Citations

INTRODUCTION: Endoscopic eradication therapy (EET) combining endoscopic resection (ER) with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) followed by ablation is the standard of care for the treatment of dysplastic Barrett's esophagus (BE). We have previously shown comparable rates of complete remission of intestinal metaplasia (CRIM) with both approaches. However, data comparing recurrence after CRIM are lacking. We compared rates of recurrence after CRIM with both techniques in a multicenter cohort. METHODS: Patients undergoing EET achieving CRIM at 3 academic institutions were included. Demographic and clinical data were abstracted. Outcomes included rates and predictors of any BE and dysplastic BE recurrence in the 2 groups. Cox-proportional hazards models and inverse probability treatment weighting (IPTW) analysis were used for analysis. RESULTS: A total of 621 patients (514 EMR and 107 ESD) achieving CRIM were included in the recurrence analysis. The incidence of any BE (15.7, 5.7 per 100 patient-years) and dysplastic BE recurrence (7.3, 5.3 per 100 patient-years) were comparable in the EMR and ESD groups, respectively. On multivariable analyses, the chances of BE recurrence were not influenced by ER technique (hazard ratio 0.87; 95% confidence interval 0.51–1.49; P = 0.62), which was also confirmed by IPTW analysis (ESD vs EMR: hazard ratio 0.98; 95% confidence interval 0.56–1.73; P = 0.94). BE length, lesion size, and history of cigarette smoking were independent predictors of BE recurrence. DISCUSSION: Patients with BE dysplasia/neoplasia achieving CRIM, initially treated with EMR/ablation, had comparable recurrence rates to ESD/ablation. Randomized trials are needed to confirm these outcomes between the 2 ER techniques.

Abstract Introduction: Barrett’s esophagus (BE) confers increased cancer risk. Endoscopic surveillance is recommended to distinguish non-dysplastic BE (NDBE), low grade dysplasia (LGD), high grade dysplasia (HGD), or adenocarcinoma (EAC) for endoscopic intervention. However, this paradigm is limited by sampling error, leading to missed/interval EAC. Herein, we aimed to classify these samples more accurately by performing whole genome methylation sequencing (WGMS) and utilizing multiple genomic features on endoscopic brush samples. Materials and methods: Endoscopic brush samples from patients with NDBE (n=18), HGD (18), EAC (18), and normal controls (18) were collected and underwent WGMS (discovery dataset). Sequence reads were processed through internal pipeline to extract CpG methylation and read level methylation ratio (alpha value). Copy number aberration (CNA) detection was performed using both CNVkit and ichorCNA. Differential methylated regions (DMRs) were identified through comparing EAC/HGD with NDBE and normal samples. Targeted methylation sequencing for selected DMRs and shallow WGMS were performed on EAC (41), HGD (26), LGD (23), NDBE (42), and normal controls (37) as validation. Ratio of the reads with alpha value>0.6 for each DMR was used for further analysis. Detected CNA segments were summarized into chromosome arm loss or gain (aneuploidy score or AS representing the number of chromosome arms gained or lost in a sample) and trimmed median absolute deviation (tMAD). Classification models were developed using the discovery set and the best performing one was applied to the validation dataset. Results: Genome-wide DNA methylation largely segregated different groups of samples as diagnosed; however, some unexpected group crossings were observed. Top 200 DMRs were identified between EAC/HGD and NDBE and normal samples. CNA changes were widespread in EAC, very common in HGD but rare in NDBE (17/18 EACs,14/18 HGDs, 5/18 NDBEs with AS>0). With tMAD > 0.015, 16/18 EACs, 8/18 HGDs but none of 18 NDBEs passed the threshold. EAC or HGD samples without detectable CNAs had very low “tumor” fraction as determined by methylation-based cell type deconvolution or ichorCNA. Similar results were found in the validation dataset. A multi-omics (AS, tMAD, estimated tumor fraction, and DMR methylation) model could predict EAC, HGD, or NDBE with 0.81 accuracy through cross validation (10X) and 0.73 in the independent dataset. This increased to 0.98 and 0.90 in separating high risk EAC/HGD from NDBE, respectively. Conclusion: Multi-omics data obtained from single WGMS allow for a comprehensive analysis of BE samples with varying dysplasia levels. Using classification modeling, these characteristics can be effectively used to accurately identify and distinguish between EAC and HGD from NDBE, suggesting their utility as adjuncts to endoscopic surveillance biopsies. Citation Format: Zhifu Sun, Caroline L. Matchett, Seth W. Slettedahl, William R. Taylor, Panwen Wang, Calise Berger, Caryn E. Anderson, Melissa A. Passe, Ramona Lansing, Collin E. Chalmers, Patrick H. Foote, Jeanette E. Eckel Passow, Doug W. Mahoney, John B. Kisiel, Prasad G. Iyer. Multi-omics cancer risk assessment of Barrett’s esophagus with DNA methylation sequencing from endoscopic brush samples [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 LB249.

