Citations

ABSTRACT The TLK2 gene encodes a serine/threonine kinase essential for chromatin assembly. Loss‐of‐function heterozygous variants were recently identified as a cause of a rare neurodevelopmental disorder ( TLK2 ‐NDD) characterized by a variable spectrum of developmental delay, autism, behavioral issues, and severe constipation. We describe two unrelated young adult females presenting with neurodevelopmental delay, neurobehavioral abnormalities, and constipation since infancy secondary to truncating TLK2 variants. Case 1 is a 26‐year‐old female who was referred to our clinic for extended assessment of new‐onset psychosis and concern for seizures. She has been diagnosed with autism spectrum disorder and has a history of developmental delay, constipation, and aggressive outbursts since early childhood. At the age of 24 years, she developed an acute onset of persistent daily auditory hallucinations with threatening content that was refractory to medical and electroconvulsive therapy. Video‐ EEG assessment found no correlates for hallucinations. Trio whole genome sequencing revealed a heterozygous de novo pathogenic TLK2 variant, NM_006852.6:c. 367C >T (p. Arg123Ter ). Case 2 is a 19‐year‐old female who was evaluated for developmental delay and intellectual disability. Her phenotype was also notable for constipation since infancy and suggestive hypothalamic features with obesity, metrorrhagia, and hypersomnia. Trio whole genome sequencing revealed a likely pathogenic heterozygous TLK2 variant NM_006852.6:c.587del(p.Ser196ThrfsTer19) inherited from an asymptomatic, mosaic father. We present the adult phenotype of two young females with truncating variants in TLK2 and unusual phenotypic features of refractory hallucinations and possible hypothalamic syndrome. While both features may be independent of TLK2 ‐NDD, evidence from schizophrenia genome‐wide association studies and tissue expression data indicates that these features might be a part of longitudinal phenotype development. Long‐term follow‐up studies are required to unfold the phenotypic spectrum of TLK2 ‐NDD and to better understand the implications of these findings for management and prognosis.

Abstract Background: Pediatric and AYA sarcomas are rare, biologically heterogeneous tumors with limited noninvasive biomarkers to guide diagnosis, personalized treatment, and disease monitoring. Standard-of-care evaluation relies on invasive biopsies that carry procedural risks and imaging modalities with limited sensitivity for detecting minimal residual disease and distinguishing tumor types. Cell-free DNA (cfDNA) methylation profiling offers a minimally invasive alternative capable of capturing tumor-derived epigenomic alterations and has consistently shown strong clinical utility in adult malignancies. However, genome-wide cfDNA methylation patterns across diverse pediatric and AYA sarcoma subtypes remain poorly defined. Methods: Plasma was collected from 93 pediatric and AYA patients (pediatric <18 years; AYA 15-39 years) representing 27 Ewing sarcoma, 17 rhabdomyosarcoma, 11 liposarcoma, 10 chordoma, 8 synovial sarcoma, 7 chondrosarcoma, 6 osteosarcoma, and 6 fibrosarcoma cases, plus 19 matched healthy donors. cfDNA was isolated from 1 mL plasma, quantified by Qubit, and assessed by Bioanalyzer. Libraries were prepared using the NEBNext EM-seq v2 workflow with PCR cycles scaled to cfDNA input amount. Genome-wide sequencing (15× target depth) was followed by alignment, deduplication, and methylation calling. MultiQC was used to assess depth, duplication rate, conversion efficiency, and CpG coverage. Global methylation summaries were computed, and methylKit was used to generate per-CpG and 1-kb tiling matrices and initiate differential methylation analyses. Results: Ewing sarcoma patients had significantly higher plasma cfDNA concentrations than age- and sex-matched healthy donors (24.4 vs 4.6 ng/mL, p < 0.0001), whereas cfDNA levels for other sarcoma subtypes overlapped with the healthy cohort. Low or undetectable cfDNA concentrations by Qubit were far more common among non-Ewing sarcoma samples (23 of 66) than Ewing sarcoma (1 of 27). All samples achieved sufficient CpG coverage for genome-wide methylation modeling. Global methylation summaries revealed no significant differences in mean β-values across sarcoma subtypes or versus healthy donors. An independent analysis of the Ewing subset identified 299 significant differentially methylated regions (DMRs), supporting the detectability of disease-specific methylation changes. Conclusions: These results demonstrate the feasibility of high-quality cfDNA methylome profiling across a large and diverse pediatric and AYA sarcoma cohort, including in plasma samples with cfDNA concentrations below the limit of detection. While global methylation levels appear broadly similar across subtypes, proof-of-concept DMR analysis in Ewing sarcoma suggests that subtype-specific epigenomic signatures could enable future noninvasive diagnostic tools for pediatric and AYA sarcomas. Citation Format: Lilli J. Greiner, Roman O. Kowalchuk, Jeff Szymanski, Pradeep S. Chauhan, Adam Amundson, Peter J. Schoettler, Wendy Allen-Rhoades, Stephanie F. Polites, Peter S. Rose, Kelly Bailey, Linda McAllister-Lucas, Anita Mahajan, Nadia Laack, Aadel Chaudhuri. Defining genome-wide cfDNA methylation landscapes in pediatric and adolescent and young adult (AYA) bone and soft-tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7885.

