Citations

Abstract Donor-derived tuberculosis is a rare complication following solid organ transplantation, and tuberculosis screening is not a current transplant prerequisite for most donors. Donor-derived tuberculosis usually presents sooner than reactivation tuberculosis, and the most common finding is fever. We present 3 cases of donor-derived tuberculosis in the recipients of 2 kidneys and 1 liver from the same donor, who presented with unexplained fevers occurring 4–5 weeks after transplantation. Initial antibacterial therapy failed in all 3 patients, leading to further testing, which identified Mycobacterium tuberculosis by culture and molecular studies. All recipients successfully received tuberculosis therapy but had significant morbidity and prolonged hospital stays. Donor-derived tuberculosis should be among the differential diagnoses of unexplained fever in solid organ transplant recipients in the first few months after transplantation. Screening protocols should be implemented for donors with an epidemiologic risk of tuberculosis, with special emphasis on deceased donors.

Abstract Objective This study was undertaken to evaluate the response to second treatments for infantile epileptic spasms syndrome (IESS). Methods Infants aged 2–24 months with IESS were prospectively enrolled in the National Infantile Spasms Cohort study at 21 pediatric epilepsy centers in the United States from 2012 to 2018. We analyzed data from infants who initially received standard treatment (hormonal therapy [adrenocorticotropic hormone, high‐dose prednisolone] or vigabatrin), had continued or recurring epileptic spasms, and received a second treatment. We excluded those with tuberous sclerosis. Treatment groups included hormonal therapy followed by vigabatrin (reference), hormonal‐to‐hormonal, hormonal‐to‐nonstandard, vigabatrin‐to‐hormonal, and vigabatrin‐to‐nonstandard. Nonstandard treatments included other antiseizure medications and dietary therapy. Treatment groups were tested for differences in 3‐month clinical remission using a binary logistic regression to estimate odds ratios (ORs). Results There were 153 infants with IESS who received second treatments. The highest rates of 3‐month remission were among infants in the hormonal‐to‐vigabatrin (22/65, 34%) and vigabatrin‐to‐hormonal (9/26, 35%) groups, followed by vigabatrin‐to‐nonstandard (3/10, 30%), hormonal‐to‐hormonal (4/22, 18%), and hormonal‐to‐nonstandard (1/30, 3.3%). Compared to the hormonal‐to‐vigabatrin group (reference), fewer infants had remission in the hormonal‐to‐nonstandard group (OR = .07, 95% confidence interval [CI] = .01–.53), and there was a trend toward fewer infants in the hormonal‐to‐hormonal group (OR = .43, 95% CI = .13–1.4, p = .17). Following initial hormonal treatment, the number needed to treat was three infants for one additional infant to have remission when treated with vigabatrin compared to nonstandard therapy as the second treatment. Significance This updated analysis with an expanded sample size provided power for additional subgroup analysis. Overall response rates were low, and at best only one third had remission after second treatment. Results support a clinical strategy of switching mechanism of action when selecting a second medication for epileptic spasms (i.e., use vigabatrin after hormonal therapy, or hormonal therapy after vigabatrin). Our findings also support the use of standard over nonstandard therapies.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Numerous factors including social determinants of health, knowledge gaps, economic challenges, workforce limitations, and health system deficiencies are associated with significant disparities in access to health care services and health outcomes for people with epilepsy (PWE). The American Epilepsy Society (AES) and the International League Against Epilepsy—North America (ILAE-NA) established a joint task force to explore and develop recommendations to address health care disparities experienced by PWE. The task force gathered foundational knowledge through meetings, public and patient organization comments and discussions to develop consensus recommendations. We enumerate the recommendations and discuss the rationale behind them to reduce disparities in epilepsy care through comprehensive research, inclusive clinical practices, robust advocacy, and targeted educational initiatives. While our recommendations are focused on the United States, we acknowledge that similar barriers and limitations exist for PWE globally and that these also need to be addressed within their local domains and with attention to unique factors therewithin.

