6–24) for the 13 patients that had MGMT undetected. One had undetermined MGMT and her OS was 21 months. The median survival for all the patients from onset of ICI was 10 months (range 1–25) and 10 of them (47.6%) survived > 12 months.

DISCUSSION

The development of IRAE was common but self-limiting, allowing continuation of the treatment in all but one patient. The combination of ICI and bevacizumab increased survival. Our data needs to be interpreted with caution, as it is a retrospective analysis of a small group of patients. However, these results warrant prospective studies using the combination of ICI and bevacizumab to treat recurrent GBM.
ATIM-36. TEM-GBM-001 STUDY: AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-α2 & ADMINISTERED TO PATIENTS WITH GLIOBLASTOMA & AN UNMETHYLATED MGMT PROMOTER
Authors: Finocchiaro Gaetano , Gentner Bernhard , Ciceri Fabio , DiMeco Francesco , Legnani Federico , Eoli Marica , Pollo Bianca , Farina Francesca , Zambanini Andrew , Mazzoleni Stefania , Russo Carlo , Naldini Luigi
Published: November 2019

BACKGROUND

Most patients with GBM & an unmethylated O-6-methylguanine-DNA methylase (MGMT) gene promoter, have a poor prognosis with approximately 20% of patients surviving to 2 years. Poor prognosis is likely related to factors including a highly immunosuppressive tumor microenvironment (TME). The TME in GBM is mainly composed of tumor associated macrophages (TAMs) & microglia. A subset of tumor-infiltrating macrophages characterized by expression of the angiopoietin receptor Tie2 (TEMs) have features of M2-TAMs, promote tumor angiogenesis & are infrequently found in normal organs. Tie2 is significantly upregulated upon homing to tumors. Gene therapy technology has allowed TEMs to be used as carriers for the local and tumor restricted release of interferon-α (IFN). IFN has antitumor effects, inhibits angiogenesis & modulates the immune system. Cell-based delivery of IFN into the TME by TEMs is expected to provide efficacy, taking advantage of pleiotropic anti-tumor effects & avoiding tolerability issues associated with systemic IFN treatment. We are currently conducting a Phase I/IIa clinical study in Milan (INCB & OSR) to evaluate this therapeutic approach (Temferon) in 21 patients with GBM & unmethylated MGMT promoter (EudraCT Number 2018-001404-11). Eligible patients are identified immediately after first surgical resection. After screening, harvesting of HSPCs occurs followed by 6 weeks of radiotherapy. Non-myeloablative conditioning consists of BCNU & thiotepa followed by administration of non-manipulated HSPCs and Temferon.

RESULTS

In Part A of the study, 3 cohorts of 3 patients will receive escalating doses of Temferon. After Part A, a single dose of Temferon will be studied in a further 12 patients (Part B). Criteria for study eligibility are the same for both Part A and Part B. Part A is ongoing with the first 2 patients recruited (June 2019) and Temferon is scheduled for administration. An update on the status and progress of the study will be provided.
ATIM-39. PHASE 2 OPEN-LABELED STUDY OF ADJUVANT TEMOZOLOMIDE PLUS TUMOR TREATING FIELDS PLUS PEMBROLIZUMAB IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (2-THE-TOP)
Authors: Tran David , Warren Sonisha , Allen Anne , Sampson Deborah , Chen Dongjiang , Thomas Nagheme , Greene Valerie , Rahman Maryam , Ghiaseddin Ashley
Published: November 2019

BACKGROUND/OBJECTIVE

Tumor treating Fields (TTFields) plus maintenance temozolomide is an approved standard treatment for newly diagnosed Glioblastoma (GBM). TTFields are alternating electric fields of low intensity and intermediate frequency delivered non-invasively via transducer arrays to tumor region. Immune checkpoints have not been studied widely in newly diagnosed GBM patients. TTFields combined with temozolomide elicit anti-mitotic effects on proliferative cancer cells and augment recruitment of immune effector cells specific for glioma cells to the tumor microenvironment where pembrolizumab further potentiates the immune reaction to achieve a synergistic therapeutic effect. This study [NCT03405792] will determine if adding pembrolizumab to TTFields and maintenance temozolomide (triple combination) increases progression-free survival (PFS) in patients with newly diagnosed GBM versus historical control (EF-14).

