Citations

PURPOSE BRAF and MEK inhibitors are standard treatments in histiocytic disorders, such as Erdheim-Chester disease (ECD). Some patients lack MAPK-pathway alterations, making these treatments less effective. METHODS We describe three patients with histiocytic disorders who have novel non-MAPK pathway alterations. These alterations were studied through genomic and in silico analyses when applicable, then treated with off-label medications rationally selected on the basis of genomic alterations. RESULTS Patient 1 had rapidly progressive ECD involving the CNS. A CSF1R in-frame deletion (p.S560_P566del) was identified, and in silico modeling predicted a gain-of-function mutation. This alteration was targeted with pexidartinib, which led to a clinical complete response (CR) within 2 months, and a partial response (PR) on imaging after 3 months. After 15 months, the disease became resistant to pexidartinib and transformed to histiocytic sarcoma. Patient 2 has skin-only involvement of a xanthogranuloma disorder. A KIF5B-FGFR1 fusion was identified on RNA sequencing and targeted with pemigatinib. At 24 months of follow-up, she remains in a clinical PR. Patient 3 has ECD involving the bone marrow, gastrointestinal tract, and subcutaneous tissues. A MEF2C-FLT3 fusion was identified and targeted with sorafenib. He achieved a clinical CR and radiographic PR within 3 months, which has continued for 30 months. CONCLUSION We report three patients with histiocytic disorders harboring novel alterations who had sustained responses to off-label kinase inhibitors specific to their histiocytic disorder. Pathogenic variants outside of the MAPK pathway, including variants of unknown significant, may be targeted with readily available small molecules.

Abstract Objective To assess the association of aPL and diffuse alveolar haemorrhage (DAH) in patients with SLE by performing a systematic review and meta-analysis. Methods Multiple databases were systematically searched from inception to February 2024. Studies were eligible if they included patients with SLE (population), reported aPL status (exposure), and DAH (outcome). We pooled the estimates as odds ratio (OR) using fixed-effect models. We examined the association between aPL and DAH, as well as associations based on aPL subtypes or concomitant APS. Results Out of 454 screened studies, nine were included in meta-analysis, encompassing 7746 patients with SLE, of whom 2016 (26.0%) were aPL-positive and 163 (2.1%) had DAH. Patients with SLE and positive aPL (any) were more likely to develop DAH than aPL-negative patients (OR = 1.76, 95% CI 1.24–2.49; I2 = 0%). Patients with SLE and positive LA (OR = 1.76, 95% CI 1.06–2.93, I2 = 35%) or positive anticardiolipin IgG (OR = 1.62, 95% CI 1.13–2.34, I2 = 0%) had a higher likelihood of developing DAH compared with patients that were negative for these aPL. An APS diagnosis was associated with a 2.5-fold increased likelihood of DAH compared with subjects without APS (OR = 2.46, 95% CI 1.23–4.92, I2 = 0%). Positivity of anti-β2 glycoprotein I IgG was not significantly associated with DAH among patients with SLE (OR = 0.78, 95% CI 0.45–1.36, I2 = 0%). Conclusion In patients with SLE, aPL positivity increases the risk of DAH compared with aPL-negative patients, particularly in those positive for LA and anticardiolipin IgG.

Abstract Background Brain tumors represent a significant global health challenge, with rising incidence and mortality impacting individuals worldwide and contributing to cancer-related morbidity and mortality. In Africa, this burden is exacerbated by limited access to advanced diagnostics, treatment options, and multidisciplinary care, compounded by the absence of standardized cancer registration and tumor biobanking. The introduction of molecular diagnostics, as outlined in the 2021 World Health Organization central nervous system (CNS) tumor classification, adds complexity to brain tumor management, particularly in regions with scarce resources. Methods To address these issues, the Brain Tumor Consortium for Africa (BTCA) was established in 2023, bringing together experts to improve CNS tumor diagnosis, patient care, and research. The initial project, conducted via an electronic questionnaire, aimed to assess neuro-oncology capacity across Sub-Saharan Africa. Results The study revealed significant gaps, with a limited number of institutions incorporating molecular subtyping into their diagnostic algorithms. The consortium’s efforts focus on enhancing local data use, informing public policy, and promoting collaboration to advance neuro-oncology practices in Africa. By fostering a network enlisting the expertise of collaborators in the fields of neurosurgery, neurology, neuropathology, anatomic pathology, and medical and radiation oncology, the BTCA seeks to improve brain tumor management through better diagnostics, infrastructure, and policy advocacy. Future directions include expanding molecular diagnostic capabilities, standardizing brain tumor biobanking, enhancing data collection, and advocating for improved brain tumor care in national health agendas. Conclusions The BTCA represents a pioneering model of collaboration and innovation in addressing the unique challenges of brain tumor care in Africa.

