tbuckley/cabot-search huggingface dataset:
PL02.2.A TRAMETINIB IN NEUROFIBROMATOSIS TYPE 1 RELATED SYMPTOMATIC PLEXIFORM NEUROFIBROMAS: ONE-YEAR FOLLOW-UP OF THE TRAIN STUDY
Authors: D C Noordhoek, S A van Dijk, P J French, E A C Wiemer, D F Hanff, O C Manintveld, W Taal
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Plexiform neurofibromas (PN) are present in 50% of the patients with neurofibromatosis type 1 (NF1). They can cause pain, neurological deficit and cosmetic problems. Recent phase 2 clinical trials have shown promising results of treatment of inoperable PN with MEK inhibitors, especially in pediatric patients. Our aim was to evaluate the effect of the MEK inhibitor trametinib in adult NF1 patients. MATERIAL AND METHODS The TRAIN study is an open-label, single arm, phase 2 trial with trametinib 2 mg daily in 30 patients with NF1 and at least one symptomatic inoperable PN. The primary outcome measure is tumor volume decrease of the pre-defined target PN lesion(s) as measured by 3D volumetric analysis on 6-monthly MR imaging. A decrease of &amp;gt;20% in total tumor volume is considered treatment response. Secondary outcome measures are pain, safety and tolerability. RESULTS Thirty patients have been enrolled since July 2020. The last patient completed one year follow-up end of May 2024. The current median follow-up is 29 months (range 12-46 months). Average age at study registration was 44 years (range 19-67 years). Eleven patients (37%) discontinued study treatment within the first year: 8 patients due to toxicity, 2 because of symptom progression and one patient because of a new contraindication for trametinib. Twenty-seven patients completed 12 months follow-up with MR imaging. The response rate was 48% within the first year of study treatment. Volume decrease ranged from: 21% to 57%. The remaining 52% of the patients had stable disease. The average Numeric Pain Rating Scale (NPRS) decreased from 5.2 at baseline to 3.5 at one year follow-up (p=0.027). The most common adverse events were acneiform rash, diarrhea, fatigue, asymptomatic anemia and hypoalbuminemia. Four severe adverse events (grade 3) occurred: pneumonitis (n=1), rhabdomyolysis (n=1) and erysipelas (n=2). CONCLUSION Approximately half of the adult NF1 patients with inoperable PNF showed a treatment response with trametinib within the first year. The average NPRS decreased significantly. However, adverse events are common and therefore more research is needed to select patients that will benefit the most from MEK inhibition.
JS07.6.A MULTI-OMICS AND DRUG RESPONSE ASSESSMENTS IN LONGITUDINAL PATIENT AVATARS UNVEIL PATIENT-SPECIFIC RECURRENCE TRAJECTORIES AND DRUG SUSCEPTIBILITIES IN GLIOBLASTOMA
Authors: A Lipsa, B Nosirov, L Ermini, A Hau, E Klein, Y A Yabo, M Mittelbronn, F Hertel, P V Nazarov, S P Niclou, A Golebiewska
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastomas (GBMs) have the worst prognosis of all adult brain tumours. Despite the aggressive standard-of-care, including surgery, radio- and chemotherapy, tumours inevitably recur and median survival remains at 18 months. GBMs exhibit complex changes at recurrence, although no common evolutionary trajectory has been identified yet. Such molecular evolution may lead to functional changes in drug response patterns. Investigations of longitudinal heterogeneity of paired primary-recurrent tumours using high resolution multi-omics profiling combined with functional investigations in matched patient avatars can provide clinically-relevant insights into tumour evolution at the individual patient level. MATERIAL AND METHODS We applied a cohort of longitudinal patient tumors and preclinical models derived thereof, propagated as primary organoids and orthotopic xenografts. Our cohort includes a unique collection of paired primary-recurrent patient avatars derived from 8 patients during their standard-of-care disease trajectory. We performed a comprehensive multi-omics profiling, including transcriptomics (bulk and single cell RNA-seq), epigenomics (DNA methylation arrays), genomics (targeted DNA-seq) and proteomics (LC-MS) to identify molecular evolution of tumors at recurrence. We further carried out an ex-vivo functional drug screen with a pharmacologically diverse 1482 compound library targeting cancer pathways and epigenetic modifiers. RESULTS High-resolution multi-omics analysis of longitudinal patient tumours and patient avatars identified patient-specific evolution of the primary tumours at recurrence following surgical resection and treatment pressure. While certain GBMs recurred without major molecular adaptation, others showed significant (epi)genetic and transcriptomic evolution towards new genetic clones and/or transcriptomic states. Majority of drug responses were similar in primary and recurrent tumours and were patient-specific. Interestingly, we observed selective susceptibilities to several epigenetic modifiers, especially Histone Deacetylase (HDAC) and Aurora Kinase (AURK) inhibitors in certain primary tumours, which were lost at recurrence. CONCLUSION Our study demonstrates the importance of combined omics and functional profiling to reveal clinical implications of longitudinal evolutionary trajectories in GBMs. Our findings imply that the impact of potentially effective drugs may differ between newly diagnosed and recurrent GBMs that might have implications in precision therapy strategies.
