bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-25. LARGE CELL/ANAPLASTIC MEDULLOBLASTOMA REPRESENTS MORE THAN ONE DISEASE ENTITY
Authors: Krause Katharina , Goschzik Tobias , Doerner Evelyn , Pietsch Torsten 
Published: June 2023

Abstract
Medulloblastoma (MB) with predominant large cell or anaplastic cytological features have been identified to be associated to an aggressive clinical course and poor survival. Because cases can show mixed cytologies, these histologically defined MB types were merged in the recent WHO classification of tumors of the CNS to large cell/anaplastic (LC/A) MB. In this study, we collected FFPE samples of 137 LC/A MB of all age groups (0-39 years) diagnosed at the DGNN Brain Tumor Reference Center in Bonn, Germany, and performed a comprehensive histological, immunophenotypical, genetic and epigenetic analysis by next-generation panel sequencing (NGS), 450k/850k methylation bead-array hybridization and molecular inversion probe (MIP) technology. 73% of cases showed predominant anaplastic histology, 27% predominant large cell histology. Methylation-based subtyping and sequencing showed that the cohort of LC/A MB represented different biological entities: 6% WNT-MB, 7% SHH-MB-TP53-wildtype, 10% SHH-MB-TP53-mutant, and 77% non-WNT/non-SHH MB (with predominant epigenetic subtype II). High-resolution copy number profiling by MIP demonstrated MYC amplification in 40% of non-WNT/non-SHH MB. MYC amplification was highly associated to infant disease and predominant large cell histology. On the contrary, predominant anaplastic histology was highly associated to non-infant disease, MYCN amplification and SHH activation. By NGS we detected recurrent mutations in 37 MB-related genes; the frequency of mutations of individual MB-related genes differed significantly between the histologically and genetically defined MB types. Our data clearly demonstrate that large cell MB and anaplastic MB represent different biological entities. Therefore, and also in respect to the future development of targeted treatment approaches to these highly malignant MB types, they should be precisely diagnosed as separate MB entities.
OTHR-03. CLASSIFICATION OF BRAIN TUMORS BY NANOPORE SEQUENCING OF CELL-FREE DNA FROM CEREBROSPINAL FLUID
Authors: Afflerbach Ann-Kristin , Rohrandt Christian , Brändl Björn , Sönksen Marthe , Hench Jürgen , Frank Stephan , Börnigen Daniela , Alawi Malik , Mynarek Martin , Winkler Beate , Ricklefs Franz , Synowitz Michael , Dührsen Lasse , Rutkowski Stefan , Wefers Annika K , Müller Franz-Josef , Schoof Melanie , Schüller Ulrich 
Published: June 2023

Abstract
For exact molecular diagnosis of CNS tumors, tumor tissue obtained through surgery is usually needed. However, knowledge on the molecular tumor type beforehand might influence surgical strategies and reduce surgery-associated risks. Molecular analyses of liquid biopsies have therefore gained increasing interest in order to secure diagnosis before surgery or to replace surgery in rare instances. Moreover, the minimally invasive nature of liquid biopsies enables a tight and longitudinal tumor monitoring with potentially higher sensitivity than imaging approaches. In this study, we applied Nanopore sequencing to 129 cell-free DNA (cfDNA) samples from the cerebrospinal fluid (CSF) of brain tumor patients, with 70.5% coming from pediatric patients. We analyzed copy number variations (CNV) and methylation patterns with a recently published random forest classifier (NanoDx). Circulating tumor DNA (ctDNA) was detected and successfully classified the tumor in 45% of all technically successful samples, both in pre- and early post-surgery samples as well as in samples from &gt;14 days post-surgery, often with clinically unclear residual tumor or disease relapse. In all samples containing detectable tumor DNA, CNV analysis was more frequently successful than methylation analysis with overall detection rates of 88% and 44%, respectively. CNV analysis revealed diagnostic alterations, such as C19MC amplifications in ETMR as well as Chr.1q gain and Chr.6q loss in PFA ependymoma, which are important prognostic markers. Methylation analysis also allowed the classification of tumors with balanced genomes, like craniopharyngiomas. Finally, we were able to perform longitudinal analyses and found aberrations in the CNV profiles that were private to the tumor relapse, highlighting the potential of liquid biopsies to detect potentially relevant changes of tumor biology. Our results show that Nanopore sequencing is a promising approach to establish initial tumor diagnosis and to monitor disease courses by lumbar punctures.
TRLS-09. USE OF A PAN-PEPTIDE CHECKPOINT INHIBITOR IN THE TREATMENT OF CENTRAL NERVOUS SYSTEM TUMORS
Authors: Moertel Christopher , Pluhar G Elizabeth , Olin Michael 
Published: June 2023

