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Introduction: Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have shown a correlation between immune cell infiltration and poorly differentiated cancers. This study evaluated the impact of poorly differentiated histology on survival in patients with advanced gastrointestinal cancers treated with immunotherapy. Methods: This study was a retrospective, single-center analysis of patients with gastrointestinal cancers treated with CPIs between 2016 and 2021. Univariate and multivariable analyses were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor and patient characteristics, progression-free survival, and overall survival. Results: A total of 123 patients were eligible and included in the analysis. Median age was 66 years (23–88 years). Majority had stage IV disease (89%), were white (65.5%), and were male (64.5%). Most common diagnoses were hepatocellular carcinoma (30.5%), gastric adenocarcinoma (16.5%), esophageal adenocarcinoma (17%), and colorectal cancer (19.8%). About 32% of the tumors were microsatellite instability-high (MSI-High/dMMR), with BRAF V600E mutation rate of 10%. About 25% of the patients received CPIs as initial treatment, while 35.5% had received two or more prior lines of therapy. Compared with well and moderately differentiated histology, patients with poorly differentiated tumors had a shorter median overall survival (mOS) (not reached [NR] vs. NR vs. 9.3 months, p = 0.0264). There was no statistically significant difference in median progression-free survival (mPFS) between histology types (2.5 vs. 4.2 vs. 2 months, p = 0.1314). On univariate survival analysis, moderately differentiated tumors correlated with a significantly longer mOS (HR: 0.48, CI: 0.24–0.93, p = 0.030) and mPFS (HR: 0.62, 95% CI: 0.38–1.00, p = 0.048) compared to poorly differentiated histology. Female patients (HR: 0.55, 95% CI: 0.34–0.90, p = 0.018) and the Eastern Cooperative Oncology Group (ECOG) of 1 (vs. ≥2) had significantly longer mPFS (HR: 0.58, 95% CI: 0.35–0.97, p = 0.036). ECOG of 1 also correlated with longer mOS (HR: 0.47, 95% CI: 0.23–0.94, p = 0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, 95% CI: 2.41–13.63, p < 0.001) and mOS (HR: 5.45, 95% CI: 1.64–18.12, p = 0.006). The number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, 95% CI: 1.03–1.39, p = 0.022) and mOS (HR: 1.23, 95% CI: 1.01–1.50, p = 0.045). On multivariable analyses, ECOG status of 0/1 versus ≥2 and MSI-High/dMMR versus MSS remained significantly associated with longer mPFS and mOS. There was no correlation with histologic differentiation status, race, or mutations such as BRAF V600E or KRAS. Conclusion: Results from this study demonstrate that poorly differentiated histology was associated with shorter mOS but was not associated with improved PFS in patients treated with CPI. Treatment-naïve patients, moderately differentiated tumors, female gender, ECOG 1, and MSI-High/dMMR were most likely to benefit from CPI.

Summary The emerging field of DNA nanotechnology harnesses DNA as a stable and generic material to assemble nanostructures with precisely defined sizes and geometries. The past 40 years have witnessed this field’s originating, branching, blossoming, bridging with, and benefiting many different areas. Interestingly, in nearly the same period, DNA has also been discovered to be able to catalyze various chemical reactions. The catalytic DNAs, especially those that can cleave DNA/RNA, are with a destructive property quite opposite to the fundamental concept of DNA nanotechnology. Nevertheless, in the past decade, they have been successfully blended into DNA nanoconstruction and expanded the construction dimension. Here, we present an overview of recent progress in the development of DNA nanotechnology promoted by the DNA/RNA-cleaving DNAs. Meanwhile, we provide an outlook of how the two seemingly distant types of DNA could further collide with and mutually benefit each other, leading to the unprecedented downstream applications in various areas.

