Citations

AbstractBackgroundNutritional status in pediatric patients undergoing heart transplantation (HT) is frequently a focus of clinical management and requires high resource utilization. Pre‐operative nutrition status has been shown to affect post‐operative mortality but no studies have been performed to assess how nutritional status may change and the risk of developing nutritional comorbidities long‐term in the post‐transplant period.MethodsA single‐center retrospective chart review of patients ≥2 years of age who underwent heart transplantation between 1/1/2005 and 4/30/2020 was performed. Patient data were collected at listing, time of transplant, 1‐year, and 3‐year follow‐up post‐transplant. Nutrition status was classified based on body mass index (BMI) percentile in the primary analysis. Alternative nutritional indices, namely the nutrition risk index (NRI), prognostic nutrition index (PNI), and BMI z‐score, were utilized in secondary analyses.ResultsOf the 63 patients included, the proportion of patients with overweight/obese status increased from 21% at listing to 41% at 3‐year follow‐up. No underweight patients at listing became overweight/obese at follow‐up. Of patients who were overweight/obese at listing, 88% maintained that status at 3‐year follow‐up. Overweight/obese status at listing, 1‐year, and 3‐year post‐transplantation were significantly associated with developing metabolic syndrome. In comparison to the alternative nutritional indices, BMI percentile best predicted post‐transplant metabolic syndrome.ConclusionsThe results suggest that pediatric patients who undergo heart transplantation are at risk of developing overweight/obesity and related nutritional sequelae (ie, metabolic syndrome). Improved surveillance and interventions targeted toward overweight/obese HT patients should be investigated to reduce the burden of associated comorbidities.

Abstract Background The current definition, prognosis, and optimal treatment (tx) for oligometastatic breast cancer (OMBC) are not fully known. With advances in multimodality breast cancer (BC) tx and overall improvement in patient (pt) outcomes, it is important to identify baseline pt factors that confer better prognosis in OMBC and assess the impact of local/regional tx and metastasis (mets)-directed tx on survival outcomes. Methods We reviewed 105 Mayo Clinic pts with OMBC (up to 5 mets) from 2003 to 2021. Pts were excluded from analysis if they were misidentified as having OMBC (n=6), did not have a primary breast mass (n=1), developed de novo BC during tx (n=1), or were lost to follow up (n=2). Categorical variables were summarized as counts. Continuous variables were reported as medians. Kaplan-Meier method was used to estimate survival and the time from diagnosis to next tx at 1, 3, and 5 years. Log-rank test was used to compare survival rates between baseline factors. Univariate Cox proportional hazards models were performed on both baseline and time-dependent factors. All tests were two-sided with p-value < 0.05 considered statistically significant. Results Total pts included were 95. Median age was 49 (range, 26-86), most (93.6%) pts were White, and 46.8% were postmenopausal. Invasive ductal carcinoma (89.5%) was the most common BC type. Median survival was 10.8 years; 1-, 3-, and 5-year survival rates were 98.9%, 87.7%, and 81%, respectively. 58 pts (61.1%) required a change in tx due to disease progression. No significant survival difference was observed in pre- vs. postmenopausal pts (p=0.71) or in groups based on hormone receptor and/or human epidermal growth factor receptor 2 status. 47 pts (49.5%) received local/regional tx; no significant difference in survival (HR 0.57, 95% CI 0.23-1.40; p=0.217) or time to next tx (HR 0.67, 95% CI 0.39-1.15; p=0.144) was seen in this subgroup. Of these pts, 36 (76.6%) received neoadjuvant chemotherapy and/or immunotherapy, 5 of whom (10.6%) also started endocrine tx preoperatively. Overall, 11/47 pts (23.4%) received neoadjuvant endocrine tx. 20 pts received systemic tx without eventual surgery, and 5 pts got palliative radiation (RT). Biopsy-confirmed mets were noted in 76 pts (80%), with bone-only mets in 50%, 30 pts (31.6%) with viscera-only mets and 7 pts (7.4%) with both bone and visceral mets. 18 pts had suspected mets on imaging but did not undergo biopsy. The hazard of death was 6.34 times higher in pts with both bone and visceral mets than those with bone-only mets (p=0.008). Pts with viscera-only mets had higher survival at 2 and 3 years than pts with bone-only or both bone and visceral mets (p=0.093). Pts with 3 mets (7/76, 7.4%) had decreased survival at 1, 2, and 3 years compared to pts with 1-2 (65/76, 85.5%) mets (p=0.6). 