METHODS

This study will enroll patients (N=24) with pathologic diagnosis of newly diagnosed GBM WHO grade 4, > 18 years after maximal surgery or biopsy followed by radiation therapy with adjuvant temozolomide (Stupp protocol). The primary endpoint is increases in PFS compared to historical control data (EF-14). Secondary endpoints include: toxicity and tolerability of the triple combination; overall survival and response rates versus historical data; augmentation of TTFields-initiated glioma-specific immune reaction by pembrolizumab. Exploratory endpoints include: metabolomics signature of immune activation by TTFields and TTFields plus pembrolizumab in serum and urine, and correlation of mutation burden in primary tumor samples with response to pembrolizumab plus TTFields. We assumed an accrual period of 12 months, an accrual rate of 2 patients per month, an additional 18 months of follow-up, and proportional hazards. Per shape parameter estimate of k=0.88 with empirical 95% confidence interval (0.82, 0.95) obtained via simulation of historical control data, a sample size of 24 patients should detect an improvement in PFS of 6 to 8 months with 80% power and a 1-sided significance level of 0.05 (Wu and Xiong, 2014).
ATIM-42. DOUBLE-BLINDED, PLACEBO CONTROLLED PHASE 2 STUDY OF ERC1671 IN RECURRENT GLIOBLASTOMA: OS CORRELATIONS WITH INITIAL AND MAXIMUM CD4+T LYMPHOCYTE COUNT IN THE PERIPHERAL BLOOD
Authors: Bota Daniela , Taylor Thomas , Xiao-Tang Kong , Fu Beverly , Alsharif Mohamad , Pretto Chrystel , Strik Ankie , Schijns Virgil , Stathopoulos Apostolos
Published: November 2019

Standard therapy for recurrent GBM is bevacizumab, a monoclonal VEGF inhibitor that targets tumor vascularization. The response to bevacizumab is transient and short-lived (4–6 months) after which patients typically develop progressive physical and mental debilitation culminating in death. ERC1671 is an allogeneic/autologous therapeutic vaccine – composed of whole, inactivated tumor cells mixed with tumor- cell lysates. The hypothesized action of ERC1671 is to potentiate the patients’ immune system against the tumor. Goals of this ongoing, phase 2 study are to to determine the safety and effectiveness (over-all survival) of ERC1671 in combination with GM-CSF and cyclophosphamide as an add-on treatment to bevacizumab at the time of GBM recurrence. To date 16 recurrent bevacizumab-naïve GBM patients have been randomized to ERC1671/GM-CSF/Cyclophosphamide + Bevacizumab or Placebo + Bevacizumab. Median age is 56.5 (39–74), 5 patients (31%) are female, and average KPS is 83 (70–100). Thirteen patients are deceased and were unblinded at the time of further progression: 5 received vaccine, 7 received placebo, and 1 is non-evaluable due to discontinuation before completing 1 cycle. Median overall survival of the deceased patients treated with ERC1671 + Bevacizumab was 328 days (10.9 months), compared to 245 days (8.2 months) for patients treated with Placebo + Bevacizumab. While sparse, the data to date suggest pre-treatment and maximal CD4+T lymphocyte count in the peripheral blood correlate with OS more strongly in the ERC1671 group than in the placebo group. First clinical results for toxicity show no difference in the distribution of AEs between the Vaccine and Placebo groups, with no Gr4/Gr5 AEs in either group. The phase 2 randomized, double-blinded study is ongoing with the addition of 2 subsites.
ATIM-46. A MULTICENTER, PHASE I, TRIAL OF RADIATION, TEMOZOLOMIDE AND RRx-001 FOLLOWED BY MAINTENANCE TEMOZOLOMIDE WITH OR WITHOUT RRx-001 IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS
Authors: Aiken Robert , Fine Howard , Butowski Nicholas
Published: November 2019

BACKGROUND

RRx-001 is an aerospace-derived radiochemosensitizer with minimal toxicity. The purpose of this trial was to establish the safety of RRx-001 plus radiotherapy and temozolomide and to look for signals of enhanced anti-tumor activity in patients with newly diagnosed glioblastoma.

