bluuebunny/crossref_metadata_2025_split huggingface dataset:
SYST-11 PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM
Authors: Chen Zhongping , Guo Chengcheng 
Published: August 2022

Abstract
VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. Pharmacokinetics (Cmax and AUC) of VAL-083 were broadly linear with respect to dose, and drug half-life was 0.8 hrs. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. The median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Eighteen (18/29; 62.1%) patients have died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. These results support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.
SYST-12 D2C7 CAR: A NOVEL CAR T CELL THAT SIMULTANEOUSLY TARGETS WILDTYPE EGFR AND ITS MUTANT ISOFORM EGFRVIII FOR TREATMENT OF GLIOMA AND BRAIN METASTASES
Authors: Wilkinson Daniel , Ryan Katherine , Wilson Joseph , Chandramohan Vidyalakshmi , Bigner Darell , Fecci Peter 
Published: August 2022

Abstract

INTRODUCTION
Chimeric antigen receptor (CAR) T-cells represent a revolutionary class of immunotherapy, achieving considerable success in hematological cancers but generally failing to control solid tumors, including gliomas, partly due to the lack of a ubiquitously-expressed target antigen. In this study, we engineered a novel CAR T-cell consisting of the D2C7scfv targeting moiety that binds a shared epitope between EGFR and EGFRvIII. EGFR is the most homogeneous antigen on glial brain tumors, and the mutant EGFR variant, EGFRvIII, is present on a considerable subset of high grade gliomas. CAR T-cells targeting EGFRvIII alone fail to treat tumors possessing as few as 5-10% EGFRvIII-negative cell. Thus, D2C7 CAR is expected to be superior to the EGFRvIII CAR.

METHODS
We retrovirally transduced T-cells with a vector encoding the D2C7scFv in tandem with intracellular signaling domains of CD28, 4-1BB, and CD3ζ to generate D2C7 CAR. We co-cultured D2C7 CAR or control CAR with fluorescently-tagged tumor cells expressing either EGFRwt or EGFRvIII to validate efficacy and specificity by flow cytometry. To determine in vivo efficacy, EGFRwt or EGFRvIII-expressing tumors were implanted intracranially in immunodeficient NSG mice. 48 hours later, D2C7 CAR, VIII CAR, or Mock CAR were administered intracranially and mice were monitored for survival.

RESULTS
D2C7 CAR specifically killed tumor cells that expressed either EGFRwt or EGFRvIII, but not cells that lacked EGFR. Intracranial D2C7 CAR administration resulted in significantly prolonged survival of mice bearing EGFRwt or EGFRvIII tumors compared to Mock CAR controls. Importantly, D2C7 CAR significantly benefitted mice bearing a heterogeneous mix of EGFRwt and EGFRvIII tumor cells, a model of tumor heterogeneity.

CONCLUSIONS
D2C7 CAR is efficacious against EGFRwt/EGFRvIII heterogeneous tumors. Intracranial administration of D2C7 CAR is predicted to safely and effectively treat a large cohort of patients due to the relatively high prevalence of EGFR and/or EGFRvIII-expressing brain tumors.
SYST-13 PHASE II STUDY OF THE COMBINATION OF LIPOSOMAL IRINOTECAN AND PEMBROLIZUMAB FOR TRIPLE-NEGATIVE BREAST CANCER (TNBC) WITH BRAIN METASTASES (BM)
Authors: Xi Jing , Luo Jingqing , O’Sullivan Ciara , Chen Nan , Stringer-Reasor Erica , Ma Cynthia , Campian Jian 
Published: August 2022

Abstract

BACKGROUND
Breast cancer is one of the most common cancers associated with brain metastases (BM). Up to 50% of patients with metastatic triple-negative breast cancer (TNBC) develop BM which portends a poor prognosis, with a median survival of 4.4-7.3 months. There is a lack of effective systemic therapy. Irinotecan is a topoisomerase-1 inhibitor with a response rate of 5-23% in advanced breast cancer. Nal-IRI is an intravenous liposomal formulation of irinotecan, with greater efficacy in tumor growth inhibition and the ability to cross the blood brain barrier (BBB) than irinotecan, resulting in a prolonged survival in preclinical TNBC BM models. Additionally, Nal-IRI has demonstrated promising anti-tumor activity in patients with TNBC- BM in a phase-I trial (NCT01770353). Pembrolizumab is a humanized anti-PD-1 monoclonal antibody which has shown efficacy in TNBC. The purpose of this study is to evaluate whether the combination of Nal-IRI and pembrolizumab can provide a synergic effect to control the CNS disease and prolong survival in TNBC with progressive BM.

