Citations

AbstractBackgroundCrystal‐storing histiocytosis (CSH) is a rare form of histiocytosis with intralysosomal accumulations of immunoglobulins or paraproteins that aggregate as crystals. Central nervous system (CNS) involvement of CSH is uncommon but should be considered in cases of persistent parenchymal enhancement on neuroimaging.MethodsWe describe one local case of CNS CSH and 10 additional cases identified by literature review.ResultsAmong 11 CSH patients, lesions involved either the dura (2/11) or brain parenchyma (9/11). Two cases had leptomeningeal enhancement. One case had spinal cord involvement. Two cases were associated with marginal zone lymphoma; one case was associated with an immunoglobulin A‐plasma cell dyscrasia. Eight of 11 cases had outcome data available: 7/8 cases had clinical and/or radiological improvement and 1/8 had radiological stability.ConclusionsCentral nervous system involvement of CSH is rare. Potential cases should be comprehensively evaluated for lymphoma or myeloma with positron emission tomography/computed tomography (CT) of the body or alternatively, CT of the chest, abdomen, pelvis and nuclear bone scan, bone marrow biopsy, serum protein electrophoresis, and cerebrospinal fluid protein electrophoresis. Treatment is targeted toward the underlying malignancy.

AbstractINTRODUCTIONPrimary age‐related tauopathy (PART) is characterized by neurofibrillary tangles and minimal β‐amyloid deposition, diagnosed postmortem. This study investigates 18F‐flortaucipir (FTP) PET imaging for antemortem PART diagnosis.METHODSWe analyzed FTP PET scans from 50 autopsy‐confirmed PART and 13 control subjects. Temporal lobe uptake was assessed both qualitatively and quantitatively. Demographic and clinicopathological characteristics and voxel‐level uptake using SPM12 were compared between FTP‐positive and FTP‐negative cases. Intra‐reader reproducibility was evaluated with Krippendorff's alpha.RESULTSMinimal/mild and moderate FTP uptake was seen in 32% of PART cases and 62% of controls, primarily in the left inferior temporal lobe. No demographic or clinicopathological differences were found between FTP‐positive and FTP‐negative cases. High intra‐reader reproducibility (α = 0.83) was noted.DISCUSSIONFTP PET imaging did not show a specific uptake pattern for PART diagnosis, indicating that in vivo PART identification using FTP PET is challenging. Similar uptake in controls suggests non‐specific uptake in PART.Highlights 18F‐flortaucipir (FTP) PET scans were analyzed for diagnosing PART antemortem. 32% of PART cases had minimal/mild FTP uptake in the left inferior temporal lobe. Similar to PART FTP uptake was found in 62% of control subjects. No specific uptake pattern was found, challenging in vivo PART diagnosis.

The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.

Abstract Objectives To define the prevalence, distribution and characteristics of patients with VEXAS (vacuoles, E1-enzyme, X-linked, autoinflammation, somatic) syndrome who have confirmed vasculitis. Methods Patients with VEXAS syndrome, verified by positive UBA1 mutation, were included. Chart review was performed to identify patient characteristics and outcomes. Vasculitis diagnosis was based on either histopathology showing vascular inflammation or non-invasive angiography findings. Summary statistics were calculated. Results Eighty-nine patients met inclusion criteria. All were male with a median age of onset of 66.9 years (interquartile range 60.1, 72.7). Median (interquartile range) follow-up was 3.8 (2.2–5.5) years, during which 21 patients (23.6%) had evidence of vasculitis. Vasculitis subtypes included small vessel vasculitis (19.1%), cutaneous medium vessel vasculitis (2.2%) and large vessel vasculitis (2.2%). No patient had more than one vessel size involved. Histopathology in small vessel vasculitis patients was consistent with cutaneous leukocytoclastic vasculitis in the majority, though one patient had leukocytoclastic peritubular capillaritis on renal biopsy. Cranial symptoms (headache, vision changes or jaw pain) were noted in 18.0%. Two additional patients not experiencing cranial symptoms exhibited large vessel involvement with confirmed carotid thickening on non-invasive angiography; one of these had a positive temporal artery biopsy. Conclusion VEXAS syndrome manifests as a variable vessel vasculitis in a quarter of patients, with cutaneous small and medium vessel involvement being particularly common. Some patients may have positive ANCA serologies or even renal vasculitis leading to misdiagnosis. Cranial symptoms are common and may mimic GCA, though documented large vessel inflammation is rare.

AbstractINTRODUCTIONUnderstanding the relationship between amyloid beta (Aβ) positron emission tomography (PET) and Aβ cerebrospinal fluid (CSF) biomarkers will define their potential utility in Aβ treatment. Few population‐based or neuropathologic comparisons have been reported.METHODSParticipants 50+ years with Aβ PET and Aβ CSF biomarkers (phosphorylated tau [p‐tau]181/Aβ42, n = 505, and Aβ42/40, n = 54) were included from the Mayo Clinic Study on Aging. From these participants, an autopsy subgroup was identified (n = 47). The relationships of Aβ PET and Aβ CSF biomarkers were assessed cross‐sectionally in all participants and longitudinally in autopsy data.RESULTSCross‐sectionally, more participants were Aβ PET+ versus Aβ CSF− than Aβ PET− versus Aβ CSF+ with an incremental effect when using Aβ PET regions selected for early Aβ deposition. The sensitivity for the first detection of Thal phase ≥ 1 in longitudinal data was higher for Aβ PET (89%) than p‐tau181/Aβ42 (64%).DISCUSSIONAβ PET can detect earlier cortical Aβ deposition than Aβ CSF biomarkers. Aβ PET+ versus Aβ CSF− findings are several‐fold greater using regional Aβ PET analyses and in peri‐threshold‐standardized uptake value ratio participants.Highlights Amyloid beta (Aβ) positron emission tomography (PET) has greater sensitivity for Aβ deposition than Aβ cerebrospinal fluid (CSF) in early Aβ development. A population‐based sample of participants (n = 505) with PET and CSF tests was used. Cortical regions showing early Aβ on Aβ PET were also used in these analyses. Neuropathology was used to validate detection of Aβ by Aβ PET and Aβ CSF biomarkers.