METHODS

In this non-randomized trial called G-FORCE-1 (NCT02871843), 18 newly diagnosed, histologically verified glioblastoma patients were enrolled. The treatment plan included 6 weeks of temozolomide and radiotherapy with RRx-001 followed by maintenance temozolomide with or without RRx-001. Four cohorts of 3 patients received intravenous RRx-001 at doses of 0.5,1,2, or 4 mg/week during radiotherapy only. An additional two cohorts of 3 patients received 4 mg/week of RRx-001 during radiotherapy and 0.5 mg/week of RRx-001 during temozolomide maintenance.

RESULTS

There were no grade 3 or 4 dose-limiting toxicity events (DLT) that appeared related to RRx-001 for the dose range of 0.5 to 4 mg/week. A maximum tolerated dose was not defined. The main adverse event related to RRx-001 was injection-site reaction. The overall response rate was 16.7% (3 PR out of 18) pending confirmation since pseudoprogression was prevalent, and the disease control rate was 61.1% (3 PR, 8 SD out of 18). The median time to tumor progression (95% confidence interval lower limit of 9.2 months to NR) and the median overall survival time (95% confidence interval lower limit of 12.9 months to NR) have not been reached after a median follow-up time of 10.3 months (range: 2.7 to 25 months.).

CONCLUSION

RRx-001 was well tolerated with concurrent temozolomide and radiotherapy and with temozolomide maintenance in 18 newly diagnosed glioblastoma patients. The primary objective to determine the MTD of RRx-001 was not met, since no DLTs occurred. The median time to progression and overall survival time have not been met after a median follow up time of 10.3 months.
ACTR-04. BIOMARK: A PHASE II STUDY OF BEVACIZUMAB BEYOND PROGRESSION FOR NEWLY DIAGNOSED GLIOBLASTOMA: SAFETY, EFFICACY AND PROSPECTIVE BIOMARKER ANALYSIS
Authors: Ichimura Koichi , Nagane Motoo , Kato Mamoru , Narita Yoshitaka , Aoki Tomokazu , Tanaka Shota , Mukasa Akitake , Wakabayashi Toshihiko , Uzuka Takeo , Nakamura Hideo , Arakawa Yoshiki , Suehiro Satoshi , Nakada Mitsutoshi , Kitahara Mai , Hibiya Yuko , Narushima Daichi , Onuki Ritsuko , Morita Satoshi , Nishikawa Ryo
Published: November 2019

BACKGROUND

Clinical benefit of continuing bevacizumab beyond progression is unknown in glioblastomas. A biomarker analysis of the AVAglio trial suggested that proneural subtype of IDH-wildtype glioblastoma patients may receive an OS benefit from a first-line bevacizumab. This study explored biomarkers that may predict survival of glioblastoma patients treated with concurrent irradiation, temozolomide (TMZ) and bevacizumab (BEV) followed by BEV beyond progression (BBP).

METHODS

In the primary protocol, newly diagnosed GBM patients aged 20–75 received concurrent TMZ (75 mg/m2, D1-42), irradiation (2 Gy x 5 QW x6) and BEV (10 mg/kg Q2W x 3) followed by ≤12 4-week cycles of TMZ (150–200 mg/m2, D1-5) plus BEV (10 mg/kg, D1 and 15) and then 2 or 3-week cycles of BEV monotherapy (15 or 10 mg/kg). Upon PD/recurrence during the primary protocol, the patients were subjected to the secondary protocol with 2-3-week cycles of BEV monotherapy with or without other chemotherapeutic agents (BBP). The primary endpoint was 2-year survival rate in patients receiving BBP. Fresh-frozen tumor specimen were subjected to genome-wide methylation, copy number, expression and mutation analysis. A subset of the control cohort of the AVAglio study was used as BEV-negative control.

