Citations

e20602 Background: DICER1 encodes a miRNA processing enzyme involved in regulation of cell proliferation and differentiation. The role of DICER1 pathogenic variants (PVs) in non-small cell lung cancer (NSCLC) is relatively unknown. Germline and/or somatic PVs have been reported in pleuropulmonary blastoma, pulmonary blastoma (PB), and low-grade/well-differentiated fetal adenocarcinoma (WDFLAC), with clustering of somatic PVs at specific metal ion binding residues referred to as hotspot alterations. PVs in CTNNB1, resulting in constitutive activation of the WNT signaling pathway, have also been implicated in PB and WDFLAC. This study seeks to establish the frequency of somatic DICER1 hotspot PVs that occur in all NSCLCs, their co-occurrence with other PVs in DICER1 and with alterations of CTNNB1/WNT signaling, and their histologic correlates. Methods: Molecular sequencing data collected from 12,146 NSCLCs at Caris Life Sciences were queried for cases featuring somatic DICER1 variants. For those tumors harboring hotspot PVs, sequencing for CTNNB1 and APC mutations was performed, as well as histological review, including examination of beta-catenin immunohistochemical (IHC) staining. Results: Of the 12,146 NSCLCs analyzed, 235 (1.9%) were found to have one or more DICER1 PVs. Of these 235, 225 cases demonstrated one variant, while 10 tumors featured two. Gene analysis revealed that 8 of the observed PVs cases contained hotspot alterations: 2 in the single variant cases and 6 in the double variant cases. The remaining 4 double variant cases harbored a combination of truncating, non-hotspot missense, or splice variants. No significant differences were observed for age or smoking status between DICER1 hotspot-positive and hotspot-negative groups. All but one tumor were considered to be in histologic spectrum of PB/WDFLAC. Of the 8 DICER1 hotspot-positive cases, 1 had a PV in APC, 4 had a CTNNB1 PV, 1 had a PV in both APC and CTNNB1, and 2 had neither. Beta-catenin IHC showed nuclear positivity in 5 tumors that had a PV in either CTNNB1 and/or APC.. Conclusions: This study demonstrates that DICER1 somatic hotspots select for morphologic features of tumor types such as PB and WDFLAC, but are not implicated in the most common forms of NSCLC. Furthermore, DICER1 hotspot-positive NSCLCs frequently harbor CTNNB1 and/or APC alterations, with many cases exhibiting nuclear staining by beta-catenin IHC, suggesting a possible synergistic relationship between DICER1 hotspot PVs and activation of the WNT signaling pathway in the formation of pulmonary tumors. These findings emphasize the importance of molecular testing in clinical practice such that detecting somatic DICER1 hotspot alterations aids in the diagnosis of rare lung cancers, which ultimately require special consideration with respect to disease severity and treatment.

AbstractCardiac physiologic pacing (CPP), encompassing cardiac resynchronization therapy (CRT) and conduction system pacing (CSP), has emerged as a pacing therapy strategy that may mitigate or prevent the development of heart failure (HF) in patients with ventricular dyssynchrony or pacing‐induced cardiomyopathy. This clinical practice guideline is intended to provide guidance on indications for CRT for HF therapy and CPP in patients with pacemaker indications or HF, patient selection, pre‐procedure evaluation and preparation, implant procedure management, follow‐up evaluation and optimization of CPP response, and use in pediatric populations. Gaps in knowledge, pointing to new directions for future research, are also identified.