Abstract
Immunotherapy has revolutionized clinical management of a select group of malignancies by offering a long-term, durable treatment response. Unfortunately, only a small percentage of brain cancers respond. The combination of multiple checkpoint inhibitors may result in serious immune-related adverse events. We have developed a Pan-Immune Checkpoint Ligand that simultaneously controls multiple immune checkpoints. The CD200 immune checkpoint modulates the immune system through a single inhibitory receptor (CD200R1) and multiple activation receptors (CD200ARs). We developed a peptide ligand, CD200AR-L, that targets the CD200ARs, which results in activation of the immune system and suppression of the inhibitory effects of CD200 and other immune checkpoints. Treatment of high-grade glioma in companion dogs with autologous tumor lysate vaccinations and CD200AR-L resulted in a two-year progression-free survival rate of 20% with no significant adverse events. We believe this response is due to the ability of CD200AR-L to modulate multiple immune checkpoints through shared signaling molecules in both the CD200 and PD-1/PD-L1 checkpoint pathways. Our preliminary data demonstrate that CD200R1 and PD-1 mediated immune checkpoint signaling is through SHIP1. CD200AR-L overcomes the immunosuppressive effects of the tumor-derived CD200 and PD-L1 by downregulating these checkpoints on both antigen-presenting cells (APC) and T-cells. CD200AR-L also downregulates PD-1 on APCs and inhibits the upregulation of PD-1 and CTLA4 on T cells. This translational research has led to the initiation of a phase I dose-escalation clinical trial for recurrent glioblastoma in adults (NCT04642937) and the writing of an IND for a pediatric HGG/DIPG trial.
TRLS-12. INTRAVENTRICULAR B7-H3 CAR T CELLS FOR DIFFUSE INTRINSIC PONTINE GLIOMA: INTERIM ANALYSIS OF BRAINCHILD-03 ARM C
Authors: Vitanza Nicholas , Ronsley Rebecca , Wilson Ashley , Huang Wenjun , Seidel Kristy , Pinto Navin , Gust Juliane , Gardner Rebecca , Jensen Michael , Park Julie 
Published: June 2023

Abstract

BACKGROUND
BrainChild-03 is a first-in-human phase 1 clinical trial delivering repeated intraventricular B7-H3 CAR T cells to children with central nervous system (CNS) tumors without lymphodepleting chemotherapy.

METHODS
We report on the ongoing Arm C for patients with diffuse intrinsic pontine glioma (DIPG), currently enrolling at the highest Dose Regimen (10x10^7 B7-H3CARs/dose). Primary endpoints are feasibility and safety. Secondary endpoints are disease response and correlatives of CAR-T activity.

RESULTS
19 patients have enrolled. All had successful CAR-T manufacturing. 17 patients were treated; 13 received sufficient doses for safety evaluation (4 doses/8 weeks) without a dose limiting toxicity (DLT). One patient had a DLT (pontine hemorrhage 8 days post-initial dose). The 5 unevaluable patients include: 2 on protocol not yet evaluable, 2 left the study due to rapid progression, and 1 did not meet eligibility to initiate treatment. Overall, patients have received 134 doses (median: 8/patient, range: 1-36). Adverse events include headache (93%), nausea/vomiting (79%), and fever (57%). Cytokine release syndrome (CRS) or immune effort cell-associated neurotoxicity syndrome (ICANS) have not occurred. Of 14 evaluable patients, 8 enrolled after progression, including some with metastases. Patients with progressive DIPG at enrollment have a median survival of 278 days post-initial dose (3/8 alive). Patients who enrolled before progression have a median overall survival of 207 days (6/6 alive) with 1 patient still receiving protocol therapy after 18 months (36 doses).
We have found localized CSF circulating CAR T cells and cytokine elevations supporting local immune activation. CSF mass spectrometry shows modulation of B7-H3 and immune analytes (CD14, CD163, CSF-1, CXCL13).