Clinical outcomes of redo surgical aortic valve replacement (redo-SAVR) compared with valve-in-valve transcatheter aortic valve replacement (VIV-TAVR) are poorly understood. This study compared short- and midterm outcomes of patients undergoing isolated redo-SAVR vs VIV-TAVR after previous SAVR.A single-institutional review of the initial use of VIV-TAVR from 2012 to 2019 identified 273 patients undergoing VIV-TAVR (n = 187) or redo-SAVR (n = 86) after prior SAVR. Outcomes analysis included a univariate analysis and Kaplan-Meier survival analysis.The Society of Thoracic Surgeons predicted risk of mortality was higher for VIV-TAVR (6.3%; interquartile range [IQR], 3.6%-10.5%) vs redo-SAVR (4.2%; IQR, 2.4%-6.9%; P.01). VIV-TAVR patients (76 years; IQR, 67.5-82.5 years) were older than redo-SAVR patients (64 years; IQR, 54-72; P.01). Redo-SAVR and VIV-TAVR had similar early mortality (1.2% vs 1.6%, P = .92). Two redo-SAVR (2.3%) and 3 VIV-TAVR patients (1.6%) died 4.8 ± 0.5 years and 4.8 ± 1.5 months after discharge, respectively. Redo-SAVR had an increased stroke rate (7.0% vs 1.1%, P = .02). Postoperative mean valve gradients were similar between VIV-TAVR (14 mm Hg; IQR, 9-21 mm Hg) and redo-SAVR patients (12 mm Hg; IQR, 8-20 mm Hg; P = .08). Postprocedure transesophageal echocardiography showed at least mild aortic insufficiency for 24 VIV-TAVR patients (16%) and 2 redo-SAVR patients (2.9%) (P = .01). The cumulative incidence of aortic valve reintervention was 5.2% for the redo-SAVR patients and 28.5% for the VIV-TAVR patients (P = .07).After previous SAVR, redo-SAVR and VIV-TAVR can both be performed with acceptable operative results. Despite treating a high-risk patient population, we found redo-SAVR and VIV-TAVR both carry similar operative outcomes. Improved valve hemodynamics were observed in redo-SAVR patients compared with VIV-TAVR patients.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key adaptor protein that regulates the NF-κB pathway, in which MALT1 functions as a scaffold protein and protease to trigger downstream signals. The abnormal expression of MALT1 is closely associated with lymphomagenesis and other diseases, including solid tumors and autoimmune diseases. MALT1 is the only protease in the underlying pathogenesis of these diseases, and its proteolytic activity can be pharmacologically regulated. Therefore, MALT1 is a potential and promising target for anti-lymphoma and other MALT1-related disease treatments. Currently, the development of MALT1 inhibitors is still in its early stages. This review presents an overview of MALT1, particularly its X-ray structures and biological functions, and elaborates on the pathogenesis of diseases associated with its dysregulation. We then summarize previously reported MALT1 inhibitors, focusing on their molecular structure, biological activity, structure-activity relationship, and limitations. Finally, we propose future research directions to accelerate the discovery of novel MALT1 inhibitors with clinical applications. Overall, this review provides a comprehensive and systematic overview of MALT1-related research advances and serves as a theoretical basis for drug discovery and research.

Purpose Most patients with metastatic melanoma show variable responses to radiation therapy and do not benefit from immune checkpoint inhibitors. Improved strategies for combination therapy that leverage potential benefits from radiation therapy and immune checkpoint inhibitors are critical. Methods and Materials We analyzed metastatic melanoma tumors in the TCGA cohort for expression of genes coding for subunits of type A γ-aminobutyric acid (GABA) receptor (GABAAR), a chloride ion channel and major inhibitory neurotransmitter receptor. Electrophysiology was used to determine whether melanoma cells possess intrinsic GABAAR activity. Melanoma cell viability studies were conducted to test whether enhancing GABAAR mediated chloride transport using benzodiazepine-impaired viability. A syngeneic melanoma mouse model was used to assay the effect of benzodiazepine on tumor volume and its ability to potentiate radiation therapy or immunotherapy. Treated tumors were analyzed for changes in gene expression by RNA sequencing and presence of tumor-infiltrating lymphocytes by flow cytometry. Results Genes coding for subunits of GABAARs express functional GABAARs in melanoma cells. By enhancing GABAAR-mediated anion transport, benzodiazepines depolarize melanoma cells and impair their viability. In vivo, benzodiazepine alone reduces tumor growth and potentiates radiation therapy and α-PD-L1 antitumor activity. The combination of benzodiazepine, radiation therapy, and α-PD-L1 results in near complete regression of treated tumors and a potent abscopal effect, mediated by increased infiltration of polyfunctional CD8+ T cells. Treated tumors show expression of cytokine–cytokine receptor interactions and overrepresentation of p53 signaling. Conclusions This study identifies an antitumor strategy combining radiation and/or an immune checkpoint inhibitor with modulation of GABAARs in melanoma using benzodiazepine.