Abstract BACKGROUND: Tumor-specific T cells are often characterized by reduced TCR signaling due to central and peripheral tolerance pathways that limit their responsiveness. These signals are further weakened by insufficient co-stimulation and active co-inhibitory pathways, collectively establishing a high threshold for activation. The integration of antigen recognition with co-stimulatory and inhibitory cues ultimately determines whether a T cell becomes activated or remains tolerant. Early TCR signaling must therefore be precisely regulated to prevent autoreactivity while still supporting protective immunity. Although phosphorylation and ubiquitination are well-established regulators of proximal TCR signaling, additional post-translational mechanisms remain less defined. SIRT2, a cytosolic NAD+-dependent deacetylase with emerging roles in immune regulation, has not been examined in the context of TCR signaling. METHODS: We evaluated proximal TCR signaling events in wild-type and SIRT2-deficient T cells using flow cytometry, immunoblotting, calcium flux assays, and RNA-sequencing. SIRT2-associated pathways were defined by mapping its interactome and acetylated substrates through mass spectrometry and immunoprecipitation. We screened LCK post-translational modifications by mass spectrometry and assessed SIRT2 enzymatic activity using an HPLC-based deacetylase assay. Conformational effects of LCK modification were examined using fluorescence-polarization binding assays and AlphaFold structural modeling. SIRT2 was deleted in human tumor infiltrating lymphocytes (TILs) via CRISPR/Cas9, and the impact of SIRT2 targeting was tested in lung cancer patient-derived xenograft models reconstituted with autologous TILs. RESULTS: SIRT2 deficiency amplified proximal TCR signaling, leading to elevated phosphorylation of early signaling mediators and increased calcium flux in both naïve and anergic T cells. Loss of SIRT2 also altered thymic selection dynamics and expanded TCR repertoire diversity. Mechanistically, SIRT2 interacted with and deacetylated LCK, the initiating kinase of proximal TCR signaling. Mass spectrometry identified lysine K228 in the LCK linker region as a SIRT2-regulated deacetylation site that governs LCK conformation and kinase activity. Functionally, SIRT2 inhibition in exhausted mouse and human TILs restored TCR signaling capacity and improved anti-tumor responses. CONCLUSION: Here we identify SIRT2-regulated deacetylation of LCK as a previously unrecognized mechanism that sets the strength and threshold of proximal TCR signaling. Accordingly, SIRT2 targeting reverses the exhausted phenotype of tumor-reactive T cells. Citation Format: Imene Hamaidi, Pingyan Cheng, Soo Young Jun, Min-Hsuan Wang, Min Zhang, Odesha Taylor, Luis Lopez-bailon, Ismail Can, Bin Fang, Anders Berglund, Bradford Perez, Ben Creelan, Andriy Marusyk, Virginia Shapiro, Haitao Ji, Jose R. Conejo-Garcia, Sungjune Kim. Sirt2 dictates TCR activation thresholds through post-translational control of LCK conformational state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4250.

