bluuebunny/crossref_metadata_2025 huggingface dataset:
P13.04.A REPRODUCIBLE CRISPR-SEQ PIPELINE FOR NGS FUNCTIONAL GENOMICS SCREENINGS FOR GLIOMA CELL LINES
Authors: Kuhlburger L , Mir Pedrol J , Haeusser L A , Walter B , Gabernet G , Merk D , Tabatabai G , Nahnsen S
Published: September 2023

BACKGROUND

The CRISPR/Cas9 genome editing technology has revolutionized the field of functional genomics by enabling precise editing of DNA. Over the past few years, CRISPR technology has been widely employed to identify genetic dependencies in a broad spectrum of applications paving the way for the discovery and validation of relevant molecular targets, for example potential drug targetsGlioblastoma are incurable primary tumors of the central nervous system. Functional genomics could enable the discovery of novel therapeutic targets or even combination therapies.

MATERIAL AND METHODS

Here, we present a bioinformatics pipeline that combines functional screens and target editing analysis to identify potential vulnerabilities and drug targets in glioblastoma or other diseases. The pipeline consists of two workflows, one performing functional screening and one performing base editing analysis. This developed CRISPR-seq pipeline is reproducible and containerized, allowing high-throughput processing. All processes are modularized in Nextflow DSL2 (Domain Specific Language) and versioned which facilitates maintainability and customization, as well as the addition of new tools. A quality control report is also automatically generated, allowing the user an overview of their ran experiments. The pipeline also helps us to keep the data FAIR (Findable, Accessible, Interoperable and Reusable) and optimized, making it easier to share with other researchers and collaborate on future studies.

RESULTS

This pipeline was applied to functional screens using CRISPR/Cas9 genome-wide knockout or activation libraries to detect genetic vulnerabilities that might enhance drug treatment efficacy, e.g. for ataxia telangiectasia and Rad3 related (ATR) inhibition in experimental glioma.With this pipeline, we were able to identify several genes that are involved in drug resistance in glioblastoma, by starting from raw data (fastq files) to genes presenting vulnerabilities.The results obtained through our pipeline provided important information on the disease's molecular mechanisms, which were subsequently confirmed through wet lab validation.

CONCLUSION

In conclusion, the crisprseq software described in this abstract is a powerful tool for identifying potential genetic dependencies. The pipeline aims at analyzing this output data in a reproducible and containerized way using Nextflow and respecting nf-core community standards. By combining functional screens and base editing analysis with bioinformatics tools, this pipeline allows for the identification of essential genes and pathways, as well as the characterization of specific mutations that contribute to the development and progression of glioblastoma.
P13.13.B INTERPRETABLE WHOLE SLIDE IMAGE PROGNOSTIC STRATIFICATION OF GLIOBLASTOMA PATIENTS FURTHERING DISEASE UNDERSTANDING
Authors: Baheti B , Innani S , Mehdiratta G , Nasrallah M P , Bakas S
Published: September 2023

BACKGROUND

Glioblastoma is the most common malignant adult brain tumor, with a grim prognosis and heterogeneous morphology. Stagnant patient prospects over the last 20 years reflect our limited disease understanding. Robust prognostic patient stratification from whole slide images (WSI) using interpretable computational methods could improve disease understanding and patient management.

MATERIAL AND METHODS

Assessment of the TCGA-GBM and TCGA-LGG data collections by the 2021 WHO classification criteria of CNS tumors identified 188 glioblastoma (IDH-wt, grade 4) cases, divided into short (<9 months, n=94) and long (>13 months, n=94) survivors. An H&E-stained WSI from each patient is selected and comprehensively pre-processed to remove artifactual and non-tissue regions by partitioning them into 256x256 patches. An interpretability mechanism via a weakly supervised attention-based multiple-instance-learning algorithm is leveraged for prognostic stratification. The attention scores are visualized as a heatmap to identify the essential ROIs driving decisions. The model is evaluated on 10-fold monte carlo cross-validation, using training (80%), validation (10%), and test (10%) sets.

RESULTS

Quantitative evaluation revealed ValidationACCURACY=70%, TestACCURACY =62%, ValidationAUC= 0.75, and TestAUC=0.68. Heatmaps indicate weight given throughout histologically malignant areas for correctly predicted long survivors, including necrosis, hypercellularity, atypia, infiltration, and proliferation. Correct prediction of short survival weighted infiltrative features, including leptomeningeal involvement. For misclassified long-survivors, necrotic areas are not heavily weighted, and gemistocytic cells are seen in a densely packed rather than infiltrating arrangement. For some misclassified short-survivors, the hot regions are hypercellular; however, these are a minority of the specimen, which predominantly showed a less cellular, fibroblastic, spindled appearance.

CONCLUSION

The interpretation of algorithmic decisions through qualitative visualization of heatmaps can offer insights into histologic regions with prognostic relevance. In the case of glioblastoma, the histologic appearance of long survivors based on a neuropathologist's observation suggests aggressive tumors traditionally considered indicative of poor prognosis. The algorithm's ability to accurately predict long survival based on these areas indicates that further investigation of these features may be warranted for improved prognostication through histologic assessment. Our findings support the use of data-driven interpretation of algorithmic decisions to identify morphological patterns with prognostic significance, which would further our understanding of glioblastoma.
P13.15.B ULTRA-FAST DEEP-LEARNED CNS TUMOR CLASSIFICATION DURING SURGERY
Authors: Vermeulen C , Pages Gallego M , Kester L , Kranendonk M , Wesseling P , Verburg N , de Witt Hamer P , Kooi E , Dankmeijer L , van der Lugt J , van Baarsen K , Hoving E , Tops B , de Ridder J
Published: September 2023

BACKGROUND

Central nervous system (CNS) tumors are the most lethal category of tumors, particularly among children. Most commonly, the first line treatment of CNS tumors is neurosurgical resection of the tumor. During this procedure a delicate balance must be struck between extent of resection and risk of comorbidity. Ideally, the surgical plan is based on a detailed classification of the tumor. However this classification is often unknown at the start of the surgery. Current practice consists of preoperative imaging and intraoperative diagnosis achieved by rapid histological assessment of frozen tumor sections. However, these tests do not always result in a clear diagnosis, and are sometimes even revised based on postoperative tissue-based diagnostics. As a result, some patients require a second surgery, while others could in hindsight have been operated less radically.