67 pts (70.5%) received mets-directed tx; RT alone was the most common modality (52/67, 77.6%), followed by surgery (6/67, 9%), RT plus surgery (5/67, 7.5%), and ablation alone (3/67, 4.5%). There was no significant difference in survival (HR 1.27, 95% CI (0.53, 3.07), p=0.589) or time to next tx (HR 0.95, 95% CI (0.56, 1.63), p=0.856) in pts who received mets-directed tx. Multivariate analysis was not performed because most findings were not statistically significant in univariate analysis. Conclusions We did not find any significant differences in survival based on characteristics like menopausal status or site or number of mets in pts with OMBC. There was a trend toward improved survival in pts with viscera-only mets, but this finding requires validation. Local/regional and mets-directed tx did not improve survival; however, survival at 1, 3, and 5 years was excellent in this OMBC pt population. Our study was limited by low pt numbers and heterogeneity in the pt population. Findings need validation in larger studies. Citation Format: Tanmayi Pai, Raza Zarrar, Zhongwei Peng, Zhuo Li, Lauren Cornell, Kostandinos Sideras, Rohit Rao, Alvaro Moreno-Aspitia, Saranya Chumsri, Sarah McLaughlin, James Jakub, Emmanuel gabriel, Sanjay Bagaria, Laura Vallow, Santo Maimone, Pooja Advani. Clinical Features and Survival Outcomes of Oligometastatic Breast Cancer Patients: The Mayo Clinic Experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-04.

Machine learning (ML) methods are proliferating in scientific research. However, the adoption of these methods has been accompanied by failures of validity, reproducibility, and generalizability. These failures can hinder scientific progress, lead to false consensus around invalid claims, and undermine the credibility of ML-based science. ML methods are often applied and fail in similar ways across disciplines. Motivated by this observation, our goal is to provide clear recommendations for conducting and reporting ML-based science. Drawing from an extensive review of past literature, we present the REFORMS checklist (recommendations for machine-learning-based science). It consists of 32 questions and a paired set of guidelines. REFORMS was developed on the basis of a consensus of 19 researchers across computer science, data science, mathematics, social sciences, and biomedical sciences. REFORMS can serve as a resource for researchers when designing and implementing a study, for referees when reviewing papers, and for journals when enforcing standards for transparency and reproducibility.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator–activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = −0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Abstract Background: TIM3 is an inhibitory immunoreceptor linked to decreased activity of immune cells in the tumor microenvironment. S095018 is a human anti-TIM3 IgG2 antibody which blocks binding of phosphatidyl serine to TIM3 promoting the stimulation of T-cells, dendritic cells (DCs) and macrophages. Sym021 is a humanized IgG1 antibody that inhibits binding of PD-1 with its ligands PD-L1 and PD-L2. Preclinical data demonstrated that Sym021 combined with S095018 results in enhanced immunostimulatory antitumor activity. Methods: S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancer whose disease progressed under treatment with at least one line of systemic therapy and who had not received prior treatment with PD-1/-L1 inhibitors (NCT04641871). The dose/schedule of Sym021 and S095018 was 3mg/kg IV Q2W and 10mg/kg IV Q2W, respectively. Primary endpoints included overall response rate (ORR) using RECIST v1.1 and incidence/severity of adverse events. Key secondary endpoints included PK parameters, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results As of 