P27.15.B OVERTREAMENT IN PATIENTS WITH AN UNRESECTABLE HIGH-GRADE GLIOMA IN DAILY CLINICAL PRACTICE
Authors: M Claassen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In unresectable high-grade glioma (HGG) patients, guidelines recommend a biopsy unless the prognosis is likely to be very unfavourable and best supportive care (BSC) should be advised. Estimating the prognosis is difficult in daily practice and poses the risk of overtreatment. OBJECTIVE In this study we assess the overtreatment of unresectable HGG patients. MATERIAL AND METHODS A retrospective analysis of patients with an unresectable HGG at the Amsterdam UMC, the Netherlands, between 2016 and 2022 was performed. Overtreatment was defined as not starting adjuvant treatment or survival &amp;lt; 3 months. Using patient (age, sex, Karnofsky Performance scale (KPS), American Society of Anesthesiologists (ASA) Physical Status Classification System) and tumor (multifocality and laterality) characteristics, a predictive model was created using logistic regression with backward elimination (P-removal = 0.05). RESULTS A total of 166 patients had an unresectable HGG of which 132 (80%) underwent a biopsy, and 33 (20%) received BSC. Overtreatment occurred in 57 (43%) biopsied patients, with 47 (82%) of these patients not starting adjuvant treatment and 10 (18%) patients surpassing within 3 months after the biopsy. Age ≥ 64.2 years (OR 2.739, p = 0.006) and a pre-biopsy KPS &amp;lt; 70 (OR 3.781, p = 0.006) were significant predictors of overtreatment. Biopsied patients had a longer survival than patients receiving BSC (respectively OS 8,6 and 3,8 months, p = &amp;lt; 0.001) However, survival of overtreated biopsy patients (OS 2,6 months) was shorter than in patients receiving BSC (p = 0.003). CONCLUSION Current decision-making in daily practice results in overtreatment in 43% of patients who are advised to undergo a biopsy. These patients have a shorter survival than those who receive BSC. Higher age and lower pre-biopsy KPS could help to identify these patients. Future research should aim to develop more robust markers to aid decision-making and prevent overtreatment of these vulnerable patients.
Metabolic Syndrome, Adipokines, and Response to Advanced Therapies in Rheumatoid Arthritis
Authors: Joshua F. Baker, George Reed, Ted R. Mikuls, Geoffrey M. Thiele, Dimitrios A. Pappas, Christina Charles‐Schoeman, Monica Guma, Leslie R. Harrold, Jeffrey R. Curtis, Joel M. Kremer
Journal: Arthritis & Rheumatology (2024)

We determined if metabolic syndrome, its components, and adipokines (adiponectin, leptin, Fibroblast Growth Factor-21) were associated with response to advanced therapies among patients with rheumatoid arthritis (RA).
Anti‐modified protein antibodies can be detected in saliva, but not in intestinal secretions of seropositive rheumatoid arthritis patients – evidence of site‐specific mucosal autoantibody secretion in <scp>RA</scp>
Authors: Veerle F. A. M. Derksen, Klara Martinsson, Anouk G. van Mourik, Carlijn A. Wagenaar, René E. M. Toes, Wendy Walrabenstein, Daniel Sjöberg, Dirkjan van Schaardenburg, Tom W. J. Huizinga, Alf Kastbom, Anna Svärd, Diane van der Woude
Journal: Arthritis & Rheumatology (2024)

Anti-citrullinated protein antibodies (ACPA) have been detected in sputum and saliva, indicating that anti-modified protein antibodies (AMPA) can be produced at mucosal sites in rheumatoid arthritis (RA) patients. However, the body's largest mucosal compartment, the gut, has not yet been examined. We therefore investigated the presence of several AMPA (antibodies against citrullinated (ACPA), carbamylated (anti-CarP) and acetylated (AAPA) proteins) at different mucosal sites, including the intestinal tract.