MATERIAL AND METHODS

Nanopore sequencing enables direct detection of DNA methylation status in real time, making it ideally suited for intraoperative sequencing and molecular tumor classification. The major challenge of this approach is that the classification must be performed on very few randomly distributed sequence reads. To this end we developed Sturgeon, a neural-network training approach that delivers classification models capable of classifying 81 different CNS tumor subtypes based on sparse methylation data. Sturgeon leverages illumina 450K DNA methylation profiles to simulate millions of nanopore sequencing experiments, which are then used to train and validate classifier models. The resulting models are portable, work across patients and sequence depths and require less than a minute of computation on a laptop CPU.

RESULTS

We demonstrate our method to be fast enough to provide a correct diagnosis with as little as 20 to 40 minutes of sequencing in 45 out of 50 retrospective pediatric brain tumor samples. We applied Sturgeon in an intraoperative setting in 25 cases, where we consistently achieve a turnaround time of 60-90 minutes from biopsy to result with a correct molecular subclassification in 18 cases and an inconclusive result in 7 cases.

CONCLUSION

Sturgeon classification can be used in parallel with intraoperative frozen section histology. In cases where it agrees with the pathologist, Sturgeon offers a valuable independent confirmation, and a more detailed molecular subclassification. In the rare cases where Sturgeon disagrees with the histology diagnosis, or where the histology is inconclusive, it has the potential to prevent misdiagnoses that would result in unnecessary risk of comorbidity, or the requirement for a second surgery.
P14.02.B LONGITUDINAL COMPARATIVE ANALYSIS OF BLOOD NEUROFILAMENTS AS BIOMARKERS OF CHEMOTHERAPY-INDUCED PERIPHERAL NEUROTOXICITY
Authors: Velasco R , Marco C , Ferrer G , Domingo-Domènech E , Stradella A , Santos C , Laquente B , Argyriou A , Bruna J
Published: September 2023

BACKGROUND

The identification of a biomarker of chemotherapy-induced peripheral neurotoxicity (CIPN) remains an unmet need. Increasing evidence supports that light-chain Neurofilament (NfL) could be useful to quantify the extend of peripheral nerve damage due to chemotherapy. The aim of the study is to ascertain differences in plasma NfL (pNfL) among agents to evaluate the clinical usefulness of pNfL.

MATERIAL AND METHODS

Prospective longitudinal comparative study including patients treated with paclitaxel (N=24) for breast cancer, brentuximab vedotin (BV) (n=20) for lymphoma and oxaliplatin (n=16) for gastrointestinal cancer. All patients were assessed using the Total Neuropathy Score-clinical, Common Toxicity Criteria for Adverse Events before (T1), at finishing (T2) and at next follow-up (T3). Serial pNfL were collected at the same timepoints and quantified using the SIMOA technique. The changes in pNfL were compared between group of agents (platinum (oxaliplatin) or microtubule disruptors (MT) (BV or paclitaxel) and correlated with clinical data, depending on the degree of CIPN. Clinically relevant (CR) was defined as > grade 2-CIPN.

RESULTS

60 patients are included, mostly women (66,7%) with median age of 52 [22-88] years. pNfL at T1 was 16,51 ± 1,65 pg/mL, and correlated with age (r= 0.284, p < 0.036). pNfL increased at T2 (141,39 ± 18,89 pg/mL) and decreased at last follow-up (T3) (28,08 ± 2,52 pg/mL) in the whole series, at a median of 3 (1-5) months after finishing chemotherapy. Patients with CR-CIPN had higher pNfL at T2 (209,90 ± 40,09 vs 103.02 ± 96.74 pg/mL, p=0.005). One third of patients receiving MT disruptors (31,6%) or platinum agents (35,7%) developed CR-CIPN. Higher pNfL level at T2 were identified in patients receiving anti MT agents than oxaliplatin (160, 27 ± 22,75 vs 70,04 ± 11,24 pg/mL), p<0,001). Among the group of MT, pNfL at T2 were higher in those receiving paclitaxel compared to BV (233,90 ± 31.84 vs 62,09 ± 9.60 pg/mL, p<0.001), despite no differences in rate of CR-CIPN (26,6% BV and 34.7% Paclitaxel, p=0.7). At T3, no differences in pNfL were identified between BV (33,53 ± 4,67 pg/mL) and paclitaxel (29,20 ± 4,24 pg/mL) treated patients. A significant correlation between pNfL and TNSc was identified (r = 0.663, p < 0.001).

