Citations

Neurostimulation is an increasingly common treatment option for medically intractable epilepsy. SANTE (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) and Responsive Neurostimulation (RNS) System are landmark neurostimulation trials that utilized either duty cycle or a responsive stimulation paradigm. A seizure-free outcome is rarely observed with responsive and duty cycle neurostimulation devices. Chronic subthreshold cortical stimulation (CSCS) is a promising treatment for adult drug-resistant epilepsy involving eloquent cortex and has demonstrated safety and efficacy. Herein, the authors describe the surgical technique as well as details of stimulation programming involved in CSCS placement to facilitate the adoption of this promising treatment. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2422

Abstract The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non–transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); and patients in cohort 3A/3B had stable ruxolitinib treatment before and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary end point was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary end point. In cohorts 1 and 3A (NTD), 27% and 50% of patients, respectively, had mean hemoglobin increase of ≥1.5 g/dL from baseline. Among TD patients, ∼50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. This trial was registered at www.ClinicalTrials.gov as #NCT03194542.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Abstract Chordoid meningiomas, rare meningioma variants, are characterized by their histopathological features and clinical behavior resembling that of other chondroid/myxoid neoplasms. We present a case of pathology-proven chordoid meningioma imaged with both 68Ga-DOTATATE and 18F-FDG PET images during a complicated postoperative course with multiple episodes of local recurrence and, ultimately, extracranial metastasis. This case underscores the aggressive behavior of chordoid meningiomas while highlighting how molecular imaging plays an important role in clinical monitoring and guidance of management.

Abstract We used deep learning (DL) to predict multiple genetic biomarkers of colorectal cancer (CRC) from routine histopathology images, aiming to identify morphological changes associated with the mutational profile of tumors. A new Transformer-based prediction model was developed which can simultaneously predict multiple biomarkers from a single histopathology image. We compared the performance of the multi-target approach to conventional single-target models. We analyzed five patient cohorts from the Genetics and Epidemiology of CRC Consortium (GECCO) with colorectal cancer (N=1,385 patients). Our model was trained on an internal data set (N=739) to predict the presence of >200 genetic alterations, focusing on genes with non-silent mutations and mutational signatures, which were assessed using targeted sequencing. We used a 7-fold cross validation and validated the model on an independent, external data set (N=646). Morphological features of microsatellite instability (MSI) are detectable by DL models in histopathology images, making MSI a potential confounding factor. Thus, we also assessed whether our model can predict genetic alterations regardless of MSI status, or whether the model identifies the MSI phenotype. For the majority of biomarkers, the multi-target transformer reached a higher prediction performance as measured by the mean Area Under the Receiver Operating Characteristic (AUROC) Curve and lower standard deviation than single-target DL models. For the external validation set, the mean AUROC of the multi-target versus the single-target model was 0.78 (+/- 0.01) versus 0.72 (+/- 0.06) for BRAF mutations, 0.88 (+/- 0.01) versus 0.86 (+/- 0.03) for hypermutation status, 0.94 (+/- 0.01) versus 0.91 (+/- 0.02) for MSI, 0.86 (+/- 0.01) versus 0.80 (+/- 0.05) for RNF43 mutations and 0.72 (+/- 0.02) versus 0.69 (+/- 0.05) for TP53 mutations, respectively. However, our analysis of the individual prediction scores suggests that the model does not identify the phenotype of the alterations themselves. Instead, the model seems to determine the status of specific genetic alterations based on their correlation with MSI. Consequently, biomarkers which are associated with microsatellite stability have prediction scores negatively correlated with predicted MSI scores. Conversely, biomarkers which are associated with MSI have prediction scores positively correlated with predicted MSI scores. Our results demonstrate potential benefits of multi-target DL models in improving the predictive power and efficacy of histology-based biomarker extraction compared to single-target DL models. However, our results crucially highlight the importance of considering potential confounders, such as MSI status in CRC, and emphasize the need for extensive analysis beyond AUROC in studies focusing on DL-based biomarker detection. Citation Format: Marco Gustav, Marko van Treeck, Zunamys I. Carrero, Chiara M. Loeffler, Nic G. Reitsam, Bruno Märkl, Asier Rabasco Meneghetti, Lisa A. Boardman, Amy J. French, Ellen L. Goode, Andrea Gsur, Stefanie Brezina, Marc J. Gunter, Neil Murphy, Paul Limburg, Stephen Thibodeau, Sebastian Foersch, Robert Steinfelder, Tabitha Harrison, Ulrike Peters, Amanda Phipps, Jakob N. Kather. Assessing microsatellite instability dominance in colorectal cancer phenotype: A multi-study initiative using multi-target transformers for genomic biomarker prediction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4924.

Abstract Despite its considerable and growing burden, there are currently no Food and Drug Administration‐approved treatments for metabolic dysfunction‐associated steatotic liver disease or its progressive form, metabolic dysfunction‐associated steatohepatitis (MASH). Several glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and other agents are in various phases of clinical development for use in MASH; an ideal therapy should reduce liver fat content, improve chronic liver disease, help mitigate metabolic comorbidities and decrease all‐cause mortality. Because of interconnected disease mechanisms, metabolic dysfunction‐associated steatotic liver disease/MASH often coexists with type 2 diabetes (T2D), obesity and cardiovascular disease. Various GLP‐1RAs are Food and Drug Administration‐approved for use in T2D, and two, liraglutide and semaglutide, are approved for overweight and obesity. GLP‐1RAs decrease glucose levels and body weight and improve cardiovascular outcomes in people with T2D who are at high risk of cardiovascular disease. In addition, GLP‐1RAs have been reported to reduce liver fat content and liver enzymes, reduce oxidative stress and improve hepatic de novo lipogenesis and the histopathology of MASH. Weight loss may contribute to these effects; however, the exact mechanisms are unknown. Adverse events that are commonly associated with GLP‐1RAs include vomiting, nausea and diarrhoea. There is a lack of evidence from meta‐analyses regarding the increased risk of acute pancreatitis and various forms of cancer with GLP‐1RAs. Large‐scale, phase 3 trials, which will provide definitive data on GLP‐1RAs and other potential therapies in MASH, are ongoing. Given the spectrum of modalities under investigation, it is hoped that these trials will support the identification of pharmacotherapies that provide clinical benefit for patients with MASH.