e21600 Background: Uveal melanoma (UM), the most common intraocular malignancy in the U.S., metastasizes in 50% of patients, frequently to the liver (~90%) with poor prognosis (median overall survival [mOS] 1 year). Metastatic UM (mUM) literature is limited (due to its rarity/complexity) and management remains challenging, as standard therapies—liver-directed approaches (e.g. transarterial chemoembolization [TACE]) and systemic therapy with tebentafusp (limited to HLA-A*02:01-positivity)—offer limited efficacy, with no durable responses or significant survival benefits. Interestingly, Delcath’s recent FOCUS Phase 3 trial demonstrated the efficacy of the melphalan/Hepatic Delivery System for unresectable mUM, with an objective response rate (ORR) of 36.3%, 1-year OS of 80%, and median progression-free survival (PFS) of 9 months. Here, we present a large retrospective study of liver-predominant mUM treated with immunoembolization (IE) at a tertiary academic center. This study provides valuable data to the underreported mUM literature. We also compare our findings with Delcath’s trial to contextualize results and identify clinical factors influencing treatment response and prognosis. Methods: We retrospectively reviewed charts of mUM patients treated with IE (age ≥18 years, 2010–2023). Data collected included demographics, clinical/pathology/molecular details, and management/outcomes. Subgroup analysis on prior systemic therapy use was performed (similar to Delcath). The primary outcome was OS at 12 and 24 months. Results: 43 patients were included (100% White, 62.8% female, median age 62). Most had choroidal type (95.3%), hepatic-only metastases (90.7%), and were treatment-naïve before IE (72.1%). Across 249 IE procedures (5.8 per patient, mean duration 9.1 months), we observed median PFS and OS of 9.2 and 23 months, respectively - comparable to Delcath’s trial (9 and 20.5 months). Despite higher disease progression in our study (62.8% vs. 25.3%) and lower best clinical response (27.9% vs. 73.7%), 1-year (67% vs. 80%) and 2-year OS rates (49% vs. 43%) were similar. Subgroup analysis revealed better outcomes in previously treated patients (n = 12) compared to treatment-naïve patients (n = 31), with improved median PFS (29.9 vs. 7.2 months) and 1- and 2-year OS (75% vs. 65% and 58.3% vs. 41.9%, respectively). This contrasts with Delcath’s findings, where prior therapy did not significantly affect PFS or OS. Median PFS was comparable in treatment-naïve groups (7.2 vs. 9 months) but markedly improved in our previously treated group (29.9 vs. 9.2 months). Conclusions: We highlight IE’s comparable efficacy to Delcath’s melphalan/Hepatic Delivery System regarding mUM PFS and OS, with added benefits for previously treated patients. While our findings advance understanding of mUM management, more prospective studies are needed to improve therapeutic strategies/patient outcomes.

Objectives: Surgical site infections (SSIs) are the most common hospital-acquired infections in the United States, of which methicillin-resistant Staphylococcus aureus (MRSA) accounts for 43%. Preoperative povidone-iodine nasal swab (PNS) is considered an effective and cost-saving treatment for Staphylococcus aureus decolonization. We aim to assess the impact of preoperative PNS on SSI incidence. Materials and Methods: This retrospective observational study utilized elective surgical cases between January 1, 2018 and May 31, 2023, at a single academic medical center. The cohort was divided into PNS and no PNS groups. The cohort was propensity-matched, and Pearson χ2/Kruskal-Wallis tests were performed to compare group differences. Multivariable logistic regression was utilized to compare events between cohorts before and after matching. An alpha of <0.05 was considered significant. Results: A total of 45,998 (22,999 per group) matched participants were evaluated. On multivariate regression, the non-PNS treatment group was associated with an increase in hospital overall SSI occurrence (OR: 1.48, P = 0.02) but not specifically in-hospital methicillin-sensitive Staphylococcus aureus SSI, MRSA-SSI, or any 30-day SSI (P > 0.05). Compared with PNS treatment and prophylactic antibiotics, in-hospital SSI was higher in the absence of PNS treatment (OR: 1.83, P < 0.001), antibiotic (OR: 2.63, P < 0.001), or both (OR: 2.06, P < 0.01). Compared with PNS treatment plus prophylactic antibiotic, in-hospital MRSA-SSI was only higher in the absence of antibiotic (OR: 2.92, P < 0.01) treatment. Conclusions: Preoperative treatment with PNS may reduce overall in-hospital SSI but has no independent impact on MRSA SSI.