METHODS
This is a phase II, single arm trial with a safety lead-in to evaluate the efficacy of nal-IRI (50-70mg/m2 IV Q2W) in combination with pembrolizumab (400mg IV Q6W). Simon’s 2-stage design is used, with 18 patients in the 1st stage and additional 24 at 2nd stage for a total of 42. The first 6 patients will serve as a safety lead-in. Key eligibilities include: histologically/cytologically confirmed TNBC with new or progressive BM; prior immunotherapy is allowed but not prior nal-IRI/irinotecan; prior sacituzumab-govitecan is permitted if disease stable for ≥16-week while on therapy and ≥24-week washout prior to starting trial; measurable disease; and ≤4 prior lines of therapy in the metastatic setting. The primary endpoint is CNS disease control rate (DCR) at 6 months using RANO-BM criteria. Secondary endpoints include CNS and non-CNS ORR, PFS and OS.
(ClinicalTrials.gov: NCT05255666)
SYST-14 CLINICAL EFFICACY OF ONC201 IN RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA (DMG) PATIENTS
Authors: Arrillaga-Romany Isabel , Kurz Sylvia , Tarapore Rohinton , Lu Guangrong , Sumrall Ashley , Butowski Nicholas , Harrison Rebecca , DeGroot John , Chi Andrew , Shonka Nicole , Umemura Yoshie , Odia Yazmin , Mehta Minesh , Nghiemphu Phioanh , Cloughesy Timothy , Taylor Lynne , Graber Jerome , Kilburn Lindsay , Dixit Karan , Chen Clark , Gardner Sharon , Aguilera Dolly , MacDonald Tobey , Cluster Andrew , Mehta Kathan , Kheradpour Albert , Melemed Allen , Allen Joshua E , Batchelor Tracey , Lassman Andrew , Wen Patrick 
Published: August 2022

Abstract

BACKGROUND
H3 K27M-mutant DMG predominantly affects children and young adults; no effective therapy is known. ONC201 is a first-in-class, anti-cancer DRD2 antagonist and ClpP agonist.

METHODS
Fifty pediatric and adult patients with recurrent H3 K27M DMG who received oral ONC201 monotherapy in clinical trials and expanded access were selected for a planned efficacy analysis. Eligibility criteria included measurable contrast-enhancing disease by RANO-HGG criteria (excluding pontine and spinal cord tumors), KPS/LPS≥60, ≥90 days from prior radiation, and adequate washout from prior anti-cancer therapy. The primary endpoint was overall response rate (ORR) by RANO-HGG criteria. Secondary endpoints included duration of response, time to response, progression-free survival (PFS), overall survival (OS), corticosteroid response rate, performance status response rate, and ORR by RANO-LGG criteria. Radiographic endpoints were assessed by dual-reader blinded independent central review. Data cutoff was May 31, 2021.

RESULTS
ORR was 20.0% (95%CI, 10.0–33.7) by RANO-HGG criteria. Median duration of response was 11.2 months (95%CI, 3.8–not reached) and median time to response was 8.3 months (range, 1.9–15.9). PFS at 6 months was 35.1% (95%CI, 21.2–49.3). The ORR was 26.0% (95%CI, 14.6–40.3) by RANO-LGG criteria. Fifteen patients (30.0%; 95%CI, 17.9–44.6) achieved an objective response by RANO-HGG and/or RANO-LGG criteria. Of 15 patients receiving ≥4 mg daily dexamethasone at baseline, 7 (46.7%; 95%CI, 21.3–73.4) achieved ≥50% confirmed reduction in dose. Of 34 patients with baseline KPS/LPS &lt;80, 7 (20.6%; 95%CI, 8.7–37.9) achieved a confirmed performance status improvement. With a median follow-up of 18.8 months, median OS was 13.7 months (95%CI, 8.0–20.3) and OS at 24 months was 34.7% (95%CI, 20.7–49.2). Twenty-five patients had serious adverse events with one possibly related to ONC201 by investigator assessment.