Background Our prior work demonstrated that questionnaires assessing psychosocial symptoms have utility for predicting improvement in patients with acute post-traumatic headache following mild traumatic brain injury. In this cohort study, we aimed to determine whether prediction accuracy can be refined by adding structural magnetic resonance imaging (MRI) brain measures to the model. Methods Adults with acute post-traumatic headache (enrolled 0–59 days post-mild traumatic brain injury) underwent T1-weighted brain MRI and completed three questionnaires (Sports Concussion Assessment Tool, Pain Catastrophizing Scale, and the Trait Anxiety Inventory Scale). Individuals with post-traumatic headache completed an electronic headache diary allowing for determination of headache improvement at three- and at six-month follow-up. Questionnaire and MRI measures were used to train prediction models of headache improvement and headache trajectory. Results Forty-three patients with post-traumatic headache (mean age = 43.0, SD = 12.4; 27 females/16 males) and 61 healthy controls were enrolled (mean age = 39.1, SD = 12.8; 39 females/22 males). The best model achieved cross-validation Area Under the Curve of 0.801 and 0.805 for predicting headache improvement at three and at six months. The top contributing MRI features for the prediction included curvature and thickness of superior, middle, and inferior temporal, fusiform, inferior parietal, and lateral occipital regions. Patients with post-traumatic headache who did not improve by three months had less thickness and higher curvature measures and notably greater baseline differences in brain structure vs. healthy controls (thickness: p < 0.001, curvature: p = 0.012) than those who had headache improvement. Conclusions A model including clinical questionnaire data and measures of brain structure accurately predicted headache improvement in patients with post-traumatic headache and achieved improvement compared to a model developed using questionnaire data alone.

Abstract Alloreactive memory T cells, unlike naive T cells, fail to be restrained by transplantation tolerance protocols or regulatory T cells, and therefore represent a critical barrier to long-term graft acceptance. Using female mice sensitized by rejection of fully-mismatched paternal skin allografts, we show that subsequent semi-allogeneic pregnancy successfully reprograms memory fetus/graft-specific CD8+ T cells (TFGS) towards hypofunction in a manner that is mechanistically distinct from naive TFGS. Post-partum memory TFGS were durably hypofunctional, exhibiting enhanced susceptibility to transplantation tolerance induction. Furthermore, multi-omics studies revealed that pregnancy induced extensive phenotypic and transcriptional modifications in memory TFGS reminiscent of T cell exhaustion. Strikingly, at loci transcriptionally modified in both naive and memory TFGS during pregnancy, chromatin remodeling was observed exclusively in memory and not naive TFGS. These data reveal a novel link between T cell memory and hypofunction via exhaustion circuits and pregnancy-mediated epigenetic imprinting. This conceptual advance has immediate clinical relevance to pregnancy and transplantation tolerance.

Objectives The objective of this longitudinal study was to determine whether brain iron accumulation, measured using magnetic resonance imaging magnetic transverse relaxation rates (T2*), is associated with response to erenumab for the treatment of migraine. Methods Participants (n = 28) with migraine, diagnosed using international classification of headache disorders 3rd edition criteria, were eligible if they had six to 25 migraine days during a four-week headache diary run-in phase. Participants received two treatments with 140 mg erenumab, one immediately following the pre-treatment run-in phase and a second treatment four weeks later. T2* data were collected immediately following the pre-treatment phase, and at two weeks and eight weeks following the first erenumab treatment. Patients were classified as erenumab responders if their migraine-day frequency at five-to-eight weeks post-initial treatment was reduced by at least 50% compared to the pre-treatment run-in phase. A longitudinal Sandwich estimator approach was used to compare longitudinal group differences (responders vs non-responders) in T2* values, associated with iron accumulation. Group visit effects were calculated with a significance threshold of p = 0.005 and cluster forming threshold of 250 voxels. T2* values of 19 healthy controls were used for a reference. The average of each significant region was compared between groups and visits with Bonferroni corrections for multiple comparisons with significance defined as p < 0.05. Results Pre- and post-treatment longitudinal imaging data were available from 28 participants with migraine for a total of 79 quantitative T2* images. Average subject age was 42 ± 13 years (25 female, three male). Of the 28 subjects studied, 53.6% were erenumab responders. Comparing longitudinal T2* between erenumab responders vs non-responders yielded two comparisons which survived the significance threshold of p < 0.05 after correction for multiple comparisons: the difference at eight weeks between the erenumab-responders and non-responders in the periaqueductal gray (mean ± standard error; responders 43 ± 1 ms vs non-responders 32.5 ± 1 ms, p = 0.002) and the anterior cingulate cortex (mean ± standard error; responders 50 ± 1 ms vs non-responders 40 ± 1 ms, p = 0.01). Conclusions Erenumab response is associated with higher T2* in the periaqueductal gray and anterior cingulate cortex, regions that participate in pain processing and modulation. T2* differences between erenumab responders vs non-responders, a measure of brain iron accumulation, are seen at eight weeks post-treatment. Less iron accumulation in the periaqueductal gray and anterior cingulate cortex might play a role in the therapeutic mechanisms of migraine reduction associated with erenumab.