CONCLUSION

Variable change of pNfL according to the type of agent and mechanism of neurotoxicity can be observed regardless of the comparable degree of clinical CIPN severity. Further studies to better dissect cut-off values for each agent are needed before implementing pNfL as CIPN biomarker.
P15.06.A HYBRID [18F]FET PET-MRI; A VALUABLE ADVANCED IMAGING TOOL TO DISCRIMINATE BETWEEN TUMOR RECURRENCE AND PSEUDOPROGRESSION IN GLIOMA PATIENTS
Authors: de Jong J , Pruis I J , Valkema R , van den Bent M J , Veldhuijzen van Zanten S E M
Published: September 2023

BACKGROUND

One of the well-known challenges in the response assessment of glioma patients is differentiating tumor recurrence from treatment-related effects, i.e. pseudoprogression. The PET tracer O-(2-18F-fluoroethyl)-L-tyrosine ([18F]FET) visualizes increased amino acid metabolism and can potentially aid differentiation between vital tumor tissue and reactive changes, and can herewith guide clinical decision-making and surgical planning. This study aimed to assess the diagnostic yield of hybrid [18F]FET PET-MRI in a series of pre-treated patients suspected of glioma recurrence.

MATERIAL AND METHODS

This retrospective study included histologically-confirmed glioma patients who had undergone standard-of-care therapy consisting of gross-total resection surgery and/or radiotherapy. [18F]FET PET-MRI scans were performed between 04/2022 and 03/2023. Patient received 204 MBq (median, range: 180-242) [18F]FET intravenously, followed directly by a 45 minute dynamic PET and simultaneous MRI including DWI and gadolinium-based sequences (PWI). Time-activity-curves (TACs), showing the mean tissue radioactivity in tumor regions of interest as a function of time, were compared to the TAC in healthy tissue. Static PET images for qualitative visual analysis were reconstructed by accumulating the 20-40 minute timeframes. Tumor recurrence (i.e., a positive scan) was defined as focal uptake exceeding uptake in healthy brain parenchyma according to the joint EANM/EANO/RANO practice guideline/SNMMI procedure standard. Outcomes were compared to previously-obtained MRIs, post-operative pathology, and clinical/radiological follow-up.

RESULTS

Thirteen patients, 31% female, median age 39 (range: 28-50), with astrocytoma (grade 2_n=2; grade 3_n=1; grade 4_n=2), oligodendroglioma (grade 2_n=6; grade 3_n=1), and glioblastoma (n=1) were included. [18F]FET PET-MRI was positive in 9/13 patients (70%), which in 5/9 (55%) was confirmed by pathology (n=3) or clinical follow-up (n=2). In 6/9 patients with a positive scan (66%), the previously-obtained MRI (time interval range: 0.5-4.1 months) showed negative (n=4) or unclear (n=2) DWI and PWI findings. Four/13 (30%) patients had a negative [18F]FET PET-MRI and did not show signs of tumor progression after an average follow-up of 3, 5, 11 and 12 months, respectively.

CONCLUSION

Simultaneous [18F]FET PET-MRI shows high potential for accurate differentiation between true tumor progression and treatment-related pseudoprogression in glioma patients with equivocal findings on MRI including DWI and PWI. The diagnostic yield of this hybrid imaging technique exceeded that of MRI-only in our case series, and thus provides a promising advanced imaging tool in the follow-up of glioma patients. We aim at prospective studies to validate the clinical value of this multimodal approach.
P15.10.A USE OF DUAL TRACERS PET AS A PREDICTIVE BIOMARKER OF THE SITE OF RECURRENCE IN HIGH GRADE GLIOMA
Authors: Alfaifi B , Agushi E , Hinz R , Jackson A , Lewis D , Coope D
Published: September 2023

BACKGROUND

High grade glioma has poor survival rate and tumour recurrence occurs despite current treatments. Positron emission tomography (PET) with [11C](R)PK11195 can evaluate translocator protein (TSPO) and [11C]methionine can assess amino acid transport. PET imaging might have the potential to detect tumour regions at baseline that will later develop as the site of recurrence. We compare TSPO measured using [11C](R)PK11195 and amino acid transport using [11C]methionine at baseline and investigate to what extend the two tracers can predict the site of tumour recurrence.

MATERIAL AND METHODS

Twelve patients with newly diagnosed high grade glioma underwent multimodal imaging studies. Preoperative MRI, [11C](R)PK11195 PET, [11C]methionine PET and postoperative (follow-up) MRI were co-registered. [11C](R)PK11195 binding potential (BPND) maps were generated using the simplified reference tissue model with grey matter cerebellar time-activity curve as tissue input function. [11C]methionine uptake was calculated as tumour to background ratio (TBR). Contrast enhancing volumes of interest (VOI) were defined on T1W post contrast. The VOI of [11C]methionine high uptake was standardized as TBR>1.7. For [11C](R)PK11195 VOI, the mean BPND + SD of grey matter voxels was calculated from individual maps of healthy control (HC; n = 50). Afterward, 95% confidence interval threshold (HC mean + 1.96 × SD) was used to describe high voxel activity in tumour (BPND>0.35). Tumour recurrence VOI was defined as contrast enhancement on the follow-up images.

RESULTS

The mean percentage overlap between high [11C](R)PK11195 BPND and [11C]methionine uptake was 48±17%. The mean percentage of each VOI showing exclusively high [11C](R)PK11195 BPND or exclusively high [11C]methionine was 25±21 or 27±22 respectively. The mean percentage overlap between high [11C](R)PK11195 and contrast enhancement is 36±14. The mean percentage of exclusively hight [11C](R)PK11195 or exclusively contrast enhancement were 38±18 or 26±25 respectively. The mean percentage overlap between high [11C]methionine and contrast enhancement were 47±12. The mean percentage of exclusively [11C]methionine or contrast enhancement were 36±20 or 17±17 respectively. The percentage volume overlap between contrast enhancing regions at recurrence and baseline [11C](R)PK11195 or [11C]methionine was 20±13 or 25±13 respectively.