Abstract Rationale. Bronchoscopy can directly assess cells in airway epithelium in participants with COPD, but it is invasive, expensive, difficult to perform at scale, and contraindicated in severe disease. Blood is much more easily available but contains only a limited subset of cell types, many of which are less relevant to lung biology. Recent advances in RNA-sequencing technology have allowed for reliable measurement of transcriptomics in a wider variety of more accessible tissues, including hair follicle cells. We collected and performed bulk RNA-seq on hair follicles as an ancillary study within the NIH-funded SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and investigated their cell type composition to better understand the opportunities and limitations of this tissue for the study of lung disease. Methods. SPIROMICS recruited individuals with and without COPD aged 40-80 years with ≥ 20 pack-years smoking history. Participant at several sites underwent collection of approximately 10 hair follicles from the head, which were immediately frozen at -80ºC in 2018-21. mRNA in hair follicles was measured by bulk RNA-seq, and cell type deconvolution was performed using GEDIT v1.7 with the provided BlueCodeV1.0.tsv reference matrix. Cell types were collapsed into broader categories by summing the estimated cell type proportions. Results. The cell type deconvolution of the hair follicle bulk RNA-seq from 80 participants with and without COPD estimated that the tissue was largely composed of immune cells (median 36%, including B cells, T cells, neutrophils, macrophages, NK cells, and monocytes) and epithelial cell types (median 31%), with the largest subgroup of epithelial cell types identified as hair follicular keratinocytes (Figure 1). The next largest component was fibroblasts (median 9%), followed by endothelial cells (median 8%). Signals for myocytes (median 5%), melanocytes (median 5%), and chondrocytes (median 5%) were also present. Conclusion. This initial study demonstrated promising signals for a variety of lung-relevant cell types in hair follicles in SPIROMICS, including immune and epithelial cells in addition to fibroblasts and endothelial cells that are not otherwise easily accessible. Hair follicle gene expression profiling shows promise for understanding numerous facets of lung biology and disease that both complements and exceeds that of other noninvasive tissues such as blood.

Introduction Very early-onset inflammatory bowel disease (VEO-IBD) involves children less than 6 years of age presenting with IBD. These patients are more likely to have inborn errors of immunity. We present a child with VEO-IBD, found to have compound heterozygous variants in the DUOX2 gene that expands on the rare association of VEO-IBD with DUOX2 insufficiency. Case Description A 5-year-old male presented with six months of watery diarrhea, with labs notable for thrombocytosis, elevated CRP, and fecal calprotectin to 1430 [ref ≤ 49 μg/g]. Endoscopy and colonoscopy with biopsy revealed intraepithelial lymphocytosis in the duodenum, eosinophilic infiltrate in the stomach, esophagitis without eosinophilia, and chronic active ileitis with eosinophils of 65/hpf in the terminal ileum, consistent with a diagnosis of Crohn’s disease. The patient underwent immune phenotyping given his young age, which revealed elevated sIL2R, IL-17, IL-5, IL-13, IL-10, and IL-6, T cell lymphocytosis, and a normal neutrophil oxidative burst. Targeted genetic sequencing revealed two heterozygous variants in the DUOX2 gene: one maternally inherited likely pathogenic splice site variant, c.2922-14_2925del; and one paternally inherited variant of uncertain significance (VUS), c.1528C&gt;T (p.Arg510Trp). The VUS is within the peroxidase-like region of the gene, which plays a crucial role in enzyme function, has a high CADD score of 25, and has a GnomAD allelic frequency of only 0.001%, suggesting possible pathogenicity. The patient is currently doing well on infliximab, with interval normalization of his cytokines. Discussion The DUOX2 gene encodes for dual NADPH oxidase (DUOX), which is responsible for the release of hydrogen peroxide as part of the innate immune defense of gut epithelial cells. In mice, DUOX2 has been shown to play an integral role in maintaining immune homeostasis in the gut biome, with knockout models showing elevated IL-17C levels in the ileum. There are few reported cases describing the association of compound heterozygous variants in DUOX2 in patients with VEO-IBD, with this being the fourth patient, to the best of our knowledge. This case highlights