Abstract Background: Tumor angiogenesis drives treatment resistance by fostering an immunosuppressive microenvironment. VEGF inhibitors (VEGFi) target the vasculature, while immune checkpoint inhibitors (ICI) do not address this mechanism directly. Quantitative Vessel Tortuosity (QVT) Score is a radiomic biomarker of vascularity previously shown to be associated with ICI response. Here, we introduce QVT Subscore, an interpretable panel that isolates distinct vascular attributes (e.g., branching, curvature, radius), enabling treatment-specific insight into vascularity MoA and vascular normalization. Methods: QVT Subscores are derived by grouping the 910 QVT features comprising QVT Score into six biological categories, summarized by principal component analysis. The panel was evaluated in 557 patients from the phase 3 SWOG S0819 trial and a real-world ICI monotherapy cohort (n=147). QVT score/subscore changes from baseline to first on-treatment CTs were assessed by paired t-test and substratified by objective response (OR). Results: While the mono-chemotherapy showed no vascularity changes, VEGFi regimens reduced QVT Score, with Branch and Curvature Subscores decreasing significantly but Vessel Volume unchanged. In contrast, ICI recipients exhibited significant increases in QVT Score and 5/6 Subscores, showing opposite changes to VEGFi in four subscores and differing effects on vessel Radius and Volume. VEGFi produced the greatest vascularity decrease in patients achieving OR, with milder decreases in non-OR. For ICI, OR showed negligible QVT change, while vascularity significantly increased in non-OR across all subscores except Radius. Conclusions: The QVT Subscore panel captures granular tumor vascular remodeling from different treatments, providing mechanistically grounded insights into clinical trial arm performance. Future work will assess the panel’s potential for identifying regimens that benefit from adding VEGFi. Citation Format: Haojia Li, Pushkar Mutha, Young Kwang Chae, Kai Zhang, Liam Il-Young Chung, Amogh Hiremath, Rhea Chitalia, Justin Yau, Omid Haji-Maghsoudi, Trishan Arul, Vamsidhar Velcheti, Anant Madabhushi, Nathaniel Braman. QVT Subscore: An interpretable radiomic panel of tumor vascularity reveals treatment-specific mechanisms-of-action (MoA) in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3751.

Abstract Background: Prostate cancer (CaP) is among the most common cancers in U.S. men, with Black men experiencing a 1.7-fold higher incidence and nearly twice the mortality rate compared with non-Hispanic White men. While early detection has improved survival, differences remain in recovery and quality of life (QoL). Sexual dysfunction after treatment affects identity, relationships, and well-being, yet stigma, cultural norms, and limited access to patient-centered care prevent open discussion. Few initiatives address the intersection of identity, stigma, and survivorship in this population. Community town halls provide a trusted, culturally responsive space for shared learning, peer connection, and open dialogue on survivorship and sexual health. Methods: Two community-engaged CaP town halls were convened by the Multidisciplinary Health Outcomes Research and Economics (MORE) Lab at the University of Oklahoma Health Campus (OUHC) to explore survivorship issues among Black CaP survivors. The first, held virtually in June 2024, included watch parties in Georgia and Texas. The second, in November 2024, was hybrid, hosted at OUHC and via Teams with a watch party at the Willa D. Johnson Recreation Center, a community center in Oklahoma City. Panelists included oncologists, psychologists, survivors, partners, and Community Advisory Board members. Both town halls featured survivor storytelling, provider Q&A, and interactive discussion. Post-event surveys captured demographics, satisfaction, and impact. Open-discussion transcripts were analyzed using Braun and Clarke’s reflexive thematic analysis, guided by a constructivist framework. Results: A total of 124 participants attended both town halls. Survey respondents (n=17; 13.7%) provided demographic and satisfaction data; remaining insights came from all participants who engaged in open dialogue. Respondents ranged in age from 19-76 years (mean=48.7 ± 21.8). Of the 17 respondents, 93% rated the events as very good or excellent; 23.5% were CaP survivors, all identifying as Black. Five themes emerged: (1) Masculinity, stigma, and silence limit help-seeking; (2) Sexual dysfunction and identity loss cause major emotional burdens; (3) Navigation challenges highlight systemic barriers; (4) Spousal and psychological support aid coping; and (5) Survivorship empowerment. Participants valued hearing “real stories from real men,” validating their experiences. Conclusions: Community town halls are a feasible and culturally relevant strategy to engage Black CaP survivors in survivorship and sexual health discussions. By centering lived experiences and facilitating two-way communication between survivors, clinicians, and researchers, these events build trust and reduce stigma. Future work will assess changes in knowledge, engagement, and confidence in care navigation and explore scaling this community-academic model to improve survivorship QoL. Citation Format: Parisa Ghasemi, Gaurav Kumar, Ernest T. Kaninjing, Adanma Ayanambakkam, Yaw A. Nyame, Amy Siston, Jordan M. Neil, Adam C. Alexander, Andrew G. McIntosh, Yan Zhao, Zsolt Nagykaldi, Kathleen A. Dwyer, Mary Ellen Young, Sabrina Dickey, Daniel Morton, Opeyemi Bolajoko, Darla E. Kendzor, Motolani E. Ogunsanya. Survivorship and sexual health: What we learned from Black men in community town halls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2483.