CONCLUSION
Repeated intraventricular B7-H3 CAR T dosing has been feasible for children with DIPG, even after progression, with evidence of local immune activation. Tolerability and prolonged stable disease suggest the potential for clinical benefit allowing for future cellular enhancements and combinations.
Exploring the Evolvability of Plant Specialized Metabolism: Uniqueness Out Of Uniformity and Uniqueness Behind Uniformity
Authors: Ono Eiichiro , Murata Jun 
Published: June 2023

Abstract
The huge structural diversity exhibited by plant specialized metabolites has primarily been considered to result from the catalytic specificity of their biosynthetic enzymes. Accordingly, enzyme gene multiplication and functional differentiation through spontaneous mutations have been established as the molecular mechanisms that drive metabolic evolution. Nevertheless, how plants have assembled and maintained such metabolic enzyme genes and the typical clusters that are observed in plant genomes, as well as why identical specialized metabolites often exist in phylogenetically remote lineages, is currently only poorly explained by a concept known as convergent evolution. Here, we compile recent knowledge on the co-presence of metabolic modules that are common in the plant kingdom but have evolved under specific historical and contextual constraints defined by the physicochemical properties of each plant specialized metabolite and the genetic presets of the biosynthetic genes. Furthermore, we discuss a common manner to generate uncommon metabolites (uniqueness out of uniformity) and an uncommon manner to generate common metabolites (uniqueness behind uniformity). This review describes the emerging aspects of the evolvability of plant specialized metabolism that underlie the vast structural diversity of plant specialized metabolites in nature.
Describing the landscape of integrated clinical educational programs for PAs and NPs
Authors: Polansky Maura N. , Gillum J. Barton , Rooney Maxwell S. , Messing Jonathan 
Published: June 2023

ABSTRACT

Purpose:
Postgraduate clinical training (PCT) has been available to PAs since the 1970s and to NPs since at least 2007. Some programs now enroll PAs and NPs. Although this new training model appears to be expanding, little data about integrated PA/NP programs are available.

Methods:
This study examined the PA/NP PCT landscape in the United States. Programs were identified from membership rosters of the Association of Postgraduate Physician Assistant Programs and the Association of Post Graduate APRN Programs. Data (program name, sponsoring institution, location, specialty, accreditation status) were identified from programs' websites.

Results:
We identified 106 programs at 42 sponsoring institutions. Various specialties, most commonly in emergency medicine, critical care, and surgery, were represented. Few were accredited.

Conclusions:
PA/NP PCT is now common, with about half of the programs accepting PAs and NPs. These programs represent a unique form of interprofessional education involving full integration of two professions in the same program and are worthy of further investigation.
Patient Perspectives and Quality of Life after Breast Reconstruction and the Impact of Subsequent Revisions
Authors: Kandi Lyndsay A. , Hammond Jacob B. , Nadone Haley , Kosiorek Heidi E. , Rebecca Alanna M. , Casey William J. , Reece Edward M. , Cronin Patricia A. , Pockaj Barbara A. 
Published: June 2023

Background:
There is limited research on the impact of revisional surgery after breast reconstruction on patient experience and postoperative quality of life (QoL).

Methods:
Patients undergoing mastectomy with immediate implant-based or autologous free-flap breast reconstruction from 2008 to 2020 were reviewed. These patients were categorized by revisions (0–1, 2–3, and 4+) and surveyed on QoL metrics using BREAST-Q and Was It Worth It? (WIWI) questionnaires. BREAST-Q QoL, satisfaction, and WIWI metrics between revision groups were evaluated.

Results:
Among 252 patients, a total of 150 patients (60%) underwent zero to one revisions, 72 patients (28%) underwent two to three revisions, and 30 patients (12%) underwent four or more revisions. Median follow-up was 6 years (range, 1–11 years). BREAST-Q satisfaction among patients with four or more revisions was significantly lower (P = 0.03), while core QoL domains (chest physical, psychosocial, and sexual well-being) did not significantly differ. Analysis of unplanned reoperations due to complications and breast satisfaction showed no significant difference in QoL scores between groups (P = 0.08). Regarding WIWI QoL metrics, four or more revisions were associated with a higher rate of worse QoL (P = 0.035) and worse overall experience (P = 0.001). Most patients in all revision groups felt it was worthwhile to undergo breast reconstruction (86%), would choose breast reconstruction again (83%), and would recommend breast reconstruction to others (79%).