the importance of further research to better understand the role of this gene in the development of inflammatory bowel disease. Table 1.DiagnosticsValueCytokine panelIL-2 &lt;2.1 (ref range ≤ 2.1)IL-2R 2259.3 (ref range 175.3 - 858.2)IL-12 &lt;1.9 (ref range ≤ 1.9)INF- γ &lt;4.2 (ref range ≤ 4.2)IL-4 &lt;2.2 (ref range ≤ 2.2)IL-5 19.1 (ref range ≤ 2.1)IL-10 11.1 (ref range ≤ 2.8)IL-13 2.5 (ref range ≤ 2.3)IL-17 5.5 (ref range ≤ 5.5)IL-1β &lt;6.5 (ref range ≤ 6.7)IL-6 6.3 (ref range ≤ 2.0)TNF-α 2.5 (ref range ≤ 7.2)ImmunoglobulinsIgA – 69 (ref range 21 – 144)IgE – 4680 (ref range 2 – 524)IgG – 734 (498 – 1332)IgM – 82 (ref range 31 – 63)Lymphocyte subset panelAbsolute CD3 3080 (ref range 1400 – 3700)Absolute CD4 1969 (ref range 700 – 2200)Absolute CD8 876 (ref range 490 – 1300)Absolute CD45RA 1505 (ref range 430 – 1500)Absolute CD45RO 652 (ref range 220 – 660)Absolute HLADR 660 (ref range 50 – 180)Absolute CD19 594 (ref range 390 – 1400)Absolute CD20 552 (ref range)Absolute NK 170 (ref range 130 – 720)EGD/ColonoscopyDuodenum - Intraepithelial lymphocytosisEsophagus mid and distal – esophagitis up to 2 eos/hpfEsophagus upper – esophagitis up to 1 eos/hpfChronic active ileitis with eosinophils (up to 65/hpf)Neutrophil oxidative burstNormal granulocyte dihydrohodamine fluorescence suggesting normal NADPH oxidase activityPrimary immunodeficiency panel1. DUOX2a. c.2922-14_2925del (splice site). Het. Likely pathogenic. GnomAD AC 99. CADD 31.b. c.1528C&gt;T (p.Arg510Trp). Het. VUS. GnomAD AC 3. CADD 25. Peroxidase-like region (mediates peroxidase activity).2. FOXI3a. c.713G&gt;A (p.Arg238Gln). Het. VUS. GnomAD AC 3. CADD 28.8. Associated with T cell lymphopenia. Not clinically relevant.3. MS4A1a. c.352A&gt;C (p.Ile118Leu). Het. VUS. CADD 17.01. Conflicting in silico prediction models. GnomAD AC 71. Associated with CVID. Not clinically relevant.4. POLD1a. c.520C&gt;T (p.Arg174Trp). Het. VUS. Associated with AD mandibular hypoplasia, deafness, progeroid features and lipodystrophy and AR T cell immunodeficiency. GnomAD AC 12. Not clinically relevant.

Abstract Squamous cell carcinoma (SCC) development in mammals is thought to require months or years from the time that initial changes occur. We show that SCCs induced by the mouse papillomavirus MmuPV1, which are generally diagnosed 4-6 months post infection, can be found as soon as 2 weeks post infection. SCCs developed within 2 weeks in immune-competent, adult FVB (FVB/NTac) mice at sites prone to human papillomavirus (HPV)-induced tumors and cancers in human patients: the base of the tongue, the anus, and the skin. The anterior tongue, less susceptible than the base of the tongue to HPV-induced cancer in humans, was resistant to rapid-onset cancer. The presence of invasive cancer in histological tissue sections was verified by multiple pathologists. These diagnoses were corroborated by the results of a classic test of malignancy: skin tumors obtained two weeks post infection grew ectopically as subcutaneous grafts in immune-deficient hosts. Preventative treatment with a novel BRD4 inhibitor dramatically reduced the frequency of ear skin SCCs present 2 weeks post infection and significantly reduced overall disease severity. Like many human papillomaviruses, MmuPV1 lacks an E5 gene. Expression of HPV16 E5 driven by the Keratin 14 promoter in FVB mice (FVB/NTac-Tg(KRT14-HPV16E5*)33Plam/Plam) significantly increased the frequency of rapid-onset invasive cancers caused by MmuPV1 at the base of the tongue and in the anus. In an E5-transgenic mouse with a persistent MmuPV1-induced ear skin lesion, we detected a lymph node metastasis at 38 weeks - further demonstrating a cancer phenotype. Cancers and less severe dysplasia induced by infection at the base of the tongue or the anus spontaneously regressed within 4 to 8 weeks of infection; however, ear lesions persisted. When CD4+ and CD8+ T cells were depleted, lesions at the base of the tongue and anus also persisted, indicating that spontaneous regression involves a T cell-mediated immune response. These results indicate that papillomavirus infection alone is sufficient to induce rapid onset of invasive cancer, and that persistence of disease depends on the tissue-specific immune microenvironment. Citation Format: Andrea Bilger, Ella T. Ward-Shaw, Denis L. Lee, Renee E. King, Shwu-Yuan Wu, Michael A. Newton, Cheng-Ming Chiang, Darya Buehler, Kristina Matkowskyj, John P. Sundberg, Rong Hu, Paul F. Lambert. Rapid-onset squamous cell carcinoma and spontaneous regression following papillomavirus infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7237.