Scalable identification of lineage-specific gene regulatory networks from metacells with NetID
Authors: Weixu Wang, Yichen Wang, Ruiqi Lyu, Dominic Grün
Journal: Genome biology (2024)

Abstract The identification of gene regulatory networks (GRNs) is crucial for understanding cellular differentiation. Single-cell RNA sequencing data encode gene-level covariations at high resolution, yet data sparsity and high dimensionality hamper accurate and scalable GRN reconstruction. To overcome these challenges, we introduce NetID leveraging homogenous metacells while avoiding spurious gene–gene correlations. Benchmarking demonstrates superior performance of NetID compared to imputation-based methods. By incorporating cell fate probability information, NetID facilitates the prediction of lineage-specific GRNs and recovers known network motifs governing bone marrow hematopoiesis, making it a powerful toolkit for deciphering gene regulatory control of cellular differentiation from large-scale single-cell transcriptome data.
Evaluation of Ki-67 expression and large cell content as prognostic markers in MZL: a multicenter cohort study
Authors: Natalie S. Grover, Kaitlin Annunzio, Marcus Watkins, Pallawi Torka, Reem Karmali, Andrea Anampa-Guzmán, Timothy S. Oh, Heather Reves, Montreh Tavakkoli, Emily Hansinger, Beth Christian, Colin Thomas, Stefan K. Barta, Praveen Ramakrishnan Geethakumari, Nancy L. Bartlett, Geoffrey Shouse, Adam J. Olszewski, Narendranath Epperla
Journal: Blood Cancer Journal (2024)

Marginal zone lymphoma (MZL) can have varied presentations and pathologic features, including high Ki-67 expression ( > 20%) as well as increased numbers of large B cells (LC). However, there are limited data available demonstrating the prognostic significance of these variables in patients with MZL. In this multi-institutional retrospective cohort study of patients with MZL treated at 10 centers, we evaluated the association between the presence of Ki-67 expression and increased LCs on survival and risk of histologic transformation (HT). A total of 785 patients were included (60% with extranodal MZL, 20% with nodal MZL, and 20% with splenic MZL). Among the 440 patients with Ki-67 staining, 22% had high Ki-67 (Ki-67 >20%). The median progression-free survival (PFS) for patients with high Ki-67 was 5.4 years compared to 7.0 years for patients with low Ki-67 (HR = 1.45, 95%CI = 1.03–2.05). Ki-67 > 20% strongly correlated with high LDH level. The risk of HT was higher in patients with increased Ki-67 than those without (5-year risk, 9.8% vs 3.87%, p = 0.01). Twelve percent of patients had LC reported on biopsy with 6% having >10% LC. The presence of LC was associated with high Ki-67 (p < 0.001), but not associated with shorter PFS or overall survival (OS). The cumulative risk for HT was higher in patients with LC compared to those without LC (5-year risk, 9.4% vs 2.9%, p = 0.04). Receipt of anthracycline-based therapy did not impact PFS or OS in either group. Ki-67 staining >20% was a prognostic factor for worse survival and strongly correlated with elevated LDH. Novel therapies should be investigated for their potential ability to overcome the high-risk features in MZL. Our data reinforce the importance of obtaining biopsies at relapse or progression, particularly in patients with baseline high Ki-67 and increased LCs, given their increased risk for HT.
