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Background Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors. Methods Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high. Results The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control. Conclusions Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors. Trial registration number NCT04510129.

AbstractObjectiveThis study aimed to evaluate the diagnostic accuracy of dried blood spot (DBS) compared with conventional serum Aquaporin‐4‐IgG (AQP4‐IgG) testing.MethodsProspective multicenter diagnostic study was conducted between April 2018 and October 2023 across medical centers in the United States, Uganda, and the Republic of Guinea. Neuromyelitis optica spectrum disorder (NMOSD) patients and controls collected blood on filter paper cards along with concurrent serum samples. These samples underwent analysis using flow cytometric live‐cell‐based assays (CBA) and enzyme‐linked immunosorbent assay (ELISA) to determine AQP4 serostatus. The accuracy of AQP4‐IgG detection between DBS and serum (gold standard) was compared.ResultsAmong 150 participants (47 cases, 103 controls), there was a strong correlation between DBS and serum samples (Spearman's correlation coefficient of 0.82). The AUC was 0.97 (95% CI: 0.92–0.99). AQP4‐IgG detection through DBS showed 87.0% sensitivity (95% CI: 0.74–0.95) and 100% specificity (95% CI: 0.96–1.00) using CBA, and 65.2% sensitivity (95% CI: 0.43–0.84) and 95.2% specificity (95% CI: 0.76–0.99) using ELISA. Serum ELISA demonstrated 69.6% sensitivity (95% CI: 0.47–0.87) and 98.4% specificity (95% CI: 0.91–0.99). The stability of DBS in detecting AQP4‐IgG persisted over 24 months for most cases.InterpretationThe DBS represents a viable alternative for detecting AQP4‐IgG in resource‐limited settings to diagnose NMOSD, offering high sensitivity and specificity comparable to serum testing. Moreover, DBS has low shipping costs, is easy to administer, and is suitable for point‐of‐care testing.

This cross-sectional study examines the frequency of increased intracranial pressure and its association with myelin oligodendrocyte glycoprotein antibody-associated disease in patients of various ages.

AbstractObjectiveThe first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON).MethodsWe included 160 patients with a first‐ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present.ResultsAccording to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody‐associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%).InterpretationAccording to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.

ObjectiveTo evaluate the cerebrospinal fluid (CSF) cytokine/chemokine profile of central nervous system (CNS) neurosarcoidosis (NS), and its utility in differential diagnosis, treatment, and prognostication.MethodsIn this case–control study, we validated 17 cytokines/chemokines (interleukin [IL]‐1‐beta, IL‐2, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12p70, IL‐13, IL‐17A, BAFF, IL‐8/CXCL8, CXCL9, CXCL10, CXCL13, GM‐CSF, interferon‐gamma, and tumor necrosis factor [TNF]‐alpha) in a multiplexed automated immunoassay system (ELLA; Bio‐Techne, Minneapolis, MN, USA), and assessed them in CSF and serum of symptomatic patients with probable or definite CNS NS (01/2011–02/2023) with gadolinium enhancement and/or CSF pleocytosis. Patients with multiple sclerosis, primary CNS lymphoma, aquaporin‐4 immunoglobulin G positivity, non‐inflammatory disorders, and healthy individuals were used as controls.ResultsA total of 32 NS patients (59% women; median age, 59 years [19–81]) were included; concurrent sera were available in 12. CSF controls consisted of 26 multiple sclerosis, 8 primary CNS lymphoma, 84 aquaporin‐4 immunoglobulin G positive, and 34 patients with non‐inflammatory disorders. Gadolinium enhancement was present in 31 of 32 NS patients, and CSF pleocytosis in 27 of 32 (84%). CSF IL‐2, IL‐6, IL‐10, IL‐13, BAFF, IL‐8/CXCL8, CXCL9, CXCL10, CXCL13, GM‐CSF, interferon‐gamma, and TNF‐alpha levels were significantly higher in NS patients compared with non‐inflammatory controls (p ≤ 0.02); elevations were more common in CSF than serum. Concurrent elevation of IL‐6, CXCL9, CXCL10, GM‐CSF, interferon‐gamma, and TNF‐alpha was present in 18 of 32 NS patients, but only in 1 control. Elevated IL‐6, IL‐10, IL‐13, CXCL9, CXL10, GM‐CSF, and TNF‐alpha associated with measures of disease activity.InterpretationNS CSF cytokine/chemokine profiles suggest T cell (mainly T helper cell type 1), macrophage, and B‐cell involvement. These signatures aid in NS diagnosis, indicate disease activity, and suggest therapeutic avenues. ANN NEUROL 2024;96:704–714

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Abstract Diversity, equity, and inclusion is a powerful goal which many of us strive toward in medicine, both in patient care and administrative leadership. As the world evolves, the practice of medicine must evolve with it. We are cognizant of the importance of the history of our medical specialties. If we do not acknowledge all parts of our history, we are doomed to repeat it. This special issue is unique and unlike anything that has previously been published in Diagnostic Cytopathology. This issue looks at some of the history of cytopathology. This historical review is followed by some of the present state of cytopathology. There are insights into global cytopathology. The final portion of this issue examines the critical need for cytotechnology schools in the United States. All of these areas are critical to the past, present, and future of cytopathology.