Abstract T cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary Thymic Epithelial Cells (mTEC) of the thymus. AIRE induces expression of SELF peripheral tissue-specific antigens for presentation to naïve T cells to promote activation/deletion of potentially autoreactive T cells. We show, for the first time to our knowledge, that tumors mimic the role of AIRE in mTEC to evade immune rejection. Thus, by expressing a broad range of SELF epitopes against which minimal functional T cell reactivities exist because of thymic deletion, AIRE acts as a master controller of SELFNESS, effectively cloaking the tumor from T cell attack. Moreover, we describe a completely novel immunotherapy in which engineered changes in AIRE expression in tumor cells alters their profile of SELFNESS, exposing both AIRE-modified, and parental unmodified, tumor cells to T cell attack. Consistent with our studies, patient RNAseq shows expression of AIRE predicts response to immune therapies with a strong correlation between AIRE expression and markers of TCR signaling. Therefore, by re-setting the immunological SELFNESS of cancer cells, this novel AIRE-mediated immunotherapy 1). converts a highly tolerized T cell compartment into a heteroclitic tumor-reactive T cell population; 2) confers de novo sensitivity to immune checkpoint blockade upon non-immunogenic tumors; 3). completely removes the need to identify potentially immunogenic tumor-associated antigens as targets for generation of de novo CD8+ and helper CD4+ T cell responses; and 4) leads to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors.

Introduction: Gray-white matter ratio (GWR) on non-contrast head computed tomography (HCT) is a helpful tool in neuro-prognostication in post-cardiac arrest patients. Its usage is unclear for those with angiography due to residual contrast. Hypothesis: GWR remains valid for neuro-prognostication in comatose patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) followed by coronary angiography (CAG) after out-hospital cardiac arrest (OHCA). Methods: We performed a retrospective study of comatose OHCA adults post ECPR and CAG at University of Minnesota from January to June 2022 with dual energy HCT within 12 hours. GWR was measured at basal ganglia, centrum semiovale, and high convexity levels. Gray matter areas of interest included caudate nucleus, putamen, thalamus, and medial cortex. The white matter areas of interest included the genu of the corpus callosum, posterior limb of the internal capsule, and medial white matter. Circular regions of interest (ROI, 10-15 mm 2 ) were placed bilaterally in corresponding areas to record the average attenuation in Hounsfield unit (HU). The basal ganglia, cerebrum, and overall GWRs were calculated as the ratio of average HU between the gray and white matter ROIs within the area. Primary outcome was inpatient death, further categorized by the primary cause being neurological or not. Logistic regression followed by receiver operating characteristic (ROC) curves was used to validate GWR in predicting death. All data analysis was performed by StataCorp Software (STATA 14). Result: 25 patients were included in the study. 18 (72%) were male with a median age of 60 (interquartile range (IQR): 45-67). The initial HCT was obtained at 2.08 hours (median, IQR: 1.37–2.43) post ECPR cannulation. 7 (28%) patients died from brain death or herniation and 15 (60%) died from non-neurological causes. None had intracranial bleeding. 1 patient had unilateral hypodensity on initial HCT, suggesting an acute embolic infarct. Patients who died had lower GWRs on initial HCT (Figure 1). ROC regression showed all GWRs demonstrated good prognostic performance on inpatient death with area under the curve (AUC) of 0.6970 (basal ganglia), 0.8485 (cerebrum), and 0.7576 (overall) (Figure 2). Conclusions: GWR in early HCT has prognostic value in predicting neurological outcomes despite residual contrast. It may be used as a risk stratification tool for comatose OHCA patients undergoing ECPR and angiography.

