Citations

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

Abstract The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN, MAPT) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. ‘Hub’ proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

Abstract Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and 52%/38%, respectively. The median progression-free and overall survival estimates for the same treatment groups were 4.9/14.3 months, 14.9 months/not reached, and 3.3/9 months, respectively. CLL with del(17p) was associated with a lower complete response rate in the total cohort (odds ratio [OR] 0.15; 95% confidence interval [CI] 0.04-0.6; p=0.01) and venetoclax-naïve subgroup (OR 0.13; 95%CI 0.02-0.66; p=0.01). TP53 mutated CLL was associated with a lower complete response rate (OR 0.15; 95%CI 0.03-0.74; p=0.02) and shorter progression-free survival (hazard ratio 3.1; 95%CI 1.21-7.95; p=0.02) only in venetoclax-naïve subgroup. No other clinical or baseline characteristics, including prior venetoclax treatment for CLL, showed statistically significant association with outcomes. Grade 3-4 neutropenia and thrombocytopenia events were most frequent with intensive chemoimmunotherapy + venetoclax; grade 3-4 infection rates were similar across treatment groups. In this difficult-to-treat RT patient population, venetoclax-based combination regimens achieved high response rates, with durable remission and survival observed in a subset of patients.

AbstractINTRODUCTIONGlial fibrillary acidic protein (GFAP) in plasma is a proxy for astrocytic activity and is elevated in amyloid‐β (Aβ)‐positive individuals, making GFAP a potential blood‐based biomarker for Alzheimer's disease (AD).METHODSWe assessed plasma GFAP in 72 Aβ‐positive participants diagnosed with the visual or language variant of AD who underwent Aβ‐ and tau‐PET. Fifty‐nine participants had follow‐up imaging. Linear regression was applied on GFAP and imaging quantities.RESULTSGFAP did not correlate with Aβ‐ or tau‐PET cross‐sectionally. There was a limited positive correlation between GFAP and rates of tau accumulation, particularly in the language variant of AD, although associations were weaker after removing one outlier patient with the highest GFAP level.DISCUSSIONAmong Aβ‐positive AD participants with atypical presentations, plasma GFAP did not correlate with levels of AD pathology on PET, suggesting that the associations between GFAP and AD pathology might plateau during the advanced phase of the disease.

The use of blue light cystoscopy (BLC) has been shown to improve bladder tumor detection. However, data demonstrating the efficacy of BLC across different races are limited. Herein, we aim to evaluate heterogeneity in the characteristics of BLC for the detection of malignant lesions among various races. Clinicopathologic information was collected from patients enrolled in the multi-institutional Cysview® registry (2014–2021) who underwent transurethral resection or biopsy of bladder tumors. Outcome variables included sensitivity and negative and positive predictive values of BLC and white light cystoscopy (WLC) for the detection of malignant lesions among various races. Overall, 2379 separate lesions/tumors were identified from 1292 patients, of whom 1095 (85%) were Caucasian, 96 (7%) were African American, 51 (4%) were Asian, and 50 (4%) were Hispanic. The sensitivity of BLC was higher than that of WLC in the total cohort, as well as in the Caucasian and Asian subgroups. The addition of BLC to WLC increased the detection rate by 10% for any malignant lesion in the total cohort, with the greatest increase in Asian patients (18%). Additionally, the positive predictive value of BLC was highest in Asian patients (94%), while Hispanic patients had the highest negative predictive value (86%). Our study showed that regardless of race, BLC increases the detection of bladder cancer when combined with WLC.