CONCLUSIONS
ONC201 monotherapy exhibits durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.
SYST-15 TARGETING AXONAL GUIDANCE WITH ANTI-ROBO1 CAR T CELLS: A NEW THERAPEUTIC STRATEGY FOR MALIGNANT BRAIN CANCER
Authors: Brakel Benjamin , Chokshi Chirayu , Rossotti Martin , Venugopal Chitra , Salim Sabra , Mobilio Daniel , Chafe Shawn , Henry Kevin , Singh Sheila 
Published: August 2022

Abstract
No standardized treatments exist for patients with treatment-refractory brain metastasis, glioblastoma and other recurrent brain tumours. Given the aggressive nature of these diseases and difficulty in modelling tumour recurrence, minimal efforts have been made to design rational therapies against them. Neurodevelopmental pathways are often highjacked and go awry in the progression of these cancers. The roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment, and we have shown that aberrant ROBO signalling promotes invasiveness and tumour growth in glioblastoma. Likewise, this signalling may contribute to the metastasis and growth of metastatic brain tumours, making the ROBO1-expressing tumour cell population an attractive and functionally relevant therapeutic target. Here, we present that ROBO1 is highly expressed on the surface of malignant and treatment-refractory brain tumour initiating cells (BTICs), prompting the development of an anti-ROBO1 CAR-T cell therapy. Using the binding region of a single-domain antibody targeting ROBO1, we developed second-generation anti-ROBO1 CAR-T cells specific and effective against malignant brain cancers, upregulating markers of activation and degranulation upon exposure to ROBO1-expressing BTICs. Additionally, orthotopic patient-derived xenograft models of malignant brain tumours treated with anti-ROBO1 CAR-T cells had a reduced tumour burden and prolonged survival, demonstrating therapeutic potential for treating brain malignancies.
SYST-16 PROPENSITY-MATCHED SURVIVAL ANALYSIS OF SECOND AND THIRD GENERATION TYROSINE KINASE INHIBITORS IN THE TREATMENT OF BRAIN METASTASES FROM LUNG CANCER PRIMARY
Authors: Bhanja Debarati , Baroz Angel , Stahl Caleb , Wilding Hannah , Mansouri Alireza 
Published: August 2022

Abstract

INTRODUCTION
Brain metastases from lung cancer (BMLC) are common and represent an aggressive form of disease. Numerous ongoing clinical trials are investigating targeted molecular therapies against epidermal growth factor receptor (EGFR), which have demonstrated blood-brain-barrier permeability and intracranial activity. However, there is limited real-world efficacy data on second and third-generation EGFR tyrosine kinase inhibitors (TKI), Afatinib and Osimertinib, for the treatment of BMLC. This study provides a real-world assessment to evaluate the impact of these agents on overall survival (OS) at the population-level.

METHODS
This retrospective cohort study queried data from TriNetX, a multi-institutional de-identified database, aggregating data from 90 U.S. healthcare organizations. Three cohorts were established, consisting of patients with BMLC treated with 1) Osimertinib, 2) Afatinib, or 3) Neither Osimertinib nor Afatinib. Cohorts 1 and 3, as well as cohorts 2 and 3, were propensity matched on demographics and comorbidities. Median overall survival (OS) was compared via Kaplan Meier analyses, using log-rank tests and Cox proportional hazards ratios (HR).