Abstract Objectives/Background Post‐traumatic headache (PTH) is a common symptom after mild traumatic brain injury (mTBI). Although there have been several studies that have used clinical features of PTH to attempt to predict headache recovery, currently no accurate methods exist for predicting individuals’ improvement from acute PTH. This study investigated the utility of clinical questionnaires for predicting (i) headache improvement at 3 and 6 months, and (ii) headache trajectories over the first 3 months. Methods We conducted a clinic‐based observational longitudinal study of patients with acute PTH who completed a battery of clinical questionnaires within 0–59 days post‐mTBI. The battery included headache history, symptom evaluation, cognitive tests, psychological tests, and scales assessing photosensitivity, hyperacusis, insomnia, cutaneous allodynia, and substance use. Each participant completed a web‐based headache diary, which was used to determine headache improvement. Results Thirty‐seven participants with acute PTH (mean age = 42.7, standard deviation [SD] = 12.0; 25 females/12 males) completed questionnaires at an average of 21.7 (SD = 13.1) days post‐mTBI. The classification of headache improvement or non‐improvement at 3 and 6 months achieved cross‐validation area under the curve (AUC) of 0.72 (95% confidence interval [CI] 0.55 to 0.89) and 0.84 (95% CI 0.66 to 1.00). Sub‐models trained using only the top five features still achieved 0.72 (95% CI 0.55 to 0.90) and 0.77 (95% CI 0.52 to 1.00) AUC. The top five contributing features were from three questionnaires: Pain Catastrophizing Scale total score and helplessness sub‐domain score; Sports Concussion Assessment Tool Symptom Evaluation total score and number of symptoms; and the State‐Trait Anxiety Inventory score. The functional regression model achieved for modeling headache trajectory over the first 3 months. Conclusion Questionnaires completed following mTBI have good utility for predicting headache improvement at 3 and 6 months in the future as well as the evolving headache trajectory. Reducing the battery to only three questionnaires, which assess post‐concussive symptom load and biopsychosocialecologic factors, was helpful to determine a reasonable prediction accuracy for headache improvement.

Abstract Objective To explore alterations in thalamic subfield volume and iron accumulation in individuals with post‐traumatic headache (PTH) relative to healthy controls. Background The thalamus plays a pivotal role in the pathomechanism of pain and headache, yet the role of the thalamus in PTH attributed to mild traumatic brain injury (mTBI) remains unclear. Methods A total of 107 participants underwent multimodal T1‐weighted and T2* brain magnetic resonance imaging. Using a clinic‐based observational study, thalamic subfield volume and thalamic iron accumulation were explored in 52 individuals with acute PTH (mean age = 41.3; standard deviation [SD] = 13.5), imaged on average 24 days post mTBI, and compared to 55 healthy controls (mean age = 38.3; SD = 11.7) without history of mTBI or migraine. Symptoms of mTBI and headache characteristics were assessed at baseline (0–59 days post mTBI) ( n = 52) and 3 months later ( n = 46) using the Symptom Evaluation of the Sports Concussion Assessment Tool (SCAT‐5) and a detailed headache history questionnaire. Results Relative to controls, individuals with acute PTH had significantly less volume in the lateral geniculate nucleus (LGN) (mean volume: PTH = 254.1, SD = 43.4 vs. controls = 278.2, SD = 39.8; p = 0.003) as well as more iron deposition in the left LGN (PTH: T2* signal = 38.6, SD = 6.5 vs. controls: T2* signal = 45.3, SD = 2.3; p = 0.048). Correlations in individuals with PTH revealed a positive relationship between left LGN T2* iron deposition and SCAT‐5 symptom severity score at baseline ( r = −0.29, p = 0.019) and maximum headache intensity at the 3‐month follow‐up ( r = −0.47, p = 0.002). Conclusion Relative to healthy controls, individuals with acute PTH had less volume and higher iron deposition in the left LGN. Higher iron deposition in the left LGN might reflect mTBI severity and poor headache recovery.