31-Oct-2023, 35 patients with stage IV biliary tract cancer (34 cholangiocarcinoma, 1 gallbladder adenocarcinoma) received S095018 in combination with Sym021. All patients were naïve to prior immune checkpoint inhibitor treatment. Twenty-two patients (62.9%) had received 1 prior antineoplastic systemic treatment for advanced/metastatic disease, 34.3% had received ≥2 prior treatments for advanced/metastatic disease. Overall, 34 patients (97.1%) discontinued treatment, 85.7% due to disease progression. Best overall response was 2 PR (5.7%), 11 SD (31.4%), 18 PD (51.4%) and 4 not evaluable. Median PFS and OS were 1.9 months (90% CI 1.8-3.7) and 13.4 months (90% CI 8.2-27.1) respectively. Disease control rate (CR+PR+SD) with SD≥16 weeks, ≥24 weeks and ≥12 months was 28.6%, 22.9% and 8.6% respectively. Treatment emergent adverse events of any grade occurring in >5% of patients included fatigue, pruritus, alkaline phosphatase increase, amylase increase, IRR (each 8.6%) and hypothyroidism, hyperthyroidism, AST increase, lipase increase and myalgia (each 5.7%). Exploratory biomarker analyses in paired tumor biopsies (N=18) showed an intratumoral increase in CD8 T-cell density, as well as upregulation of gene signatures related to IFNg signaling, antigen presentation, T-cell activation and cytotoxicity upon treatment. Baseline tumor biopsies from the two patients who achieved confirmed PR showed high PD-L1 expression. Conclusions: S095018 in combination with Sym021 exhibited antitumor activity in patients with advanced/metastatic recurrent biliary tract cancer who had not received prior treatment with PD-1/-L1 inhibitors. The combination was well tolerated without new safety signals. Further biomarker analysis is ongoing. Citation Format: Francois Ghiringhelli, Richard Kim, Teresa Macarulla, Irene Moreno, Albiruni Razak, Jordi Rodon, Chih-Yi Liao, Thomas Marron, Judith Raimbourg, Helene Kaplon, Julia Geromini, Najah Harouki, Christelle Rodrigues, Pauline Darcel, Niels Jorgen Skartved, Rikke Hald, Daleen Lopez-Ravnborg, Peng He, Xenophon Ianopoulos, Vasileios Askoxylakis, Nehal J. Lakhani, Sarah Davis, Amit Mahipal. A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT133.

Abstract Background: Fibroblast growth factor receptor (FGFR) alterations occur across various malignancies and are potent oncogenic drivers in multiple tumor types. FGFR inhibitors have demonstrated efficacy in several cancers with FGFR alterations. Tinengotinib is a novel kinase inhibitor with high potency to a variety of FGFR 1/2/3 kinase domain mutations and has shown promising efficacy in several ongoing clinical studies. Here, we present pooled data of tinengotinib in previously treated solid tumor patients (pts) with actionable FGFR1-3 mutations from four trials (NCT03654547, NCT04742959, NCT04919642, NCT05253053). Methods: Eligible pts received tinengotinib orally once daily (daily dose ranging from 5-12mg) until disease progression. Analyses of best overall response (BOR) rate, disease control rate (DCR), median progression-free survival (mPFS), median duration of response (mDOR) and treatment-related adverse events (TRAEs) were performed. Results: As of 3-Aug-2023, 53 solid tumor pts with actionable FGFR1-3 mutations were enrolled between Dec-2019 to Aug-2023 in the US and China. The median follow-up time was 14.5 (range, 3.3-43.8) months. Median age was 58 years (range, 29-83). Most pts were female (62%), had ECOG of 1 (68%) and were heavily pretreated with 55% having ≥3 lines of prior antitumor therapy. The most frequent FGFR mutation enrolled was in FGFR2 (77%) followed by FGFR1 (19%) and FGFR3 (11%). 25 pts (47%) had received prior therapy with FGFR inhibitor. A total of 45 pts were efficacy-evaluable, including cholangiocarcinoma (CCA, n=25), colon cancer (n=5), breast cancer (n=3), prostate cancer (n=3), head and neck cancer (n=3), urothelial cancer (n=3), pancreatic cancer (n=1), gastric cancer (n=1) and leiomyosarcoma (n=1). mPFS reached 6.83 (95% CI, 4.90-8.34) months. Partial responses were observed in 16/45 (35.6%) pts across 6 distinct tumor types, including CCA, breast, prostate, urothelium, colon and head and neck cancer. mDOR was 6.74 (95% CI, 3.52-9.46) months. For 44 pts with measurable target lesions per RECISTv1.1, the