Context.— Generative artificial intelligence (GAI) technologies are likely to dramatically impact health care workflows in clinical pathology (CP). Applications in CP include education, data mining, decision support, result summaries, and patient trend assessments. Objective.— To review use cases of GAI in CP, with a particular focus on large language models. Specific examples are provided for the applications of GAI in the subspecialties of clinical chemistry, microbiology, hematopathology, and molecular diagnostics. Additionally, the review addresses potential pitfalls of GAI paradigms. Data Sources.— Current literature on GAI in health care was reviewed broadly. The use case scenarios for each CP subspecialty review common data sources generated in each subspecialty. The potential for utilization of CP data in the GAI context was subsequently assessed, focusing on issues such as future reporting paradigms, impact on quality metrics, and potential for translational research activities. Conclusions.— GAI is a powerful tool with the potential to revolutionize health care for patients and practitioners alike. However, GAI must be implemented with much caution considering various shortcomings of the technology such as biases, hallucinations, practical challenges of implementing GAI in existing CP workflows, and end-user acceptance. Human-in-the-loop models of GAI implementation have the potential to revolutionize CP by delivering deeper, meaningful insights into patient outcomes both at an individual and a population level.

Abstract Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer’s disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5–0.9 Hz) and delta (1–3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by −0.0082 (95% CI: −0.0143; −0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.

Abstract Disclosure: J. Hewlett: None. S. Mohan: None. C.J. Davidge-Pitts: None. J. Abeykoon: None. R. Go: None. D.Z. Erickson: None. Objective: Erdheim-Chester Disease (ECD) is a multisystem histiocytic disorder which can infiltrate the pituitary gland, often leading to endocrine dysfunction. Central Arginine Vasopressin Deficiency (cAVP-D) commonly affects ECD patients, and those harboring BRAFV600E are reported to have an increased risk. Insufficient data exist about the risk associated with other mutations, and if cAVP-D or pituitary imaging improves with targeted therapies (TT). Methods: We conducted a review of a prospectively maintained database of adults with ECD treated at a tertiary center between 1992-2023. Objectives of this study were to identify mutations associated with cAVP-D and assess for improvement in cAVP-D (remission of disease or decrease in dose of desmopressin) or pituitary gland involvement (via MRI imaging) following TT for ECD. Results: Of 148 patients with ECD, the majority were male (98, 66.2%) and the mean age at diagnosis was 56.5 years [range: 19-82]. Median length of follow-up was 24 months (95% CI, 17 to 27). Of 121 (81.8%) patients with molecular testing results, 89 (73.6%) harbored a somatic mutation. 67 of 89 (75.3%) carried BRAF mutations, with BRAFV600E in 61 (91.0%) and missense mutations/fusions in 6 (9.0%). 22 of 89 (24.7%) patients harbored other somatic mutations, with MAP2K1 in 13 (14.6%) being the most common. 35 (23.6%) patients were diagnosed with cAVP-D, and the median onset of polyuria and polydipsia prior to diagnosis of ECD was 51 months (95% CI, -120 to -6). Molecular testing was performed in 28 patients with cAVP-D: 17 (60.7%) harbored BRAF mutation and 3 (10.7%) MAP2K1 mutation. There was no significant association between the presence of cAVP-D and MAP2K1 (p=0.69, 95% CI, -0.08 to 0.21). The association between cAVP-D and BRAF did not reach statistical significance (p=0.07, 95%CI, -0.03 to 0.38). Additionally, there was no association between BRAF and timing of cAVP-D symptoms before ECD diagnosis (p=0.08, 95% CI -163.4 to 10.3). Pituitary MRI was available in 32 patients with cAVP-D (91.4%) showing infundibular involvement in 17 (53.1%) and loss of the posterior bright spot in 5 (15.6%). 28 (80%) patients with cAVP-D received systemic therapy, 18 (64.3%) of whom received TT. One patient with cAVP-D was able to discontinue desmopressin. Improvement of pituitary MRI was noted in 7 (21.9%), among whom 4 received TT, 2 received systemic non-TT, and 1 was lost to follow-up. There was no significant MRI improvement associated with TT (p=0.67, 95% CI -0.30 to 0.42). Conclusion: In this large cohort of patients with ECD, of whom the majority underwent molecular testing, we identified no association between MAP2K1 mutation and cAVP-D, and no impact of TT on the clinical course or MRI findings associated with cAVP-D. BRAF mutation carriers were more likely to have cAVP-D and more likely to have onset of symptoms closer to ECD diagnosis, but the results did not reach statistical significance. Presentation: 6/2/2024