Abstract While chimeric antigen receptor T (CART) cell therapy has shown remarkable success, the development of exhaustion limits durable response. We identified a role for interleukin (IL)-4 in the development of CART cell exhaustion through three independent approaches including: 1) a genome-wide CRISPR knockout screen using healthy donor CART cells in an in vitro model for exhaustion, 2) RNA and ATAC sequencing on freshly produced and chronically stimulated healthy donor CART cells, and 3) RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the Zuma-1 clinical trial that led to the FDA approval of axi-cel. Further, in vitro validation studies revealed that CD19 directed CART (CART19) cells chronically stimulated in the presence of human recombinant IL-4 (hrIL-4) displayed signs of exhaustion such as 1) decreased proliferation (p = 0.01), 2) increased coexpression of inhibitory receptors (p = 0.01), and 3) decreased production of IL-2 and interferon (IFN)-γ (p= 0.02, p = 0.002). Encouragingly, CART19 cells combined with an IL-4 monoclonal antibody improved antitumor activity (p = 0.045) and expansion (p = 0.01) while also decreasing the co-expression of inhibitory receptors (p = 0.02) in a mantle cell lymphoma xenograft mouse model. Building on these results, we asked if IL-4 driven exhaustion results from a direct impact of IL-4 on CART cells. To test this, we used a tumor-free assay where CART19 cells were chronically stimulated with CD19 beads in the presence of hrIL-4 or diluent. CART cells treated with hrIL-4 displayed an exhausted phenotype characterized by increased co-expression of inhibitory receptors (p = 0.04) and decreased production of IL-2 (p = 0.01). Next, we asked if IL-4 driven CART cell exhaustion is dependent on the costimulatory domain. We tested the impact of IL-4 on both CD28ζ and 41BBζ costimulated CART19 cells. Similar to our previous studies with CART19-28ζ cells, chronic stimulation of CART19-BBζ cells in the presence of hrIL-4 enhanced the exhausted phenotype as seen by increased co-expression of inhibitory receptors (p = 0.04) and decreased production of IL-2 and IFN-γ (p = 0.08 and p = 0.007). Finally, we asked if IL-4 induces exhaustion independently of its classic role in Th2 polarization of CD4 CART cells. Following CART production, we isolated CD8 cells and chronically stimulated them in the presence of hrIL-4 or diluent. CD8 CART cells treated with hrIL-4 displayed an enhanced exhausted profile as seen by 1) decreased proliferative ability (p &lt; 0.0001), 2) increased co-expression of inhibitory receptors (p = 0.01), and 3) decreased production of IL-2 and IFN-γ (p &lt; 0.0001, p = 0.004). Together, our data indicates a novel role for IL-4 in the development of CART cell exhaustion that is independent of tumor cells, costimulatory domain, and CD4 cells. As such, we believe IL-4 neutralization may be a widely applicable and actionable approach to improve the durable response to CART cell therapy. Citation Format: Carli M. Stewart, Elizabeth L. Siegler, Truc N. Huynh, R. Leo Sakemura, Brooke Kimball, Long Mai, Kun Yun, James H. Girsch, Jennifer Feigin, Omar Gutierrez Ruiz, Makena Rodriguez, Ekene Ogbodo, Ismail Can, Claudia Manriquez Roman, Olivia Sirpilla, Hong Xia, Jenny Kim, Justin Budka, Mike Mattie, Nathalie Scholler, Simone Filosto, Saad S. Kenderian. IL-4 drives CART cell exhaustion in a CD4 independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 37.

Abstract Antibody-drug conjugates (ADCs) are increasingly being used in clinic, and many novel ADCs are being tested in clinical trials. Most ADCs act by delivering cytotoxic payloads into target cells. The activity of most ADCs is predicated upon internalization to release the cytotoxic payloads intracellularly to act on the malignant cells. The degree of ADC internalization is incomplete or absent for many cell surface targets, limiting the activity of ADCs. PROTACs are heterobifunctional molecules that result in the polyubiquitylation of their targets by inducing proximity with E3 ligases. The proteasome then recognizes the poly-ubiquitin chains and degrades these targets. We hypothesized that PROTACs that act on the same targets as ADCs could improve the internalization and efficacy of these ADCs. Using multiple cell lines derived from breast, lung or pancreatic cancers that express the oncogenic cell surface proteins EGFR (ERBB1), HER2 (ERBB2) or MET (HGF), we measured antibody internalization with live cell imaging. Antibodies were labeled with a pH sensitive reagent that fluoresces red (640 nm) upon exposure to acidic environments. Fluorescence was measured over time to create an area under the curve which was compared between the cell lines that were treated with and without PROTACs. Antibody internalization was observed in all cell lines that expressed the targets recognized by the antibodies. The addition of PROTACs targeting the same oncogenic cell surface proteins as the antibodies significantly increased antibody internalization beyond that observed without PROTACs. Internalization of antibodies was confirmed by measuring intracellular immunoglobulins by Western blot. Antibody internalization with PROTACs was dose-dependent, increased over time and was blocked by either the clatharin inhibitor Dyngo4a or the proteasome inhibitor MG132. In the case of HER2 for which there are FDA-approved anti-HER2 ADCs, the cytotoxicity of trastuzumab emtansine (TDM1) significantly increased with the addition of a HER2-targeting PROTAC across a range of doses. PROTACs that target the same oncogenic cell surface proteins as antibodies improve antibody internalization and ADC cytotoxicity, in a process dependent upon clatharin and the proteasome. This novel application of PROTACs may impact the use of ADCs, and provides a rationale to combine these agents in clinical trials. Citation Format: Ezequiel J. Tolosa, Lin Yang, Jennifer Ayers-Ringler, Jayapal Mallareddy, Janet Schaefer-Klein, Farhad Kosari, Amar Natarajan, Aaron S. Mansfield. Proteolysis targeting chimera (PROTAC)-driven internalization of antibodies targeting oncogenic cell surface receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4518.