BOR rate and DCR were 36.4% and 86.4%, respectively. For 22 pts with prior FGFR inhibitor, mPFS was 5.98 (95% CI, 3.75-9.10) months and their BOR rate and DCR were 40.9% and 86.4%. TRAEs were reported in 46 (86.8%) pts, with 13 (24.5%) Grade (G) 1-2, 30 (56.6%) G3, 2 (3.8%) G4, and no G5. The most common TRAEs (≥20%) were hypertension, stomatitis, diarrhea, nausea, blood thyroid stimulating hormone increased, fatigue and anemia. Side effects were manageable and reversible with dose hold and/or dose reduction. Conclusions: We observed promising clinical benefit with tinengotinib in heavily pretreated solid tumor pts with FGFR1-3 mutations. The side effects profile was manageable and no new safety signals have been identified. Further research is planned to evaluate the safety and efficacy of tinengotinib in pts with FGFR1-3 mutations across a wider variety of tumor types. Citation Format: Sarina A. Piha-Paul, Chih-Yi "Andy" Liao, Lionel Fonkoua, Amit MahipaI, Sanjay Goel, Christos Fountzilas, Lin Shen, Daneng Li, Dustin Deming, Farshid Dayyani, Weiqing Han, Zuoxing Niu, Jean Fan, Peng Peng, Hui Wang, Peng Huang, Frank Wu, Milind Javle. Tinengotinib in patients with advanced solid tumors harboring actionable FGFR1-3 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB162.

AbstractPurposeTo develop a method that achieves simultaneous brain and neck time‐of‐flight (ToF) magnetic resonance angiography (MRA) within feasible scan timeframes.MethodsLocalized quadratic (LQ) encoding is efficient for both signal‐to‐noise ratio (SNR) and in‐flow enhancement. We proposed a spiral multiband LQ method to enable simultaneous intracranial and carotid ToF‐MRA within a single scan. To address the venous signal contamination that becomes a challenge with multiband (MB) ToF, tilt‐optimized non‐saturated excitation (TONE) and partial‐Fourier slice selection (PFSS) were further introduced in the LQ framework to mitigate the venous signal and improve artery contrast. A sequential spiral MB and LQ reconstruction pipeline was employed to obtain the brain‐and‐neck image volumes.ResultsThe proposed MB method was able to achieve simultaneous brain and neck ToF‐MRA within a 2:50‐min scan. The complementarily boosted SNR‐efficiency by MB and LQ acquisitions allows for the increased spatial coverage without increase in scan time or noticeable compromise in SNR. The incorporation of both TONE and PFSS effectively alleviated the venous contamination with improved small vessel sensitivity. Selection of scan parameters such as the LQ factor and flip angle reflected the trade‐off among SNR, blood contrast, and venous suppression.ConclusionsA novel MB spiral LQ approach was proposed to enable fast intracranial and carotid ToF‐MRA with minimized venous corruption. The method has shown promise in MRA applications where large spatial coverage is necessary.

Background The varicella-zoster virus (VZV), belonging to the group of human α-herpesviruses, has yet to be developed as a platform for oncolytic virotherapy, despite indications from clinical case reports suggesting a potential association between VZV infection and cancer remission. Methods Here, we constructed oncolytic VZV candidates based on the vaccine strain vOka and the laboratory strain Ellen. These newly engineered viruses were subsequently assessed for their oncolytic properties in the human MeWo melanoma xenograft model and the mouse B16-F10-nectin1 melanoma syngeneic model. Results In the MeWo xenograft model, both vOka and Ellen exhibited potent antitumor efficacy. However, it was observed that introducing a hyperfusogenic mutation into glycoprotein B led to a reduction in VZV’s effectiveness. Notably, the deletion of ORF8 (encodes viral deoxyuridine triphosphatase) attenuated the replication of VZV both in vitro and in vivo, but it did not compromise VZV’s oncolytic potency. We further armed the VZV Ellen-ΔORF8 vector with a tet-off controlled mouse single-chain IL12 (scIL12) gene cassette. This augmented virus was validated for its oncolytic activity and triggered systemic antitumor immune responses in the immunocompetent B16-F10-nectin1 model. Conclusions These findings highlight the potential of using Ellen-ΔORF8-tet-off-scIL12 as a novel VZV-based oncolytic virotherapy.