RESULTS

A total of 94 GBM patients were enrolled at 39 centers between June 2015 and January 2017. Efficacy analyses were based on the full analysis set (FAS) cohort (N=90), excluding non-GBM diagnosis by central review. The median time to PD/recurrence was 453 days in the FAS and 348 days in patients receiving BBP (N=27). The 2-year survival rate (90% CI) was 52.4% (43.3–60.8%) and 28.8% (15.4–43.7%), respectively. The 2-year survival rate in GBM patients receiving BBP was lower than expected (50%). That of proneural and mesenchymal IDH-wt GBM in the biomarker cohort (n=83) were 52.9% (31.7–70.3%) and 56.6% (41.6–69.1%), respectively. A full biomarker analysis will be presented.
ACTR-26. SAFETY AND EFFICACY OF BEVACIZUMAB PLUS TTFIELDS IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM): DATA FROM A PHASE II CLINICAL TRIAL
Authors: Fallah Jaleh , Chaudhary Rekha , Rogers Lisa , (Auston) Wei Wei , Brewer Cathy , Peereboom David , Ahluwalia Manmeet
Published: November 2019

BACKGROUND

Studies of bevacizumab monotherapy and TTFields monotherapy have shown activity but limited clinical benefit in patients with recurrent GBM. In an open label, single-arm, phase 2 clinical trial, the safety and efficacy of the combination of bevacizumab and TTFields was studied in patients with recurrent GBM.

METHOD

Bevacizumab-naïve patients with histologically confirmed GBM or other grade IV glioma, with recurrent disease after radiotherapy and temozolomide chemotherapy, were eligible. Bevacizumab dose was 10mg/kg intravenously every 2 weeks and TTFields was worn at least 18 hours daily. The primary endpoint was safety, progression-free survival at 6 months (PFS6) and overall survival at 12 months (OS12). Treatment was continued until disease progression or unacceptable toxicity. Survival outcomes were assessed using the Kaplan-Meier method. Treatment-related adverse events were reported according to CTCAE, v4.0 criteria.

RESULTS

25 patients were enrolled and 23 were eligible for data analysis: 18 (78%) men and 5 (22%) women, median age 60 years (range 17–78). 21 patients were Caucasian, 1 was African American and 1 of unknown race. Median follow-up was 6.0 months (range 2.4–22). Seven patients (30 %) had disease progression. Median PFS was 9.9 (95% CI: 6.7-NA) months. PFS rate at 6 months (PFS6) was 71% (95% CI: 0.54–0.94). Median overall survival was 9.9 (95%CI 7.3-NA) months. OS rate at 12 months (OS12) was 42% (95%CI 0.24–0.74). 7 patients (30%) had grade 3 toxicity (cough, dysphagia, muscle weakness, hyperglycemia, hypertension, psychosis, seizure, lymphopenia, transaminitis). 1 patient developed grade 4 muscle weakness in the lower extremities.

CONCLUSION

Treatment with the combination of bevacizumab and TTFields in patients with recurrent GBM is safe and feasible and has shown clinical efficacy.
ACTR-30. UPDATED EFFICACY AND SAFETY OF DABRAFENIB PLUS TRAMETINIB IN PATIENTS WITH RECURRENT/REFRACTORY BRAF V600E–MUTATED HIGH-GRADE GLIOMA (HGG) AND LOW-GRADE GLIOMA (LGG)
Authors: Wen Patrick , Stein Alexander , van den Bent Martin , De Greve Jacques , Dietrich Sascha , De Vos Filip , von Bubnoff Nikolas , van Linde Myra , Lai Albert , Prager Gerald , Campone Mario , Fasolo Angelica , Lopez-Martin Jose , Min Kim Tae , Mason Warren , Hofheinz Ralf-Dieter , Blay Jean-Yves , Cho Daniel , Gazzah Anas , Gomez-Roca Carlos , Yachnin Jeffrey , Boran Aislyn , Burgess Paul , Palanichamy Ilan , Gasal Eduard , Subbiah Vivek
Published: November 2019

BACKGROUND

There is a lack of treatment options for HGG and LGG patients. BRAFV600E mutations are uncommon in glioma, with a poor long-term prognosis. Combined BRAF/MEK inhibition extends progression-free survival (PFS) and overall survival (OS) in BRAF V600E–mutated melanoma, non small-cell lung cancer, and anaplastic thyroid cancer.

METHODS

This phase 2, open-label trial (NCT02034110) evaluated dabrafenib (BRAF inhibitor, 150mg BID) plus trametinib (MEK inhibitor, 2mg QD) in patients with BRAF V600E mutations in 9 rare tumor types, including HGG and LGG. Eligible patients had histologically-confirmed recurrent or progressive glioma (LGG:WHO grade 1 or 2; HGG:WHO grade 3 or 4), with HGG patients required to have received radiotherapy and first-line chemotherapy, or concurrent chemoradiation. Treatment continued until unacceptable toxicity, disease progression, or death. Primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety.