The lifespan and kinetics of human dendritic cell subsets and their precursors in health and inflammation
Authors: Ruth Lubin, Amit A. Patel, Jonas Mackerodt, Yan Zhang, Rotem Gvili, Kevin Mulder, Charles-Antoine Dutertre, Parinaaz Jalali, James R.W. Glanville, Idit Hazan, Nikhila Sridharan, Gurion Rivkin, Ayse Akarca, Teresa Marafioti, Derek W. Gilroy, Leonid Kandel, Alexander Mildner, Asaf Wilensky, Becca Asquith, Florent Ginhoux, Derek Macallan, Simon Yona
Journal: The Journal of Experimental Medicine (2024)

Dendritic cells (DC) are specialized mononuclear phagocytes that link innate and adaptive immunity. They comprise two principal subsets: plasmacytoid DC (pDC) and conventional DC (cDC). Understanding the generation, differentiation, and migration of cDC is critical for immune homeostasis. Through human in vivo deuterium-glucose labeling, we observed the rapid appearance of AXL+ Siglec6+ DC (ASDC) in the bloodstream. ASDC circulate for ∼2.16 days, while cDC1 and DC2 circulate for ∼1.32 and ∼2.20 days, respectively, upon release from the bone marrow. Interestingly, DC3, a cDC subset that shares several similarities with monocytes, exhibits a labeling profile closely resembling that of DC2. In a human in vivo model of cutaneous inflammation, ASDC were recruited to the inflammatory site, displaying a distinctive effector signature. Taken together, these results quantify the ephemeral circulating lifespan of human cDC and propose functions of cDC and their precursors that are rapidly recruited to sites of inflammation.
Neoantigen sequestrated autophagosomes as therapeutic cancer vaccines
Authors: Jinxie Zhang, Jiahui Cao, Liuchang Wang, Sitong Li, Fanqiang Meng, Xin Liang, Hanyu Jiang, Ran Luo, Dunwan Zhu, Fan Zhang, Linhua Zhang, Xudong Zhang, Lin Mei
Journal: Journal of Controlled Release (2024)
Quantification of nutrient fluxes during acute exercise in mice
Authors: Jessie Axsom, Tara TeSlaa, Won Dong Lee, Qingwei Chu, Alexis Cowan, Marc R Bornstein, Michael D Neinast, Caroline R Bartman, Megan C Blair, Kristina Li, Chelsea Thorsheim, Joshua D Rabinowitz, Zoltan Arany
Journal: Cell Metabolism (2024)
Injectable hydrogel microsphere-bomb for MRSA-infected chronic osteomyelitis
Authors: Jiayi Guo, Xian Shu, Shan Yu, Cuiping Guo, Guangxin Shen, Longsheng Chen, Jiayi Zhou, Jiangwei Xiao, Huilong Guo, Yi Chen, Zhiwen Zeng, Ping Wang
Journal: Journal of Controlled Release (2024)
Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing
Authors: Qizhang Wang, Guanglin Niu, Zhuang Liu, Maria A Toma, Jennifer Geara, Xiaowei Bian, Letian Zhang, Minna Piipponen, Dongqing Li, Aoxue Wang, Pehr Sommar, Ning Xu Landén
Journal: British Journal of Dermatology (2024)

Skin wound healing involves a complex gene expression program that remains largely undiscovered in humans. Circular RNAs (circRNAs) and microRNAs (miRNAs) are key players in this process.
P18.09.A CLINICAL AND MOLECULAR CHARACTERIZATION OF ADULT DIFFUSE MIDLINE GLIOMAS, H3 K27M-MUTANT
Authors: N Grassl, A Suwala, T Kessler, N Etminan, A Unterberg, M Breckwoldt, M Bendszus, C Groden, J Debus, M Ehmann, W Wick, F Sahm, M Platten, K Sahm
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG), H3 K27M-altered is a central nervous system tumor that occurs predominantly in children and young adults. They are characterized by distinct epigenetic features, whose therapeutic consequences remain ill defined. MATERIAL AND METHODS In this retrospective multicenter cohort study 52 adult patients with H3 K27M-mutant DMG and matched H3-wildtype glioma were characterized with respect to location, radiological features, methylation profile and clinical course. RESULTS DMGs were predominantly located in the thalamus, brainstem or spinal cord, but also occurred in the cerebellum and cerebral hemispheres. 35% of H3 K27M-mutant gliomas did not show contrast enhancement on MRI and only 43% had central necrosis. A third of adult H3 K27M-mutant gliomas, especially in spinal location, had distant progression resulting in shorter progression free survival (PFS). Addition of alkylating chemotherapy with temozolomide to radiotherapy did not result in prolonged PFS or overall survival (OS). A distinct methylation signature on the q arm of chromosome 15 differentiated patients with favorable OS form patients with short OS. CONCLUSION Adult DMGs occur throughout the CNS and are characterized by distinct epigenetic, radiological and clinical features.