Abstract Breast cancer risk assessment tools are widely used in clinical practice to guide decisions regarding screening timing and modality, lifestyle interventions, genetic testing, preventive therapy, and risk-reducing surgery. Although a number of tools designed for the general population are used in practice, they face a series of challenges including: (i) modest discriminatory ability due to lack of a unified model that flexibly incorporates a comprehensive set of risk factors; (ii) inability to produce subtype-specific risk estimates, relevant for tailoring screening and/or preventive strategies (e.g. prophylactic endocrine therapy that is effective only for hormone receptor positive tumors); (iii) lack of data from diverse populations to build models that work well for all women; and, (iv) scarcity of opportunities for comparative validation of different models. The Breast Cancer Risk Prediction Project (BCRPP), a collaboration currently including 20 prospective cohorts from the National Cancer Institute’s Cohort Consortium, is addressing these challenges by harmonizing, sharing, and analyzing data on over 1.8 million women, over 115, 000 of whom have developed breast cancer. The BCRPP is developing a comprehensive tool that will predict breast cancer risk, overall and by subtypes, across major racial and ethnic groups in the United States. This tool incorporates known and emerging risk factors (e.g. reproductive history, anthropometry, smoking, alcohol intake, medication use, mammography, family history, and measured genotypes). In parallel to model building and validation efforts, BCRPP investigators are developing privacy-preserving web and mobile interfaces to deliver the risk tools to patients and clinicians. Here we present descriptive data on participating cohorts (e.g. dates of enrollment, ages at enrollment, length of follow up, numbers of cases by subtype), summarize missing data patterns and our approach to model development and validation that accounts for heterogeneity in missingness patterns across cohorts, and describe data governance procedures and data sharing infrastructure (including pooled and federated analyses, to account for policy limitations on sharing individual data). Descriptive information and procedures for requesting and accessing data are available via the BCRPP data platform (https://epidataplatforms.cancer.gov/bcrpp/). Although originally assembled for risk model development, these data on a large and diverse sample of women with extensive harmonized risk factors and covariates can be a resource to address other outstanding questions in breast cancer epidemiology across time, the lifecourse, and diverse populations. Citation Format: Peter Kraft, Laura Beane-Freeman, Julie Palmer, Ellen O'Meara, Jeanine Genkinger, James Lacey, Thomas Rohan, Lauren Teras, Marian L. Neuhouser, Kala Visvanathan, Celine Vachon, Roger Milne, Christopher Haiman, Yu Chen, Heather Eliassen, Cari Kitahara, Katie O'Brien, Emily White, Garnet Anderson, I-Min Lee, Archie Campbell, Renee Fortner, Ylva Lagerros, Sven Sandin, Mia Gaudet, Montserrat Garcia-Closas, Nilanjan Chatterjee. The Breast Cancer Risk Prediction Project: a resource of 1.8 million women with diverse backgrounds from 20 prospective cohorts to improve breast cancer risk prediction and advance breast cancer epidemiology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3583.