Introduction: Pulsed field ablation (PFA) is an adaptation of direct current ablation first used for catheter ablation in the 1980s. Expectations of a reduced risk profile led to the current resurgence in investment and interest in the technology as a potential alternative energy source for ablations to treat atrial fibrillation (AF). However, reports of adverse events, including new risks, are increasing. Research Question: How many adverse effects are reported with the use of newly available PFA systems? Aims: Quantify and describe the adverse events from PFA reported to date in the Food and Drug Administration’s (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. Methods: We searched the U.S. FDA’s MAUDE database for all reports filed with the code “QZI”, which is the product code for PFA systems created with the first FDA approvals in February 2024. All reports from inception through April 2024 (a total of 3 months) were included in this review. Per manufacturer presentation in May 2024, approximately 1000 cases utilizing PFA had been captured in a post-market registry of the predominant commercially used technology, but the exact number of cases can not be determined from MAUDE data. Results: A total of 217 adverse events were reported over the first 3 months of US approval, with 91 of these considered patient injuries. These injuries included 10 cases of cardiac tamponade, 7 reports of postoperative arrhythmia, 6 instances of device-related tissue entrapment, 5 cases of hemolysis with impaired renal function, 5 cases of stroke or TIA, including both embolic and hemorrhagic, 3 cases of intraoperative heart block, 2 coronary spasms, and 2 cases of intraoperative ST elevation. (Figure) Of the 91 reported patient safety events, 46 required hospitalization, 13 cases required temporary pacing, 11 required pericardiocentesis, 4 required dialysis, 4 required cardiothoracic surgery, and 2 required cardioversion. Conclusions: A number of adverse events have been reported to the MAUDE database in the first 3 months of FDA approval of PFA. The cardiac electrophysiology community should remain vigilant to ensure that the benefit-risk profile remains acceptable for patient safety.

Introduction: Among patients with cardiogenic shock (CS), high right atrial pressure (RAP) and low mean arterial pressure (MAP) are associated with in-hospital mortality. Pressure-adjusted heart rate (PAHR), defined as heart rate * RAP-to-MAP ratio (HR * [RAP/MAP]), integrates these parameters and has been used to identify cardiovascular dysfunction in critical illness. Higher PAHR values associate with higher surgical ICU mortality, but the prognostic significance of PAHR has not been assessed in cardiac intensive care unit (CICU) patients with CS. Hypothesis: We hypothesized that higher PAHR values are associated with higher risk of in-hospital mortality in patients with CS. Methods: The Critical Care Cardiology Trials Network (CCCTN) is a multinational registry of CICUs coordinated by the TIMI Study Group. Among CS admissions (2018-2023) undergoing invasive hemodynamic assessment within 24h of CICU admission, we calculated PAHR (in bpm) and assessed its relationship with in-hospital mortality. Patients on temporary mechanical circulatory support were excluded. Odds ratios were adjusted for age, sex, vasoactive-inotropic score (VIS), SCAI stage, and preceding cardiac arrest. Subgroup analyses stratifying by CS subtype were performed. Results: Among the 1411 CS admissions in the analysis cohort (mean age 61 years, 31% women), 18% had AMI-CS, 75% had HF-CS, and 7% had secondary CS. At the time of assessment (median 1.4h after CICU admission), 75% were on vasoactive support (median VIS 3.8). Median HR was 92 (Q1-Q3 77-109) bpm, RAP 15 (Q1-Q3 10-19) mmHg, MAP 75 (Q1-Q3 67-87) mmHg, and PAHR 17 (Q1-Q3 11-24) bpm. A stepwise gradient of higher in-hospital mortality with increasing PAHR values (p-trend <0.001; Fig ) was observed. In adjusted models, a higher PAHR was associated with higher in-hospital mortality (aOR per 10-bpm, 1.35 [95% CI, 1.15-1.58]), and had stronger prognostic associations with mortality than its individual hemodynamic components (Fig) . Conclusion: Higher PAHR is strongly associated with in-hospital mortality in CS patients. PAHR, a simple parameter which is readily calculable without needing a pulmonary artery catheter, may aid in identifying CS patients at higher risk of death.