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma. Previous studies have shown that DLBCL cells are susceptible to GPX4 (Glutathione peroxidase 4)-regulated ferroptosis, an iron-dependent type of programmed cell death characterized by increased reactive oxygen species and excessive lipid peroxidation. In addition to GPX4, FSP1 (Ferroptosis suppressor protein 1, previously known as AIFM2) is a glutathione-independent repressor of ferroptosis that has shown prognostic significance in solid tumors. In this study, we aimed to reveal the significance of GPX4 and FSP1 in DLBCL. Patients and Methods: We performed immunohistochemistry (IHC) for GPX4 and FSP1 in a large cohorts of patients with de novo DLBCL, and evaluated their cytoplasmic and nuclear expression. Prognostic analysis was performed for FSP1 and GPX4 expression in patients treated with rituximab (R)-CHOP or CHOP chemotherapy, respective of TP53 mutation status, as p53 regulates ferroptosis and TP53 mutation is associated with poorer prognosis in DLBCL. Results: FSP1 expression with a ≥10% cutoff was positive in 42.3% of DLBCL cases. Patients with TP53 mutations had a non-significant trend of higher mean FSP1 expression than those with wild-type (Wt) TP53 (P=0.11). Prognostic analysis revealed that cytoplasmic FSP1+ expression was associated with significantly poorer overall survival and progression-free survival in Wt-TP53 DLBCLs treated with R-CHOP (P=0.016 and P=0.003, respectively), and only showed non-significant unfavorable trends in TP53 mutated DLBCLs and patients treated with CHOP. In contrast, GPX4 expression did not show a significant unfavorable prognostic effect in DLBCL, and in fact, was associated with a non-significant trend of better survival. Previously we have quantified immune cell abundance and PD-1/PD-L1 expression in the tumor microenvironment of the study cohort using multiplex fluorescent IHC. Correlative analysis found that FSP1+ patients had significantly higher mean and median abundance of CD68+ cells (both M1 and M2 macrophages) and CD11c+ cells than FSP1- patients. Further analysis in Wt-TP53 and mutated TP53 subcohorts found that only in the TP53 mutated DLBCL subcohort, FSP1 expression was associated with significantly higher mean and median CD163-CD68+ (M1) and overall CD68+ macrophages, whereas in the Wt-TP53 DLBCL subcohort, FSP1 expression was associated with significantly higher median (but not mean) CD163+CD68+ (M2) macrophages and CD11c+ cells. Summary: Cytoplasmic FSP1 expression but not GPX4 had significantly adverse prognostic effect in patients with Wt-TP53 DLBCL treated with standard immunochemotherapy. Our results also suggest that in addition to ferroptosis regulation, macrophage abundance was relevant for the prognostic effects of FSP1 expression. Citation Format: Beibei Lyu, Zijun Xu-Monette, Xiaoxian X. Zhao, Eric D. Hsi, Ming Chen, Carlo Visco, Alexandar Tzankov, Karen Dybkaer, Mu-En Wang, Chang Wang, Qingyan Au, Harry Nunns, Zenggang Pan, Benjamin Parsons, Santiago Montes-Moreno, Fenghuang Zhan, Michael B. Møller, Leon Bernal-Mizrachi, Youli Zu, Shanxiang Zhang, Weina Chen, Govind Bhagat, Yong Li, KEN H. YOUNG. Expression of the ferroptosis suppressor FSP1 but not GPX4 shows significant adverse prognostic effect in diffuse large B-cell lymphoma with wild-type TP53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4661.