RESULTS

Interim analysis (IA) #14 (data cutoff: April 2, 2018) reported additional 3 months follow-up, with 49 patients enrolled (HGG, n=39; LGG, n=10) and 3 patients not evaluable for response. In HGG patients, ORR was 27% (10/37; 95%CI: 13.8%-44.1%), including CR (n=1), PR (n=9), and SD (n=11), with 16 patients currently ongoing treatment. In LGG patients, ORR was 56% (5/9; 95%CI: 26.8%-79.3%), including PR (n=5) and SD (n=4), with 6 patients currently ongoing treatment. OS, PFS, and DOR will be presented (IA#15). In HGG patients, adverse events (AEs) included fatigue (33%), headache (31%), rash (28%), and pyrexia (23%); grade 3/4 AEs included neutropenia (8%) and fatigue (5%). In LGG patients, AEs included headache (70%), fatigue, pyrexia (60% each), nausea, and arthralgia (50% each); grade 3/4 AEs included fatigue (20%).

CONCLUSIONS

Dabrafenib plus trametinib demonstrated promising efficacy in patients with recurrent or refractory BRAF V600E‒mutated HGG or LGG, with manageable AEs and no new safety signals.
ACTR-32. NRG ONCOLOGY RTOG 1205: RANDOMIZED PHASE II TRIAL OF CONCURRENT BEVACIZUMAB AND RE-IRRADIATION VS. BEVACIZUMAB ALONE AS TREATMENT FOR RECURRENT GLIOBLASTOMA
Authors: Tsien Christina , Pugh Stephanie , Dicker adam , Raizer Jeffrey , Matuszak Martha , Lallana Enrico , Huang Jiayi , algan ozer , Taylor Nicholas , Portelance Lorraine , Villano John , T Hamm John , S Oh Kevin , N Ali Arif , Kim Michelle , Lindhorst Scott , Mehta Minesh
Published: November 2019

This study sought to determine whether re-irradiation (ReRT) and concurrent bevacizumab (BEV) improves overall survival (OS) compared to BEV alone in recurrent glioblastoma (GBM). Patients (pts) were randomized 1:1 to ReRT (35 Gy/10 fractions) plus BEV (IV 10 mg/kg q2 wks) vs. BEV alone. With 160 pts, there was 80% power to detect a 31% reduction in death hazard for BEV+RT at a one-sided significance level of 0.10 using a log rank test. OS and PFS were estimated by Kaplan-Meier and HRs estimated by exact binomial distribution. Objective response was assessed using MacDonald and RANO criteria. From 11/2012 to 4/2016, 182 pts were randomized, with 170 eligible, analyzable pts. 11 pts did not receive protocol treatment. Patient characteristics (age, KPS, re-resection rates) were balanced between arms. Median f/u for censored pts was 12.8 months (mos; min-max, 0.03–52.8). BEV+ReRT did not improve OS vs BEV alone, with median OS of 10.1 vs 9.7 mos, (HR=0.98, 95% CI=0.70–1.38, p=0.46). Median PFS for BEV+RT and BEV was 7.1 vs. 3.8 mos, respectively (HR=0.73, 95% CI=0.53–1.0, p=0.051). BEV+ReRT improved 6-mo PFS rate (PFS6): 54 vs. 29%, (HR=0.42, 95% CI=0.34–0.5, p=0.001). Overall, treatment was well tolerated: 5% acute and 0% delayed grade 3+ treatment-related AE. Most patients died from recurrent GBM. CONCLUSION: RTOG 1205 is the first, prospective, randomized multi-institutional study to evaluate the safety and efficacy of ReRT in recurrent GBM using modern RT techniques. Overall, ReRT was shown to be safe and well tolerated. BEV+ReRT did not demonstrate a benefit in OS but an improved PFS6, and clinically meaningful PFS improvement. Molecular correlates of response analyses are ongoing. Funded by U10CA180868, U10CA180822 from the National Cancer Institute.
ACTR-43. GENOMIC ANALYSIS OF RESPONDERS OF PHASE II TRIAL OF TEMOZOLOMIDE AND TRC-102 (BASE EXCISION REPAIR INHIBITOR) IN BEVACIZUMAB-NAÏVE GLIOBLASTOMA AT FIRST RECURRENCE
Authors: Ahluwalia Manmeet , Dhruv Harshil , Fallah Jaleh , Berens Michael , Drappatz Jan , Ye Xiaobu , Lesser Glenn , Cloughesy Timothy , Walbert Tobias , Holdhoff Matthias , Peereboom David , Nabors Louis , Wen Patrick , Grossman Stuart , Rogers Lisa
Published: November 2019