Objectives: The aims of the study are to develop a prostate cancer risk prediction model that combines clinical and magnetic resonance imaging (MRI)–related findings and to assess the impact of adding Prostate Imaging-Reporting and Data System (PI-RADS) ≥3 lesions-level findings on its diagnostic performance. Methods: This 3-center retrospective study included prostate MRI examinations performed with clinical suspicion of clinically significant prostate cancer (csPCa) between 2018 and 2022. Pathological diagnosis within 1 year after the MRI was used to diagnose csPCa. Seven clinical, 3 patient-level MRI-related, and 4 lesion-level MRI-related findings were extracted. After feature selection, 2 logistic regression models with and without lesions-level findings were created using data from facility I and II (development cohort). The area under the receiver operating characteristic curve (AUC) between the 2 models was compared in the PI-RADS ≥3 population in the development cohort and Facility III (validation cohort) using the Delong test. Interfacility differences of the selected predictive variables were evaluated using the Kruskal-Wallis test or chi-squared test. Results: Selected lesion-level features included the peripheral zone involvement and apparent diffusion coefficient (ADC) values. The model with lesions-level findings had significantly higher AUC than the model without in 655 examinations in the development cohort (0.81 vs 0.79, respectively, P = 0.005), but not in 553 examinations in the validation cohort (0.77 vs 0.76, respectively). Large interfacility differences were seen in the ADC distribution (P < 0.001) and csPCa proportion in PI-RADS 3–5 (P < 0.001). Conclusions: Adding lesions-level findings improved the csPCa discrimination in the development but not the validation cohort. Interfacility differences impeded model generalization, including the distribution of reported ADC values and PI-RADS score-level csPCa proportion.

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy globally, and the vast majority of cases are treated with primary surgical resection and adjuvant therapy. Our group has pioneered the use of HNSCC circulating tumor DNA (ctDNA) in surgical effluent collected postoperatively from surgical drains (surgical drain fluid, SDF) as a novel proximal bioanalyte for measuring minimal residual disease after surgery. We now profile the immune cell composition of SDF compared to paired peripheral blood mononuclear cells (PBMCs), and correlate SDF immune cell profiles with clinical variables and oncologic outcomes in HNSCC. Method: SDF and peripheral venous blood were collected 24 hours postoperatively from 58 HNSCC patients, including 11 HPV (+) and 47 HPV (-) patients undergoing standard of care surgical resection, lymph node dissection, and adjuvant therapy. Freshly collected SDF cells and PBMCs were cryopreserved until profiling by multicolor flow cytometry for respective leukocyte compositions. Analyses were used to define the following viable CD45+ leukocyte subsets: total T cells, CD4 T-cells CD8 T-cells, Treg cells, B-cells, non- classical monocytes, classical monocytes, natural killer (NK) cells, classical dendritic cells (cDC), plasmacytoid DC (pDC), macrophages, and monocytic myeloid-derived suppressive cells (MDSCs). Immune cell percentages were correlated with clinical characteristics and cancer recurrence. Results: CD45+ leukocytes comprised &gt;99.5% of SDF cells, with very few EPCAM+ tumor cells (&lt; 10^-4). HPV status did not significantly affect SDF immune cell composition, and no significant differences were noted by tumor site (larynx, oral cavity, oropharynx), or extracapsular lymph node extension. Among 13 HPV (-) HNSCC patients with paired peripheral blood drawn concurrently, SDF had a higher proportion of B-cells(16.8% vs. 9%, p=0.044), NK cells(56% vs. 12%, P&lt;0.001), monocytes(14% vs. 1%, P&lt;0.001), and macrophages(3.1% vs. 0.46%, P&lt;0.001) compared to PBMCs, and a lower proportion of CD4+ T cells(1% vs. 24%, P&lt;0.001), CD8+ T cells(0.6% vs. 18%, P&lt;0.001), MDSCs(2.1% vs. 3.4%, P=0.029), and pDCs(0.1% vs. 0.2%, P=0.014). HPV (-) HNSCC patients that went on to recur (n=9) had a significantly higher proportions of SDF monocytes (total, classical, and non- classical) and CD56dimCD16+ NK cells (all P&lt;0.001) compared to non-recurrent patients (n=38). Patients who went on to recur also had a significantly lower proportion of SDF B-cells (P&lt;0.001), CD56bright NK cells(P=0.01), and macrophages (P=0.018) compared to non- recurrent cases. No significant differences were noted with respect to proportions of CD3+, CD4+, CD8+ T-cells, DC, and MDSC cells. Conclusion: SDF from HNSCC patients contains unique immune cell populations and may provide new insights into postoperative tumor immunity. Differences in SDF immune cell composition by oncologic outcome in patients that go on to recur, highlighting potential prognostic and predictive applications of SDF immune cell profiling for adjuvant therapy decision-making. Citation Format: Zhongping Xu, Noah Earland, Lucien Khalil, Lazar Vujanovic, Danny Azmi Elias, Riyue Bao, Jason J. Luke, Aadel A. Chaudhuri, Jose P. Zevallos. Immune cell composition in surgical drain fluid as a novel prognostic marker in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B031.