Abstract Introduction: The National Cancer Institute estimated almost 317,000 new breast cancer and over 13,000 new cervical cancer cases in 2025. While the National Breast and Cervical Cancer Early Detection Program has served millions of women over the past two decades, inequities in cancer screening, subsequently delayed diagnosis, and timely and appropriate treatment remain a public health challenge in the United States. Despite the substantial impact of social determinants of health (SDOH) on cancer screening, few studies have accounted for SDOH at the individual level when assessing breast and cervical cancer screening adherence. The primary objective of this study is to examine whether the individual-level SDOH, measured using HOUsing-based SocioEconomic Status (HOUSES) index, is associated with breast and cervical cancer screening non-adherence (not current on respective USPSTF recommendations for age and frequency). Methods: In this retrospective study, patients were identified as those receiving primary care in the Mayo Clinic Health System and Mayo Clinic (Rochester, MN). The Midwest Quality Metrics panel was then used to assess patients due for screening for breast or cervical cancer in July 2023. The HOUSES, using home address and publicly available data on the residence which measures and categorizes housing status into quartiles, was obtained using the electronic health records (EHRs)-linkable patient-level information. Logistic regression analyses were conducted, controlling for Census block group-level adverse social exposome from the Area Deprivation Index, age, and comorbidities. Results are presented as odds ratios (OR) with corresponding 95% confidence intervals (CI). Results: For breast cancer, among 128,462 eligible patients, 20.1% (n= 25,857) were non-adherent. Compared to the highest HOUSES quartile (Q4), lower HOUSES groups showed significantly higher odds of non-adherence: Q3 OR=1.20 (95% CI=1.15, 1.25), Q2 OR=1.45; (95% CI=1.40, 1.53), and Q1 OR=1.90 (95% CI=1.81, 1.99). For cervical cancer, among 175,712 eligible patients, 29.9% (n=52,533) were non-adherent. Compared to the highest HOUSES quartile (Q4), lower HOUSES groups showed significantly higher odds of non-adherence: Q3 OR=1.07 (95% CI=1.03, 1.10), Q2 OR=1.16; (95% CI=1.12, 1.20), and Q1 OR=1.36 (95% CI=1.31, 1.41). Conclusions: A clinically meaningful association between the HOUSES index and cancer screening adherence was observed. A lower HOUSES index was associated with higher odds of non-adherence for both breast and cervical cancer screening, even after accounting for neighborhood-level risk, age, and comorbidities. Incorporating HOUSES into EHRs can be a practical “screening-for-screening” tool that enables close monitoring of higher-risk patients without additional burden of surveys. Citation Format: Eunice Y. Park, Madison Beenken, Dave Watson, Chung Il Wi, Tufia Haddad, Gladys Asiedu, Karla BALLMAN, James R. Cerhan, Carolyn Flock, Brian Lynch, Folakemi T. Odedina, Scott H. Okuno, Young J Juhn, . HOUSES as a screening tool for cancer screening: Patient-level housing-based socioeconomic status and breast and cervical cancer screening adherence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7599.

Abstract Background: Cancer survivorship requires significant contributions from family caregivers at home. This role can be burdensome because family members play a vital role in the physical, functional, and emotional well-being of patients diagnosed with cancer. Although optimum care throughout the care continuum requires significant caregiver support at home, family caregivers' contribution to survivorship care is usually neglected. We provide the preliminary outcomes of caregivers' challenges and experiences in providing care and survivorship support to Black cancer survivors. We also identified ways to provide support for family caregivers. Methods: This qualitative study obtained information from 8 caregivers who care for Black cancer survivors who have completed treatment in the United States. The study used a phenomenological design to obtain data from participants. In-depth interviews focused on participants' lived experiences caring for Black patients with cancer. The study captured caregivers' personal stories of how they dealt with diagnosis, feelings, emotions, reactions, understanding of the disease, prognosis, and treatment options and decision process, as well as survivorship of their care recipients. All interviews were video recorded and transcribed verbatim. The transcript of each participant's interview was reviewed, analyzed, and coded, with emerging themes interpreted. Results: The major cahllenges identified were (1) lack of knowledge of cancer, the disease and treatment course before the diagnoses; (2) home care burden, which include the challenges of combining care for a sick person at home with caring for other members of the family and taking care of domestic chores; (3) patient care navigation, including identifying healthcare professional for specialist care, adequate health insurances, scheduling doctors' appointment, transportation, insurance and treatment paperwork; (4) financial challenges, especially keeping up with job, family income reduction, increase out of pocket spendings, as well as expensive drugs and treatment co-pays. Most of the caregivers agreed that they neglected their personal health while caring for their care recipient. All caregivers wished they received more information and training on how to care for a patient with cancer. Possible solutions identified were care packets providing information on cancer and how to provide care at home, patient care navigation to social determinants of health and financial support programs, counselling for mental health and emotional support, peer support groups for caregivers, health checks, and a contact to call for support. Conclusion: Caring for cancer patients at home is very challenging; having a care packet and caregiving training is important to support survivorship and reduce the caregiving burden experienced by family caregivers. Citation Format: Opeyemi Oreoluwa Bolajoko, Jada Melton, Mary Ellen Young, Folakemi T. Odedina. Perspectives on cancer survivorship: Voices of family caregivers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1248.