Conclusions:
Overall, a majority of patients undergoing revisions after breast reconstruction still have a worthwhile experience. Although reoperations after breast reconstruction do not significantly impact long-term BREAST-Q QoL domains, patients undergoing four or more revisions have significantly lower breast satisfaction, worse QoL, and a postoperative experience worse than expected.
European Society of Hypertension recommendations for the validation of cuffless blood pressure measuring devices: European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability
Authors: Stergiou George S. , Avolio Alberto P. , Palatini Paolo , Kyriakoulis Konstantinos G. , Schutte Aletta E. , Mieke Stephan , Kollias Anastasios , Parati Gianfranco , Asmar Roland , Pantazis Nikos , Stamoulopoulos Achilleas , Asayama Kei , Castiglioni Paolo , De La Sierra Alejandro , Hahn Jin-Oh , Kario Kazuomi , McManus Richard J. , Myers Martin , Ohkubo Takayoshi , Shroff Sanjeev G. , Tan Isabella , Wang Jiguang , Zhang Yuanting , Kreutz Reinhold , O’Brien Eoin , Mukkamala Ramakrishna 
Published: June 2023

Background:There is intense effort to develop cuffless blood pressure (BP) measuring devices, and several are already on the market claiming that they provide accurate measurements. These devices are heterogeneous in measurement principle, intended use, functions, and calibration, and have special accuracy issues requiring different validation than classic cuff BP monitors. To date, there are no generally accepted protocols for their validation to ensure adequate accuracy for clinical use.Objective:This statement by the European Society of Hypertension (ESH) Working Group on BP Monitoring and Cardiovascular Variability recommends procedures for validating intermittent cuffless BP devices (providing measurements every >30 sec and usually 30–60 min, or upon user initiation), which are most common.Validation procedures:Six validation tests are defined for evaluating different aspects of intermittent cuffless devices: static test (absolute BP accuracy); device position test (hydrostatic pressure effect robustness); treatment test (BP decrease accuracy); awake/asleep test (BP change accuracy); exercise test (BP increase accuracy); and recalibration test (cuff calibration stability over time). Not all these tests are required for a given device. The necessary tests depend on whether the device requires individual user calibration, measures automatically or manually, and takes measurements in more than one position.Conclusion:The validation of cuffless BP devices is complex and needs to be tailored according to their functions and calibration. These ESH recommendations present specific, clinically meaningful, and pragmatic validation procedures for different types of intermittent cuffless devices to ensure that only accurate devices will be used in the evaluation and management of hypertension.
Is Transcatheter Aortic Valve Implantation Effective in Improving Quality of Life?
Authors: Pollock Meg , Hutchinson Alison M. , Ockerby Cherene , Driscoll Andrea 
Published: June 2023

Background
Aortic stenosis (AS) without surgical intervention is associated with morbidity and mortality and is the most common valvular disease in the western world. Transcatheter aortic valve implantation (TAVI) is a minimally invasive surgical option that has become a common treatment for people unable to undergo open aortic valve replacement; despite the increase in TAVI offerings in the last decade, patient quality of life (QoL) outcomes postoperatively are poorly understood.

Objective
The aim of this review was to determine whether TAVI is effective in improving QoL.

Method
A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted, and the protocol was registered on PROSPERO (CRD42019122753). MEDLINE, CINAHL, EMBASE, and PsycINFO were searched for studies published between 2008 and 2021. Search terms included “transcatheter aortic valve replacement” and “quality of life” and their synonyms. Included studies were evaluated, dependent on study design, using either the Risk of Bias-2 or the Newcastle-Ottawa Scale. Seventy studies were included in the review.

Results
Authors of the studies used a wide variety of QoL assessment instruments and follow-up durations; authors of most studies identified an improvement in QoL, and a small number identified a decline in QoL or no change from baseline.