CONCLUSION

The two PET tracers have high overlap although some regions are specific for high TSPO binding without high methionine uptake which could reflect an inflammatory component within the tumour microenvironment. The common regions between methionine and contrast enhancement is larger than TSPO binding which could represent that TSPO binding is less effected by disrupted blood-brain barrier. The mean percentage overlap with VOI representing tumour recurrence were similar.
P17.15.A THANK PHASE I TRIAL OF DNX-2440 ONCOLYTIC ADENOVIRUS IN PATIENTS WITH FIRST OR SECOND RECURRENCE OF GLIOBLASTOMA: PRELIMINARY RESULTS
Authors: Gallego Perez-Larraya J , de la Nava D , González-Huárriz M , García-Moure M , Labiano S , Zalacaín M , Marrodán L , Ausejo I , Laspidea V , Hervás I , Puigdelloses M , Esparragosa I , Giráldez M , Serrano M , Domínguez P , Díez-Valle R , Fueyo J , Gomez-Manzano C , Patiño A , Tejada S , Bejarano B , Alonso M
Published: September 2023

BACKGROUND

Oncolytic immunovirotherapy is emerging as a potential therapeutic approach in neuro-oncology. The oncolytic adenovirus DNX-2401, genetically engineered for selective replication and enhanced infectivity in tumor cells, has shown efficacy in adult patients with recurrent glioblastoma (GBM). In order to overcome the immunosuppressive brain-tumor microenvironment and thus enhance its antiglioma effect, DNX-2440 is a new armed virus which contains the same modifications but additionally incorporates OX40 ligand to induce the expression of such molecule in tumor cells and so increase the antitumor immune response.

MATERIAL AND METHODS

We are conducting a phase I open-label single-center study to investigate the safety and efficacy of a single intratumoral injection of DNX-2440 in patients with first or second recurrence of GBM. This is a dose escalation study, with a 3 + 3 design, evaluating an initial dose of 4x10e9 viral particles (vp) and a target dose of 4x10e10 vp. A single measurable lesion bigger than 10 mm in two perpendicular diameters and smaller than 25 cc is required for inclusion in the study.

RESULTS

To date 16 patients (6 [37.5%] female, 10 [62.5%] male) have been enrolled and treated with DNX-2401. Median age is 55 years (range, 39-80) and median KPS is 80 (range 70-90). As per protocol, surgery consisted of biopsy in all patients followed by intratumoral injection of DNX-2440. No dose limiting toxicity has been registered during the dose escalation phase (first cohort of 3 patients receiving 4x10e9 vp, and second cohort of 3 patients receiving 4x10e10 vp), and the remainder patients have received the target dose of 4x10e10 vp in the dose expansion cohort. Safety profile is acceptable with no serious adverse events related to DNX-2440 reported to date. Clinical benefit with tumor size reduction and prolonged survival have already been confirmed in 3 patients. Correlative analyses evaluating immune response in blood samples are ongoing.

CONCLUSION

Our current data suggest that intratumoral injection of DNX-2440 is feasible and safe, and seems to provide a clinical benefit in some patients with recurrent GBM. Furthermore, this trial illustrates the potential of oncolytic virus platforms to reshape the brain-tumor microenvironment and its interesting role in combination strategies with other immune-oncology agents for treating this disease.
P19.01.A INVESTIGATING THE MORPHOLOGICAL HETEROGENEITY OF GLIOBLASTOMA STEM CELLS AND ITS ROLE IN TUMOUR PROLIFERATION AND INVASIVENESS
Authors: Barelli C , Kaluthantrige Don F , Bertani I , Villa G , Osei I , Iannuzzi R , Vinceti A , Brognaro E , Sottoriva A , Iorio F , Kalebic N
Published: September 2023

BACKGROUND

Glioblastoma is the most common and aggressive primary brain tumour. Cancer hijacks developmental pathways and several studies have identified a stem cell-like population in glioblastoma following neurodevelopmental trajectories. In the foetal neocortex, a type of neural stem cell called basal progenitor is thought to be responsible for neocortical expansion. Basal progenitors exist in different morphotypes, and greater morphological complexity underlies their increased proliferation. We thus propose that cell morphology also plays a role in the proliferation and invasiveness of glioblastoma stem cells.

MATERIAL AND METHODS

We characterise the morphological heterogeneity of glioblastoma stem cells by immunostaining of human primary bulk tumour and peritumoral tissue. To then understand the function of cell morphology in tumour progression, we genetically manipulate morpho-regulatory molecules in 2D glioblastoma stem cells that show a genetic dependency on the target molecules based on cancer dependency maps.

RESULTS

We show that glioblastoma stem cells have a vast morphological heterogeneity in human primary bulk tumour and peritumoral tissue. The morphotypes observed are conserved in 2D glioblastoma stem cells and they are reminiscent of neural progenitors in the developing neocortex. We then test whether the genetic manipulation of those morpho-regulatory molecules which control the proliferation of basal progenitors in the fetal neocortex also affects the proliferation and invasiveness of glioblastoma stem cells.

CONCLUSION

Glioblastoma stem cells display extensive morphological heterogeneity, like basal progenitors in the developing neocortex. Morpho-regulatory molecules do not only control cell shape but may contribute to the proliferation and invasiveness of glioblastoma stem cells. We envision that the identification of morpho-regulatory molecules controlling tumour progression will open new therapeutic windows through pharmacological targeting and drug repurposing.
P20.02.B ELECTRO-CLINICAL, NEUROIMAGING FEATURES AND NEUROPATHOLOGICAL CHARACTERIZATION OF POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG (PLNTY)
Authors: Anghileri E , Didato G , Deleo F , Doniselli F M , Moscatelli M , Rizzi M , Paterra R , de Curtis M , Farinotti M , Freri E , Esposito S , Pollo B , Silvani A , Marucci G
Published: September 2023

BACKGROUND

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) has been recently recognized by 2021 WHO Central nervous system classification. It is an epileptogenic tumor type, affecting mostly children and young adults, with peculiar radiological, and pathomolecular features. PLNTY is a very rare tumor, described in only 52 cases up to now. Herein, we describe 13 patients with electro-clinical and neuroimaging findings, associated to histopathological and molecular findings.