BACKGROUND

Temozolomide forms O6-methylguanine (O6mG), 7-methylguanine (N7mG), and 3- methyladenine (N3mA) DNA adducts. The O6mG DNA adduct is repaired by MGMT. N7mG and N3mA DNA adducts are removed by the base excision repair (BER) pathway, initiated by N- methylpurine DNA glycosolase (MPG). TRC-102 is a BER inhibitor that binds to the apurinic site created through the action of MPG.

METHODS

A phase II study of adult glioblastoma in first recurrence was performed in the Adult Brain Tumor Consortium with temozolomide, 150 mg/ m2 and TRC-102, 150 mg (1–5/ 28 days). Primary objective included radiographic response rate. Secondary objectives included safety and PFS-6. Exploratory objectives included tumor expression of N-methylpurine DNA glycosylase (MPG). The study tested hypothesis that combination therapy will achieve 30% RR. To understand the context of vulnerability to TRC102 we performed RNA sequencing on treatment naïve tissue from 7 patients.

RESULTS

Nineteen patients were enrolled in first stage. Median age was 60 years (range: 48–76), 53% females, median KPS was 80 (range: 70–90). Median cycles of treatment was 2 (range: 1–12). No responses were observed. Median OS was 11.0 months (95% CI: 8–18 months), median PFS was 2.0 months (95% CI: 1.8–3.6 months). PFS-6 rate was 10.5 % (2/19). The combination was safe. MPG staining was negative in six, 1+ in five and 2+ in three patients. PFS of 11 + months in two patients (exceptional responders) was associated with MPG expression. Preliminary analysis on RNA sequencing revealed significant enrichment for DNA Damage Response pathways (MsigDB), chromosomal instability gene signature (CIN70 and CIN25), and proliferative gene signature (PCNA25) in these 2 patients.

CONCLUSIONS

TRC 102 with temozolomide has acceptable safety but did not meet the primary endpoint of response. Gene signature of MsigDB, CIN70, CIN25 and PCNA25 was seen in exceptional responders and biomarker driven study is planned.
ACTR-55. OPTIMIZED TREAT-RESECT-TREAT STUDY DESIGN FOR CONVECTION-ENHANCED DELIVERY OF A FIRST-IN-CLASS BIOLOGIC IN THE TREATMENT OF GLIOBLASTOMA
Authors: Immidisetti Amanda , Nwagwu Chibueze , Shawn Carbonell W , Carbonell Anne-Marie
Published: November 2019

INTRODUCTION

Development of effective treatments for high-grade glioma (HGG) including glioblastoma is hampered by 1) the blood brain barrier, 2) an infiltrative growth pattern, 3) rapid development of adaptive therapeutic resistance, and 4) dose-limiting toxicity due to systemic exposure. Novel therapeutics and delivery techniques are warranted to overcome these obstacles and meaningfully improve patient outcomes. OS2966 is the first ever clinical-ready therapeutic candidate against the adhesion receptor subunit, CD29/β1 integrin. CD29 is highly overexpressed in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy including immunotherapies. Here, we present a novel phase I trial design addressing all four obstacles plaguing effective treatment of HGG, while also enabling biomarker development.

STUDY DESIGN

This 2-part, ascending concentration, phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically-indicated resection. In part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which is used for intratumoral convection-enhanced delivery (CED) of OS2966. Subsequently, patients undergo their clinically-indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched, pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design.

DISCUSSION

The present study design leverages multiple innovations including: 1) the latest CED technology, 2) two-part design including neoadjuvant intratumoral administration, 3) a first-in-class investigational therapeutic, and 4) concentration-based dosing. A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active.