Abstract Background This study evaluated the effect of an artificial intelligence (AI)-based clinical decision support system on the performance and diagnostic confidence of endoscopists in their assessment of Barrett’s esophagus (BE). Methods 96 standardized endoscopy videos were assessed by 22 endoscopists with varying degrees of BE experience from 12 centers. Assessment was randomized into two video sets: group A (review first without AI and second with AI) and group B (review first with AI and second without AI). Endoscopists were required to evaluate each video for the presence of Barrett’s esophagus-related neoplasia (BERN) and then decide on a spot for a targeted biopsy. After the second assessment, they were allowed to change their clinical decision and confidence level. Results AI had a stand-alone sensitivity, specificity, and accuracy of 92.2%, 68.9%, and 81.3%, respectively. Without AI, BE experts had an overall sensitivity, specificity, and accuracy of 83.3%, 58.1%, and 71.5%, respectively. With AI, BE nonexperts showed a significant improvement in sensitivity and specificity when videos were assessed a second time with AI (sensitivity 69.8% [95%CI 65.2%–74.2%] to 78.0% [95%CI 74.0%–82.0%]; specificity 67.3% [95%CI 62.5%–72.2%] to 72.7% [95%CI 68.2%–77.3%]). In addition, the diagnostic confidence of BE nonexperts improved significantly with AI. Conclusion BE nonexperts benefitted significantly from additional AI. BE experts and nonexperts remained significantly below the stand-alone performance of AI, suggesting that there may be other factors influencing endoscopists’ decisions to follow or discard AI advice.

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, underscoring the critical need for the identification of new actionable therapeutic targets. We previously identified the Transmembrane Serine Protease TMPRSS11B as a novel gene that promotes the transformation of human bronchial epithelial cells in vitro and induces tumorigenesis in vivo. TMPRSS11B promotes extracellular release of Basigin, an obligate chaperone of the lactate monocarboxylate transporters MCT1/4, enhancing lactate export and glycolytic metabolism, and thereby promoting tumorigenesis. Importantly, TMPRSS11B is frequently overexpressed in human lung squamous cell cancers (LSCC) and high expression is associated with poor patient survival. Moreover, as a cell surface protein and enzyme, TMPRSS11B represents a tractable target for therapeutic intervention. To investigate whether TMPRSS11B activity impacts the host immune system and the tumor microenvironment (TME), we evaluated the effect of Tmprss11b depletion in a syngeneic LSCC mouse model, KLN205. Tmprss11b loss of function in KLN205 LSCC cells significantly reduced tumor burden in immunocompetent mice and triggered an accumulation of CD4+ T cells. We are currently extending these studies by investigating the effect of Tmprss11b loss of function using CRISPR/Cas9 editing in the Rosa26LSL-Sox2-IRES-GFP; Nkx2-1 fl/fl; Lkb1fl/fl (SNL) mouse model of LSCC. Tumor burden analysis and pH-sensitive fluorescent imaging are ongoing to assess changes in lactate accumulation. Moreover, RNA FISH analysis and spatial transcriptomics revealed that Tmprss11b expression is highly enriched in lung squamous tumors compared to lung adenocarcinomas and normal lung in SNL mice. Spatial analysis of the transcriptome is currently ongoing to assess the effects of Tmprss11b expression on the TME. Collectively, these studies will elucidate the molecular mechanisms through which TMPRSS11B promotes tumor growth and alters the tumor microenvironment in LSCC. Citation Format: Hari Shankar Sunil, Barrett L. Updegraff, Jingfei Zhu, Lisa Thomas, Bret M. Evers, Jean R. Clemenceau, Isabel Barnfather, John D. Minna, Ralph J. Deberardinis, Trudy G. Oliver, Tae Hyun Hwang, Kathryn A. O'Donnell. Transmembrane serine protease TMPRSS11B promotes tumorigenesis in lung squamous cell carcinoma through enhanced lactate export and modulation of the tumor microenvironment [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 1793.