MATERIAL AND METHODS

We selected PLNTY patients from our Cancer Registry (Apr 2017-Dec 2022), and collected electro-clinical, radiological and histo-molecular data. Minimum follow-up was 6 months. Exams included EEG, long-term scalp video-EEG, pre-surgical brain computer tomography and Magnetic Brain Imaging (MRI). Immunohistochemistry included CD34, IDH1-R132H, GFAP, synaptophysin, ATRX, p53 and FGFR3. IDH1-2, BRAF (V600E) sequencing, Kiaa1549:BRAF, FGFR3:TACC3, FGFR2:kii1598 and FGFR2:CTNNA3 fusion analyses will be performed.

RESULTS

We describe 13 patients, median age 20.6 years (range 12.3-46.4). Most patients showed memory/executive impairment and had epilepsy, with an onset from 5 months-21 years before surgery. The main feature of seizures was a difficult localization and even lateralization, both semiologically and electrographically. Post-surgical seizure control was excellent.The tumors (n=11/13 temporal) presented as solid or solid-cystic cortical mass with no mass effect and unclear hedges. Calcifications were present in 4, and cysts in 6 cases. Microscopically the tumors showed infiltrative growth pattern, oligodendroglial-like cells, strong and often diffuse CD34 immunostaining, and frequent intra-tumoral calcifications. Malformation of cortical development, namely FCD type IIIB, was associated to PLNTY in 2 cases. Proliferation activity (MIB-1 LI) was very low (1%) in all cases except one (MIB-1 LI which reached 3%).

CONCLUSION

This study significantly extends the number of reported PLNTY associated to epilepsy, mostly characterized by bilateral interictal epileptiform discharges and difficult to lateralize seizures.The MRI features were heterogeneous and the differential diagnosis should include also dysplasia and glioneuronal tumors. PLNTY, despite its name, occurs also in adults, and electro-clinical and radiological diagnosis can be challenging. As recently described, PLNTY can show the MAPK pathway activating alterations, that are under investigation in our cohort to eventually clarify their role in the evolution of the disease.

SUPPORT

the study is partially supported by the Health Italian Minister (RC).
P22.01.A PERSON-CENTRED PRACTICE: EXPLORING FAMILY STRENGTH BY USING GENOGRAMS AND ECOMAPS
Authors: Mathiasen M , Suhr Kjærgaard S , Piil K
Published: September 2023

BACKGROUND

Illness of a family member impacts the entire family. Family relationships, roles and tasks often change, and neuro-oncological caregivers experience a high level of burden and distress when playing a vital role in the informal care of the patient. The theory of Family Systems Nursing advises to approach the family rather than merely the patient. Within Family System Nursing the Family Nursing Conversations is an important intervention that focus on the interactions within a family and between the nurse and the family. The Calgary Family Assessment and Intervention Model (CFAM/CFIM) guide clinical practice to be family focused. According to these models, the drawings of genograms and ecomaps are efficient tools to graphicly portray the specific family constellation and social relationships. This presentation shows how genograms and ecograms can be applied to strength the dialogue with a family when implementing family-focused conversations.

MATERIAL AND

Methods In the neuro-oncological outpatient clinic at the University Hospital of Copenhagen we offer family and/or caregiver conversations. At the initial conversation, a genogram and an ecogram are drawn. By visualizing the family structure and interrelationships, the family is illustrated as a unit and the family can see their constellation in relation to each other and to the outside world.

RESULTS

Based upon the genograms and ecograms, a dialogue takes place. They have shown to be important tools to visualize the structure, with strengths and challenges within a family system. Further, they provide a good starting point for a family-focused communication. However, to implement these tools, training is required. Therefore, we have prepared teaching material to healthcare professionals. This material has been tested in family-focused conversations.

CONCLUSION

The use of genograms and ecomaps have proven to be efficient for a family-focused approach in a neuro-oncological outpatient clinic. They facilitate a good starting point for a family to identify their relationships and resources. During the conversations the family/caregivers often gain new insights and management strategies for coping.
Systematic review of hearing loss in dental professionals
Authors: Hartland J C , Tejada G , Riedel E J , Chen A H-L , Mascarenhas O , Kroon J
Published: September 2023

Background

Hearing loss leads to increased irritability and disengagement in social activities and conversations, which may impact quality of life. Dental professionals are at risk of developing hearing loss through daily exposure to noise from a wide range of equipment that produces significantly high decibels and noise frequencies.

Aims

The aim of this systematic review was to investigate the risk of hearing loss in dental professionals, including dentists, dental specialists, dental hygienists and dental assistants.

Methods

This review was conducted following the Cochrane Handbook for Systematic Reviews. PubMed, Scopus, Embase, Cochrane, Science Direct, Google Scholar and ProQuest were searched up to March 2023. Seventeen of 416 studies met the inclusion criteria. Quality assessment was performed according to the Newcastle–Ottawa Scale for cohort and case–control studies, and a modified version of this tool for cross-sectional studies.

Results

The majority of included studies (82%) found a positive association with hearing loss for dentists and dental specialists, with years of clinical experience identified as a prominent risk factor. Dental hygienists and dental assistants were less commonly reported in the literature. Difference between the left and right ears was found in 71% of studies, with the left ear more affected in both dentists and dental assistants due to proximity to the noise-inducing equipment.