RESULTS
After matching, we identified 1,990 BMLC patients treated with Osimertinib (cohort 1) and 1,990 treated without Afatinib and Osimertinib (cohort 3). Median OS was 21.2 months and 13.5 months for the two cohorts, respectively (p &lt; 0.0001; HR [95% CI], 0.69 [0.63-0.77]). Furthermore, we identified 685 BMLC patients treated with Afatinib (cohort 2) and 685 treated without Afatinib and Osimertinib (cohort 3) after matching. Median OS was 19.0 months and 11.5 months, respectively (p &lt; 0.0185; HR [95% CI], 0.83 [0.71-0.97]).

CONCLUSION
Afatinib and Osimertinib demonstrated a significant survival benefit for patients with BMLC, with comparable, if not better, results to other therapeutic options. These findings suggest strong intracranial efficacy of these agents, while indicating a greater generalizability of the results. Further prospective studies are warranted to better understand their potential role in the BMLC treatment paradigm.
Clinical and molecular features of disseminated pediatric low-grade glioma and glioneuronal tumors: a systematic review and survival analysis
Authors: Haizel-Cobbina Joseline , Thakkar Rut , Richard Kelsey , Du Liping , Levine Adrian , Bennett Julie , Hawkins Cynthia , Tabori Uri , Dewan Michael C 
Published: August 2022

Abstract

Background
Disseminated pediatric low-grade gliomas and glioneuronal tumors (dpLGG/GNTs) are associated with a poorer prognosis than nondisseminated pLGG/GNTs. To date there is no comprehensive report characterizing the genome profile of dpLGG/GNTs and their relative survival. This systematic review aims to identify the pattern of genetic alterations and long-term outcomes described for dpLGG/GNT.

Methods
A systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively.

Results
Fifty studies published from 1994 to 2020 were included in this review with 366 cases reported. There was sporadic reporting of genetic alterations. The most common molecular alterations observed among subjects were 1p deletion (75%) and BRAF-KIAA1549 fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of subjects demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone (59%) to surgical resection (41%) and CSF diversion (28%). Overall, 73% of cases were alive at last follow-up. Survival did not vary by tumor type or timing of dissemination. All studies reviewed either ranked low or moderate for both quality and risk of bias assessments.

Conclusions
Chromosome 1p deletion and BRAF-KIAA1549 fusion were the most common alterations identified in dpLGG/GNT cases reviewed. The relative molecular heterogeneity between DLGG and DLGNT, however, deserves further exploration and ultimately correlation with their biologic behavior to better understand the pathogenesis of dpLGG/GNT.
Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity
Authors: Fischer Aurélie , Zhang Lu , Elbéji Abir , Wilmes Paul , Oustric Pauline , Staub Therese , Nazarov Petr V , Ollert Markus , Fagherazzi Guy 
Published: August 2022

Abstract

Background
“Long COVID” is characterized by a variety of symptoms and an important burden for affected people. Our objective was to describe long COVID symptomatology according to initial coronavirus disease 2019 (COVID-19) severity.

Methods
Predi-COVID cohort study participants, recruited at the time of acute COVID-19 infection, completed a detailed 12-month symptom and quality of life questionnaire. Frequencies and co-occurrences of symptoms were assessed.

Results
Among the 289 participants who fully completed the 12-month questionnaire, 59.5% reported at least 1 symptom, with a median of 6 symptoms. Participants with an initial moderate or severe acute illness declared more frequently 1 or more symptoms (82.6% vs 38.6%, P &lt; .001) and had on average 6.8 more symptoms (95% confidence interval, 4.18–9.38) than initially asymptomatic participants who developed symptoms after the acute infection. Overall, 12.5% of the participants could not envisage coping with their symptoms in the long term. Frequently reported symptoms, such as neurological and cardiovascular symptoms, but also less frequent ones such as gastrointestinal symptoms, tended to cluster.

Conclusions
Frequencies and burden of symptoms present 12 months after acute COVID-19 infection increased with the severity of the acute illness. Long COVID likely consists of multiple subcategories rather than a single entity. This work will contribute to the better understanding of long COVID and to the definition of precision health strategies.