Conclusion
Although authors of the vast majority of studies identified an improvement in QoL, there was very little consistency in instrument choice or follow-up duration; this made analysis and comparison difficult. A consistent approach to measuring QoL for patients who undergo TAVI is needed to enable comparison of outcomes. A richer, more nuanced understanding of QoL outcomes after TAVI could help clinicians support patient decision making and evaluate outcomes.
Activity Monitoring in Parkinson Disease: A Qualitative Study of Implementation Determinants
Authors: Fowler King Bridget , MacDonald Jillian , Stoff Laura , Nettnin Ella , Jayaraman Arun , Goldman Jennifer G. , Rafferty Miriam 
Published: June 2023

Background and Purpose:
There is interest in incorporating digital health technology in routine practice. We integrate multiple stakeholder perspectives to describe implementation determinants (barriers and facilitators) regarding digital health technology use to facilitate exercise behavior change for people with Parkinson disease in outpatient physical therapy.

Methods:
The purposeful sample included people with Parkinson disease (n = 13), outpatient physical therapists (n = 12), and advanced technology stakeholders including researchers and reimbursement specialists (n = 13). Semistructured interviews were used to elicit implementation determinants related to using digital health technology for activity monitoring and exercise behavior change. Deductive codes based on the Consolidated Framework for Implementation Research were used to describe implementation determinants.

Results:
Key implementation determinants were similar across stakeholder groups. Essential characteristics of digital health technology included design quality and packaging, adaptability, complexity, and cost. Implementation of digital health technology by physical therapists and people with Parkinson disease was influenced by their knowledge, attitudes, and varied confidence levels in using digital health technology. Inner setting organizational determinants included available resources and access to knowledge/information. Process determinants included device interoperability with medical record systems and workflow integration. Outer setting barriers included lack of external policies, regulations, and collaboration with device companies.

Discussion and Conclusions:
Future implementation interventions should address key determinants, including required processes for how and when physical therapists instruct people with Parkinson disease on digital health technology, organizational readiness, workflow integration, and characteristics of physical therapists and people with Parkinson disease who may have ingrained beliefs regarding their ability and willingness to use digital health technology. Although site-specific barriers should be addressed, digital health technology knowledge translation tools tailored to individuals with varied confidence levels may be generalizable across clinics.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content available at: http://links.lww.com/JNPT/A436).
Psychological distress in patients with cancer at the Kenyatta National Hospital in Nairobi, Kenya, during the COVID-19 pandemic
Authors: Ong'ondi Matilda , Njuguna Irene , Obulumire Ronniey , Munyoro Esther , Okech Violet , Ann Njoroge , Bultz Barry 
Published: June 2023

Abstract

Background:
Psychosocial care for oncology patients is now recognized as a critical aspect of care because it has a positive impact on patient outcomes. Various screening tools have been validated to objectively measure the levels of distress, such as the National Comprehensive Cancer Network distress thermometer. However, there is little evidence of its use in sub-Saharan Africa, where the cancer burden continues to increase. This study sought to evaluate the levels of psychological distress in patients with cancer and the impact of the COVID-19 pandemic.

Methods:
This was a single-center cross-sectional study among patients with a histological diagnosis of cancer attending the hemato-oncology and radio-oncology units at the Kenyatta National Hospital, a referral tertiary center. We used the National Comprehensive Cancer Network Distress Thermometer and Problem Checklist to define psychological distress, fear of COVID-19 scale, and Corona Anxiety Score to determine the level of fear and anxiety caused by COVID-19 given the study happened during the pandemic, and the Eastern Cooperative Oncology Group (ECOG) to assess the performance status.

Results:
Of the 361 patients, the median age was 54 years (interquartile range, 43–63), and most were female (70%). The leading cancer diagnosis was breast cancer (26%), followed by cervical cancer (24%), with most of the patients having advanced disease and 28% having ECOG 3. Most (80%) patients were able to continue with their treatment despite the COVID-19 pandemic; however, 71% had a high level of fear of COVID-19 but minimal anxiety symptoms based on Corona Anxiety Score. The mean distress thermometer score was 2.7 (SD, 2.6), with 30% having a high level of distress (4 or above). ECOG status was the only variable significantly associated with high levels of distress, with the strongest association observed in the highest ECOG status (ECOG 4: OR, 6.8 [95% CI, 2.8–16.6] P < .001). Transportation was the main problem in the practical domain (62%) while fears and worries in the emotional domain (46% and 49%, respectively), and pain (65%) were the main physical problems.

Conclusions:
One-third of patients experienced high levels of distress. These patients reported significant concerns, such as transportation, fears, worry, and pain, in the problem checklist. There is a need to incorporate screening for distress into our patient population to help identify these patients and institute appropriate interventions.