Conclusions

Dental professionals are at risk of hearing loss in their workplace, especially linked to years of clinical experience, which highlights the need for prevention and appropriate ear-protective devices.
Adjuvant Capecitabine for Biliary Cancer and the Importance of Looking Beyond P-Values
Authors: Fojo Antonio Tito , Neugut Alfred I
Published: September 2023

This article continues the discussion on the results of the BILCAP trial and advocates for careful examination and consideration of data in its entirety to inform a clinician’s decision.
Population-level annotation of lncRNAs in Arabidopsis reveals extensive expression variation associated with transposable element–like silencing
Authors: Kornienko Aleksandra E , Nizhynska Viktoria , Molla Morales Almudena , Pisupati Rahul , Nordborg Magnus
Published: September 2023

Long noncoding RNAs (lncRNAs) are understudied and underannotated in plants. In mammals, lncRNA loci are nearly as ubiquitous as protein-coding genes, and their expression is highly variable between individuals of the same species. Using Arabidopsis thaliana as a model, we aimed to elucidate the true scope of lncRNA transcription across plants from different regions and study its natural variation. We used transcriptome deep sequencing data sets spanning hundreds of natural accessions and several developmental stages to create a population-wide annotation of lncRNAs, revealing thousands of previously unannotated lncRNA loci. While lncRNA transcription is ubiquitous in the genome, most loci appear to be actively silenced and their expression is extremely variable between natural accessions. This high expression variability is largely caused by the high variability of repressive chromatin levels at lncRNA loci. High variability was particularly common for intergenic lncRNAs (lincRNAs), where pieces of transposable elements (TEs) present in 50% of these lincRNA loci are associated with increased silencing and variation, and such lncRNAs tend to be targeted by the TE silencing machinery. We created a population-wide lncRNA annotation in Arabidopsis and improve our understanding of plant lncRNA genome biology, raising fundamental questions about what causes transcription and silencing across the genome.
Evaluation of apple (Malus domestica) cider vinegar and garlic (Allium sativum) extract as phytogenic substitutes for growth-promoting dietary antibiotics in sexed broiler chickens
Authors: Chabalala Oscar , Bhebhe Evison , Fushai Felix
Published: September 2023

Tightening global regulations on the use of subclinical dietary antibiotics to enhance broiler growth are in response to increasing concern about the risk of resistance and their residues in animal products. The study evaluated the potential of apple cider vinegar (ACV) and garlic extract (GAE) as safer, phytogenic alternatives. A batch of 390 mixed-sex Ross 308-d-old broiler chicks was received into an open, deep litter house, and feather sexed in the second week into 30 experimental units of 13 birds per 2.03 m2 pen. From days 1 to 22, all chicks were on a 200 g/kg crude protein, coccidiostat-treated commercial starter diet. During the grower (16 to 28 days) and finisher (29 to 42 days) phases, chick pens were assigned treatments in a 2 (sex) × 5 (additives) factorial experiment replicated three times. The GAE was a pure extract, while ACV was produced by fermenting 1,000 g fresh apple and 80 g supplementary brown cane sugar in 1.3 liters of water for 4 wk. The five treatments comprised antibiotic (15% granular zinc bacitracin and 12% valinomycin sodium, each at 500 g/tonne) grower (190 g/kg crude protein, 13.0 MJ ME/kg) and finisher (165 g/kg crude protein, 13.2 MJ ME/kg) commercial diets with untreated drinking water as positive controls (PC), antibiotic-free duplicates of the PC diets with untreated drinking water as the negative controls (NC), with 3 mL/L filtered ACV in drinking water (T1), 2 mL/L filtered GAE-treated drinking water (T2), or mixed (3 mL/L ACV + 2mL/L GAE) additive drinking water (T3). Males had higher (P < 0.05) feed intake than females in both growth phases. Birds on the PC gained more (P < 0.05) weight than others. Birds on the PC consumed more feed (P < 0.05) during the finisher phase than T1, T2, and the NC. Birds on the PC had a lower (P < 0.05) grower-phase feed convesion (feed:gain) ratio (FCR) than others, and lower (P < 0.05) FCR during the finisher phase than birds on T1 and T3. Birds on the PC had higher (P < 0.05) percent spleen weight than birds on T1, with smaller proventriculi (P < 0.05) than on NC, T1, T2, and T3, and smaller gizzard weight than birds on the T2 and T3. Birds on the NC exhibited less dressing percentage (P < 0.05) than all other treatments. Meat pH was higher (P < 0.05) in males. In conclusion, in contrast to dietary antibiotics, except for improved dressing percentage, the ACV and GAE did not express phytogenic benefit at the experimental dosage.
Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development
Authors: Vikramdeo Kunwar Somesh , Anand Shashi , Sudan Sarabjeet Kour , Pramanik Paramahansa , Singh Seema , Godwin Andrew K. , Singh Ajay Pratap , Dasgupta Santanu
Published: September 2023