P18.08.A CCNU/TMZ IN ELDERLY PATIENTS WITH MGMT-METHYLATED GLIOBLASTOMA: A MULTICENTRIC RETROSPECTIVE COHORT
Authors: J Weller, T Zeyen, N Schäfer, P Hau, M Glas, J Werner, N Galldiks, C Seidel, T Kowalski, C Schaub, M Sabel, R Drexler, M Schneider, U Herrlinger
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Lomustine-temozolomide combination therapy (CCNU/TMZ), in addition to standard radiotherapy, improves survival in MGMT-methylated newly diagnosed glioblastoma. As the CeTeG/NOA-09 trial included patients aged up to 70 years, the feasibility of CCNU/TMZ in older patients remains unknown. MATERIAL AND METHODS Retrospective multicentric analysis of patients aged &amp;gt;70 years with newly diagnosed MGMT-methylated glioblastoma, IDH-wildtype, receiving at least one dose of CCNU/TMZ according to the CeTeG/NOA-09 protocol. RESULTS Seventeen patients with a median age of 72 years (range, 71-78) were included. 71% (n=12) were male, the median KPS was 80% (IQR, 80-90), and the extent of resection was biopsy in 18% (n=3), partial resection in 24% (n=4), and gross total resection in 59% of cases (n=10). The median number of chemotherapy courses was five (IQR, 2-6). After a median follow-up of 19.1 months (IQR, 11.2-29.8), the median progression-free survival was 13.5 months (95%CI, 7.9-not reached) and the median overall survival was 20.7 months (95%CI, 17.6-not reached). Updated data will be presented at the meeting. CONCLUSION Combined radiochemotherapy with CCNU/TMZ is feasible in glioblastoma patients aged &amp;gt;70 years, and encouraging survival times were observed. Future prospective analyses involving CCNU/TMZ for MGMT-methylated glioblastoma might consider including elderly patients.
P18.10.B CLINICAL AND NEUROPATHOLOGICAL MARKERS FOR DISTINGUISHING BETWEEN IDH-MUTANT ASTROCYTOMAS OF WHO GRADE 2 AND 3
Authors: J Blobner, P N Harter, J Weller, N Teske, V Ruf, S Schönecker, R Forbrig, N L Albert, L von Baumgarten, J Tonn, N Thon, P Karschnia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The neuropathological criteria of anaplasia to distinguish between IDH-mutant astrocytomas of WHO grade 2 and 3 are ill-defined by the WHO 2021 classification. Following the positive phase III trial results and the expected approval of Vorasidenib for astrocytomas grade 2, a salient point of the discussion remains which markers might be of prognostic relevance to distinguish between grade 2 and 3 tumors. MATERIAL AND METHODS We retrospectively searched our institutional database for patients meeting the diagnostic criteria for IDH-mutant astrocytomas according to the WHO 2021 classification. Clinical, neuropathological, and molecular data were collected; and outcome was compared using log-rank analysis. Prognostic markers identified on univariate analysis were forwarded into a multivariate model. RESULTS We identified 99 patients with IDH-mutant astrocytomas in which detailed neuropathological and clinical information were available for review, including 63 tumors (63.6%) which were assigned to WHO grade 2 and 36 tumors (36.4%) assigned to WHO grade 3. At a median follow-up of 7.5 years, median progression-free survival was 5.7 years for WHO grade 2 tumors and 4.4 years for WHO grade 3 tumors. Median overall survival for WHO grade 2 and WHO grade 3 tumors was not reached. On univariate analysis, higher WHO grade, an increased number of mitoses on histopathology, elevated Ki67 indices on immunohistochemistry, and the presence of contrast enhancement on pre-operative imaging were associated with less favourable outcome. However, only the presence of contrast enhancement retained its prognostic significance when forwarded into a multivariate model (p = 0.034 for overall survival, p = 0.012 for progression-free survival). The findings on the association between contrast enhancement and outcome were confirmed in treatment-based subgroups, including individuals treated with a watch-and-scan approach (n = 30), radiotherapy (n = 25), or chemotherapy (n = 33). Notably, neuropathological measurements of proliferation were generally higher in patients who underwent open resection compared to biopsy. CONCLUSION While our findings await confirmation in larger prospective cohorts, neuropathological criteria for anaplasia might need to be accompanied by clinical information including contrast enhancement to prognostically distinguish grade 2 from grade 3 tumors particularly in patients undergoing biopsy given the risk for undersampling. Centralized slide review is currently ongoing to exclude neuropathological inter-rater variability due to the retrospective nature of our study.