Abstract Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer patient derived-tumor xenograft (PDTX) models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using whole-exome sequencing. PDTX 3D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular-targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6i. This combination was evaluated in PDTX three-dimensional (3D) spheroids and in vivo experiments with responses measured by tumor volumes, PSA, and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single-agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, whereas tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single-agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in patients with mCRPC whose tumor expresses wild-type retinoblastoma 1.

Abstract Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took β blockers (BBs) with hydrochlorothiazide (HCTZ), (−5.05 mmHg; 95% confidence interval [CI], 10.0 to −0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (−5.47 mmHg; 95% CI, 10.9 to −0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

Background and Objectives: It is unclear whether induced hypertension in acute ischemic stroke (AIS) may improve long-term outcomes. We conducted a systematic review and meta-analysis to compare the safety and efficacy of induced hypertension vs standard medical care in patients presenting with acute ischemic stroke within 72 hours of symptom onset. Methods: Two reviewers systematically searched PubMed using the prespecified terms “induced hypertension” or “blood pressure augmentation” plus “ischemic stroke” for clinical trials that reported functional independence (mRS 0-2) at 90 days. The safety outcome was symptomatic intracranial hemorrhage (sICH). Pooled odds ratio (OR) and 95% CI across trials were synthesized using fixed-effect model based on Mantel-Haenszel methods. Forest plots were constructed. Results: Three clinical trials with 270 AIS patients treated with induced hypertension (n=126) or standard medical care (n= 144) were included. Mean age was 66.6 years, 35.2% were women, and the mean initial NIHSS was 7.5. The rate of functional independence at 90 days was higher in patients treated with induced hypertension (70.6%) versus control (54.9%) (OR 1.88; 95% CI 1.13-3.11; p=0.01). sICH did not differ between patients treated with induced hypertension (<1%) versus control (<1%) (OR 1.03; 95% CI 0.14-7.45; p=0.98). Discussion: Among patients presenting with acute ischemic stroke with 72 hours of symptoms onset, induced hypertension resulted in better functional outcome at 90 days than standard medical care and did not increase risk of sICH. Large RCTs to test this observation are ongoing and needed to guide clinical practice.

AbstractUnesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5‐aminoimidazole‐4‐carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m2) was administered to patients with LMS via 1‐h intravenous (i.v.) infusion on day 1 of every 21‐day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (b.i.w.), starting on day 2 of every cycle, except for cycle 2 (C2), where unesbulin was dosed either on day 1 together with DTIC or on day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached maximum plasma concentration (Cmax) immediately or shortly after end of infusion at 1.0 and 1.4 h (time to Cmax), respectively. Co‐administration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2‐mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC Cmax by 69.4% and area under concentration‐time curve to infinity by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m2 i.v. DTIC q21d and 300 mg unesbulin b.i.w. in a staggered regimen is well‐tolerated in patients with LMS.

INTRODUCTION: Wide-area transepithelial sampling with 3-dimensional computer-assisted analysis (WATS 3D ) has been shown to increase the detection rate of dysplasia (and intestinal metaplasia) in patients with Barrett's esophagus (BE). The purpose of this study was to evaluate the interobserver variability and accuracy of diagnosing BE-associated dysplasia in WATS 3D specimens among gastrointestinal (GI) pathologists without prior experience with this technology. METHODS: Five GI pathologists underwent a 4-hour in-person (at microscope) and virtual training session and then evaluated digital images of discrete cellular foci from 60 WATS 3D cases with BE (20 nondysplastic BE [NDBE], 20 low-grade dysplasia [LGD], and 20 high-grade dysplasia/esophageal adenocarcinoma [HGD/EAC]). Each case consisted of 1 hematoxylin and eosin–stained image (cell block), and 1 liquid cytology or papanicolaou-stained smear image (120 images in total). RESULTS: The overall kappa value among the 5 study pathologists was excellent (overall kappa = 0.93; kappa = 0.93 and 0.97 for cell block and smear specimens, respectively). There were no significant differences noted in kappa values in interpretation of the cell block vs smear specimens or in any of the individual diagnostic categories when the latter were evaluated separately. Furthermore, agreement was perfect (100%) regarding detection of neoplasia (either LGD, HGD, or EAC). Diagnoses were made with complete confidence in 91% of instances. DISCUSSION: We conclude that GI pathologists, without any prior experience in interpretation of WATS 3D specimens, can undergo a short training session and then diagnose these specimens with a very high level of accuracy and reproducibility.