Early detection and recurrence prediction are challenging in triple‐negative breast cancer (TNBC) patients. We aimed to develop mitochondrial DNA (mtDNA)‐based liquid biomarkers to improve TNBC management. Mitochondrial genome (MG) enrichment and next‐generation sequencing mapped the entire MG in 73 samples (64 tissues and 9 extracellular vesicles [EV] samples) from 32 metastatic TNBCs. We measured mtDNA and cardiolipin (CL) contents, NDUFB8, and SDHB protein expression in tumors and in corresponding circulating EVs. We identified 168 nonsynonymous mtDNA mutations, with 73% (123/186) coding and 27% (45/168) noncoding in nature. Twenty percent of mutations were nucleotide transversions. Respiratory complex I (RCI) was the key target, which harbored 44% (74/168) of the overall mtDNA mutations. A panel of 11 hotspot mtDNA mutations was identified among 19%–38% TNBCs, which were detectable in the serum‐derived EVs with 82% specificity. Overall, 38% of the metastatic tumor‐signature mtDNA mutations were traceable in the EVs. An appreciable number of mtDNA mutations were homoplasmic (18%, 31/168), novel (14%, 23/168), and potentially pathogenic (9%, 15/168). The overall and RCI‐specific mtDNA mutational load was higher in women with African compared to European ancestry accompanied by an exclusive abundance of respiratory complex (RC) protein NDUFB8 (RCI) and SDHB (RCII) therein. Increased mtDNA (p < 0.0001) content was recorded in both tumors and EVs along with an abundance of CL (p = 0.0001) content in the EVs. Aggressive tumor‐signature mtDNA mutation detection and measurement of mtDNA and CL contents in the EVs bear the potential to formulate noninvasive early detection and recurrence prediction strategies.
A Novel Method for Assessing the 3-dimensional Morphology of Cartilaginous Acetabulum Via Childhood Magnetic Resonance Imaging
Authors: Nakamura Tomoyuki , Wada Akifusa , Natori Takahiro , Kawaguchi Kengo , Takamura Kazuyuki , Yanagida Haruhisa , Yamaguchi Toru
Published: September 2023

Background:

Periarticular cartilage is abundant in children, making evaluations of 3-dimensional (D) cartilaginous acetabular morphology using x-ray or computed tomography (CT) difficult. The study aimed to visualize the 3D cartilaginous acetabular morphology in normal children and patients with pediatric developmental dysplasia of the hip (DDH).

Methods:

Magnetic resonance imaging (MRI) of 17 female children without acetabular dysplasia at 7.5 years and CT of 33 normal female adolescents with mature bones at 14.6 years were used as controls. Subjects were 26 female patients with unilateral DDH who underwent angulated Salter innominate osteotomy (A-SIO) at 5.5 years. Preoperative and postoperative MRIs were performed at 5.2 and 7.0 years, respectively. The MRI sequence was 3D-MEDIC. The medial intersection (point A) of the line connecting the centers of the bilateral femoral head and the femoral head were defined as point zero. The 3D coordinates (X, Y, Z) of the cartilaginous acetabular edge (point C) from anterior to posterior were calculated. Subsequently, a 3D scatter plot was created using 3D graph software. The subjects were divided into 6 groups, including control MRI, control CT, unaffected DDH before and after A-SIO, and affected DDH before and after A-SIO. The femoral head coverage ratio (FHCR: AC/AB) was used to quantify coverage and was compared in each group.

Results:

In the control MRI group, the acetabular coverage was small anteriorly, largest anterolaterally, and gradually decreased posteriorly, similar to the bony acetabulum in adolescents. In the affected DDH before A-SIO group, the coverage was significantly lower than that of the control MRI and unaffected DDH groups. After A-SIO, the morphology improved beyond the unaffected DDH and the control MRI group.

Conclusions:

The global defect of the cartilaginous acetabulum in the affected DDH group was significantly improved to normal morphology after A-SIO. Evaluating the cartilaginous acetabulum using MRI was useful for assessing hip morphology in childhood.

Level of Evidence:

Level III—retrospective comparative study.
A Biomechanical Evaluation of Casting Technique and Cast Core Size Effect
Authors: Sprenkle Trenton P. , Chong Alexander C.M. , Shearer Jordan D. , Fisher Brandon T. , Sauer Brian R.
Published: September 2023

Backgrounds:

The goals of this study were to (1) compare the effect of casting technique on biomechanical function with different casting materials and different cast core diameters, and (2) compare the strength of a cast based on the number of layers in relation to the core diameter.

Methods:

Two standardized cylindrical cast model sizes were used to simulate forearm and short leg casts (core diameter: 60 mm, 100 mm) with 2 different casting techniques (non-smoothing vs. smoothing with lamination), utilizing 2 casting materials [fiberglass and Plaster of Paris (POP)]. Each cast was created using 3 different layers (Fiberglass: 2 to 4 layers; POP: 3 to 5 layers). Ultimate load-to-failure and flexural rigidity were analyzed through cyclic 4-point bend testing.

Results:

The biomechanical comparison between forearm and short leg casts were significantly different regardless of the same number of layers for both casting materials and between 2 casting techniques. Increased cast thickness significantly increased the ultimate load-to-failure and bending strength. An increased core diameter size significantly decreased the cast’s ultimate load-to-failure (fiberglass: 50% to 108%; POP: 10% to 93%) and bending strength (fiberglass: 17% to 35%; POP: 37% to 49%). Casting technique with smoothing with lamination technique had a negative biomechanical effect on POP and a minimal effect on fiberglass.

Conclusion:

The number of layers to apply for a cast should be based on the size of the extremity. Smoothing and lamination technique did not significantly improve the cast mechanical behavior.

Clinical Relevance:

The findings of this study provide valuable evidence, analysis, and supplementary knowledge that helps guide physicians in proper casting technique.
Management and nursing strategies for different patterns of adverse events in patients with urological cancer treated with immune checkpoint inhibitors
Authors: Huang Xiaojuan , Li Xiaolei , Ma Lulin , Liu Chunxia
Published: September 2023

Background

This study aimed to explore the patterns of treatment-related adverse events (AEs) associated with immune checkpoint inhibitor (ICI) monotherapy and in combination with chemotherapy or tyrosine kinase inhibitor (TKI) therapy and to summarize the corresponding management and nursing strategies.