Clinical Trials Registration
NCT04380987.
The Intersection of Antimicrobial Stewardship, the Pharmaceutical Industry, and the Federal Legislature
Authors: Gregory Eric , Martin Craig 
Published: August 2022

Abstract
To mitigate the dangers of inappropriate antimicrobial use leading to increased multidrug-resistant organisms and mortality, antimicrobial stewardship programs have become a mainstay in many health systems. Unfortunately, some pharmaceutical manufacturers simultaneously have ended antimicrobial research and development efforts altogether due to suboptimal return on investments. An optimal and sustainable antimicrobial armamentarium requires a broad alliance between antimicrobial stewardship programs, the pharmaceutical industry, the legislature, and federal and state agencies. Public–private relationships such as the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) and legislative policies creating push and pull incentives, including the Generating Antibiotic Incentives Now (GAIN), Developing an Innovative Strategy for Antimicrobial-Resistant Microorganisms (DISARM), and Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (PASTEUR) Acts, are each a step in the right direction, but more work remains. Understanding these legislative actions is imperative for all clinicians, as is teamwork from those involved in the antimicrobial field to develop and maintain the life cycle of each drug that harbors societal value.
Within-retailer price dispersion in e-commerce: Prevalence, magnitude, and determinants
Authors: Fedoseeva Svetlana , Irek Judith 
Published: August 2022

Abstract
Whereas between-retailer price discrepancies are well documented, less is known about price differentiations within a single chain. This article investigates the prevalence and the magnitude of online within-retailer price dispersion over time. Amazon is the US largest online food retailer (and the second largest retailer in the entire US grocery market), and we use the rich daily price data on food and beverages sold by Amazon Fresh in New York City and Los Angeles to shed light on the prevalence, magnitude, and determinants of the within-retailer price dispersion over time. We show that differences in economic indicators, competitive pressure, and COVID-19 exposure across locations contribute to price dispersion. Once those factors are controlled for, we observe a negative linear time trend in the share and magnitude of non-identical prices confirming an increasing market integration as e-commerce matures.
Sounding the Archival Silence: Searching for Music in the Nineteenth-Century English Asylum
Authors: Golding Rosemary 
Published: August 2022

Summary
The music of the nineteenth-century English asylum provides a rare insight into the place of music within the structure of a medical institution during this period. Yet with archives literally ‘silent’, how far can the sound and experience of music be retrieved and reconstructed? Drawing on critical archive theory and the idea of the soundscape as well as musicological and historical practice, this article questions how we can investigate asylum soundscapes through the silences of the archive, and how we can use the resulting processes to deepen our relationship with the archive and enrichen other aspects of historical and archive studies. I argue that in drawing attention to new forms of evidence in order to address the literal ‘silence’ of the nineteenth-century asylum, new approaches to metaphorical ‘silences’ can be found.
Immunomodulatory and Regenerative Effects of MSC-Derived Extracellular Vesicles to Treat Acute GVHD
Authors: Fujii Sumie , Miura Yasuo 
Published: August 2022

AbstractThe development of human mesenchymal stromal/stem cell (MSC)-based therapy has focused on exploring biological nanoparticles secreted from MSCs. There is emerging evidence that the immunomodulatory and regenerative effects of MSCs can be recapitulated by extracellular vesicles released from MSCs (MSC-EVs). Off-the-shelf allogeneic human MSC products are clinically available to treat acute graft-versus-host disease (GVHD), but real-world data have revealed the limitations of these products as well as their feasibility, safety, and efficacy. MSC-EVs may have advantages over parental MSCs as drugs because of their distinguished biodistribution and importantly dose-dependent therapeutic effects. Recent research has shed light on the role of microRNAs in the mode-of-action of MSC-EVs. A group of specific microRNAs alone or in combination with membrane proteins, membrane lipids, and soluble factors present in MSC-EVs play key roles in the regulation of GVHD. In this concise review, we review the regulation of T-cell-mediated adaptive immunity and antigen-presenting cell-mediated innate immunity by MSC-EVs and the direct regenerative effects on damaged cells in association with the immunopathology of GVHD.