ABSTRACT Background Rhabdomyosarcoma is the most common soft tissue sarcoma in pediatrics and infants are reported to have inferior outcomes. ARST1431 recommended delayed primary excision (DPE) while discouraging radiation (RT) deviations. This analysis compared outcomes among very young and older patients in this study. Procedures Demographic and tumor characteristics were summarized using frequencies and percentages. Local failure (LF) frequency was summarized by age group, RT, and DPE status. Event‐free survival (EFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared between age groups using the log‐rank test. Results Of 296 patients, 48 (16.2%) were <24 months: 14 (4.7%) < 12 months, 34 (11.5%) 12–24 months–compared with 248 (83.8%) ≥24 months. DPE was performed in: 7 (50%), <12 months; 9 (26%), 12–24 months; 56 (22%), ≥24 months. RT was given to 9 (64%), 27 (79%), and 195 (79%) of <12, 12–24, and >24 months, respectively. LF in DPE+RT was 8.3% and 6.1%, < 24 months and ≥ 24 months, respectively, compared to 29.3% and 20.5% for RT without DPE. The 4‐year EFS did not vary: 56% (95% CI = 26.5, 86.0), 68% (95% CI = 51.2, 84.1), and 61% (95% CI = 54.2, 68.3) <12, 12–24, and >24 months old, respectively. Conclusions Outcomes in younger children are comparable to older children with local failure more common in those without DPE. Optimization of local control will be important for future studies. Trial Registration Number NCT02567435

Objective: This study aimed to examine whether parent–child interaction therapy (PCIT), compared with other therapy modalities, was associated with differences in substance use and psychiatric outcomes in a cohort of children with attention-deficit/hyperactivity disorder (ADHD). Methods: This retrospective cohort study was conducted using medical record data from the Rochester Epidemiology Project (REP). The sample included 643 children aged ≤7 years who were diagnosed with ADHD and received either stimulant or nonstimulant medication, along with psychosocial therapy. Participants were categorized into two groups: those who documented exposure to PCIT versus other therapy modalities such as behavioral management, play therapy, cognitive behavioral therapy, parent management training, occupational therapy, speech therapy, parenting class, applied behavior analysis, and social skills training. Conditional logistic regression models were used to examine differences in baseline characteristics and outcomes between the two treatment groups. Results: Individuals in the PCIT group were more likely to have private insurance (66% vs. 57%; p = 0.016) and to fall into higher socioeconomic status quartiles ( p = 0.024) at baseline. PCIT recipients also had a higher prevalence of emotional and behavioral disturbances at baseline (40% vs. 25%; p < 0.001). The median age of the participants at follow-up was 19.6 years, indicating a median follow-up period of approximately 13 years from the initiation of treatment. At follow-up, the PCIT group demonstrated higher rates of problematic alcohol (24% vs. 17%; HR = 1.50, 95% CI: [1.02, 2.20]; p = 0.038) and cannabis use (25% vs. 18%; HR = 1.48, 95% CI: [1.03, 2.15]; p = 0.037). However, after controlling for covariates in the adjusted model, no statistically significant differences emerged between the groups across any substance use outcome. No significant differences were observed in other psychiatric diagnoses or mental health service utilization. Conclusions: Findings indicate that individuals who documented exposure to PCIT demonstrated elevated rates of alcohol and cannabis use in young adulthood, but had no other differences in psychiatric outcomes. While this aligns with prior literature reporting increased substance use risk in ADHD populations, our study cannot confirm this association relative to non-ADHD controls because such a comparison was not included. These associations likely reflect underlying differences in clinical severity and clinical comorbidities at baseline, rather than a direct effect of PCIT. Further investigation is warranted to determine the treatment effects based on baseline risk factors.