Materials and methods

A total of 69 patients with malignant urological tumors who received ICI treatment between June 2019 and October 2022 were retrospectively analyzed, and AEs that occurred during treatment were observed and reported. Based on the different types of treatment, the patients were divided into ICI monotherapy, ICI plus chemotherapy, and ICI plus TKI therapy groups. Subgroup analysis was performed. The incidence, distribution, and severity of AEs in the different subgroups were evaluated.

Results

A total of 138 AEs occurred in 69 patients, among which grade 1 plus 2, and grade 3 plus 4 AEs accounted for 78.99% and 21.01%, respectively. The incidence of AEs per patient in the ICI-TKI therapy group was the highest (3.75 times/person), followed by the ICI-chemotherapy (2.33 times/person) and ICI monotherapy (0.82 times/person) groups. Specific AEs, such as fatigue, nausea, and myelosuppression, were much more common in the ICI-gemcitabine and cisplatin group, whereas renal injury, skin lesions, and diarrhea were most common ones in the ICI-TKI group.

Conclusions

Immune checkpoint inhibitors are new treatment options for advanced urological tumors and renal cell carcinoma. Distinctive AE patterns were observed among the different treatment groups. Therefore, strict and meticulous clinical management and nursing measures are required to ensure the safety of patients receiving ICI treatment.
Pulse pressure and its association with body composition among Chinese men and women without diagnosed hypertension: the China Kadoorie Biobank
Authors: Ma Guoqing , Li Junqi , Xie Jiawen , Li Yunfeng , Xu Kun , He Yafang , Yang Jiaomei , Du Huaidong , Liu Xin
Published: September 2023

Background:

Wide brachial pulse pressure (PP) has been associated with cardiovascular events, while its population distribution and association with body composition were poorly characterized in large populations.

Methods:

We evaluated the age and sex distributions of PP and its associations with body composition using baseline data from the China Kadoorie Biobank. A total of 434 200 participants without diagnosed hypertension were included in the analysis. Wide PP was defined as PP above 65 mmHg. Body composition variables, including BMI, waist circumference, waist-to-hip ratio (WHR), fat mass index (FMI), fat-free mass index (FFMI), and body fat percentage (BF%), were obtained from bioelectrical impedance analysis.

Results:

Overall, 14.3% of the participants had wide PP. Older age was consistently associated with wider PP in women but only after the andropause stage in men. The independent associations of BMI with wide PP were stronger than other body composition measures. The adjusted differences (men/women, mmHg) in PP per standard deviation (SD) increase in BMI (1.55/1.47) were higher than other body composition (BF%: 0.32/0.64, waist circumference: 0.33/0.39; WHR: 0.49/0.42). In addition, sex differences were observed. In men, the per SD difference in PP was higher for FFMI than for FMI (0.91 vs. 0.67, P < 0.05), whereas in women, it was higher for FMI than for FFMI (1.01 vs. 0.72, P < 0.05).

Conclusion:

Our nationwide population-based study presented the sex-specific distribution of PP over age and identified differential associations of PP with fat and fat-free mass in men and women.
Trend of blood pressure changes among children from 2012 to 2022: findings from student health surveillance in Eastern China
Authors: Zhang Xiyan , Zhou Yonglin , Yang Jie , Wang Yan , Xiang Yao , Ma Hongxia , Lu Wei
Published: September 2023

Objectives:

The primary objective of this study is to examine the secular trends in blood pressure levels from 2012 to 2022 in eastern China. Additionally, to compare two standards [International Blood Pressure Reference for Children and Adolescents (ICBP) and the National Blood Pressure Reference for Chinese Han Children and Adolescents (CCBP)], we calculate the 95th percentile of blood pressure levels for students in developed regions (ECCBP). Secondly, the study aims to investigate potential contributors to elevated blood pressure, including sex, age, behaviors, and mental health. Lastly, the study seeks to estimate the total population aged 7–18 years with elevated blood pressure in Eastern China based on three references.

Methods:

The data used in this study were obtained from the Student Health Surveillance program in Jiangsu Province, which has been collecting data since 2012. Trained project members, skilled nurses, and doctors measured anthropometric variables. Additionally, online student questionnaires were administered in 2017, 2019, and 2021 to collect personal information behavior patterns, and mental health.

Results:

The study examined blood pressure changes in 123 013 children and adolescents in Eastern China from 2012 to 2022. Significant increases were observed in systolic blood pressure (SBP) and pulse pressure difference. Prevalence of elevated blood pressure followed a similar trend with ECCBP and CCBP, ranging from 17.2%/16.3% (2012–2015) to 11.6%/14.6% (2020–2022). Notably, BP with ICBP showed a significant increase in both prevalence and population, from 12.6% [6 713 679, 95% confidence interval (CI): 6 708 931 to 6 718 427] to 14.5% (7 004 208, 95% CI: 6 999 411 to 7 009 004). The study further emphasizes the significant impact of various risk factors on elevated blood pressure among children and adolescents, particularly the detrimental effect of depression on blood pressure, with the odds ratios (OR) in 2021 being 1.310 (95% CI, 1.290–1.330) for ECCBP, 1.239 (95% CI, 1.223–1.255) for CCBP, and 1.189 (95% CI, 1.176–1.202) for ICBP.

Conclusion:

The study revealed significant changes in the population and prevalence of elevated blood pressure in Eastern China from 2012 to 2022. The findings indicate a decline in the prevalence of elevated blood pressure (referred to as CCBP or ECCBP), while highlighting an increasing trend in elevated blood pressure (referred to as ICBP). Untreated high blood pressure can lead to serious cardiovascular diseases in adulthood, underscoring the importance of early prevention and management, particularly through nonpharmacological methods and regular monitoring for students in Eastern China. Raising awareness among educators, parents, and healthcare providers about the association between mental health and elevated blood pressure is essential.