Metal recognition by nucleic acids provides an intriguing route for biosensing of metal. Toward this goal, a key prerequisite is the acquisition of nucleic acids that can selectively respond to specific metals. Herein, we report for the first time the discovery of two small DNAs that can specifically bind Ni2+ and discriminate against similar ions, particularly, Co2+. Their minimal effective constructs are 60-70 nucleotides (nt) in length with Ni2+ binding even at harsh denaturing conditions of 8 M urea and 50 mM EDTA. Using isothermal titration calorimetry (ITC), we estimated the dissociation constant (KD) of a representative DNA to be 24.0 ± 4.5 μM, with a 9:1 stoichiometry of Ni2+ bound to DNA. As being engineered into nanosized particles, these DNAs can act like nanosponges to specifically adsorb Ni2+ from artificial wastewater, demonstrating their potential as a novel molecular tool for high-quality nickel enrichment and detection.

Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Here, a novel series of pyrimidin-2-amino-pyrazol hydroxamate derivatives as JAK and HDAC dual inhibitors was designed, synthesized, and evaluated, among which 8m possessed potent and balanced activities against both JAK2 and HDAC6 with half-maximal inhibitory concentration at the nanomolar level. 8m exhibited improved antiproliferative and proapoptotic activities over SAHA and ruxolitinib in several hematological cell lines. Remarkably, 8m exhibited more potent antiproliferation effect than the combination of SAHA and ruxolitinib in HEL cells bearing JAK2V617F mutation. Pharmacokinetic studies in mice showed that 8m possessed good bioavailability after intraperitoneal administration. Finally, 8m showed antitumor efficacy with no significant toxicity in a HEL xenograft model....

e12616 Background: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and in all but the smallest tumors, neoadjuvant chemotherapy (NACT) is part of the standard of care. Black women (BW) suffer a poorer prognosis than white women (WW) with TNBC, and whether this is due to differences in treatment, disease biology, or socioeconomic variables is not fully known. This study, conducted at a racially diverse academic medical center, aimed to investigate factors associated with unfavorable outcomes in BW with TNBC. Methods: 131 patients with TNBC received NACT from 2008-2017 at Winship Cancer Institute were included in this retrospective study. Descriptive statistics were applied to delineate the relationship with racial disparity. Clinical outcomes include progression free survival (PFS) and distance metastasis free survival (DMFS) and were analysis using Cox proportional hazard model. Results: Among 131 patients with TNBC treated with NACT, 58.5% were BW and median age was 55. BW and WW had similar disease staging at diagnosis and similar pathologic responses to treatment. Yet, BW were less likely to complete NACT compared with WW (80.8% BW completed NACT vs 98.0% WW, p=0.005). BW were more likely to either not complete NACT or to require dose reduction or dose delay (42.5% BW vs. 23.1% WW, p=0.024). Coexisting hypertension (65.8% BW vs. 35.2% WW), elevated BMI (31.7% BW vs. 27.5% WW), or covered by Medicaid (29.3% BW vs. 13.0% WW) were more common among BW. Medicaid insurance was associated with worse progression-free survival (HR 2.49, p=0.015) and distant metastasis free survival (DMFS, HR 2.73, p=0.018). Dose delays were associated with worse DMFS (HR 3.02, p=0.017). Discussion: In this study, we found that BW were less likely to complete NACT than WW, more likely to suffer dose delays, and more likely to require dose reductions. BW were also more likely to have Medicaid insurance, another factor that correlated with inferior outcomes; perhaps because patients with Medicaid insurance are also more likely to suffer from reduced access to transportation, childcare, and other infrastructure critical to maintaining a schedule for NACT. More research is needed to understand the reasons for the dose delays, dose reductions, and failures to complete NACT so that interventions can be designed to address them. Conclusions: As we move into the era of chemoimmunotherapy for TNBC, where drug combinations and treatment schedules are becoming even more complex, a better understanding of the reasons for dose delays, dose reductions, and treatment discontinuations will be key to maintaining optimal outcomes for TNBC patients, regardless of race.

PURPOSE: Most metastatic melanoma patients show variable responses to radiotherapy and do not benefit from immune checkpoint inhibitors (ICIs). Improved strategies for combination therapy that leverage potential benefits from radiotherapy and ICI are critical. METHODS AND MATERIALS: We analyzed metastatic melanoma tumors in the TCGA cohort for expression of genes coding for subunits of Type-A γ-aminobutyric acid (GABA) receptor (GABA(A)R), a chloride ion channel and major inhibitory neurotransmitter receptor. Electrophysiology was used to determine if melanoma cells possess intrinsic GABA(A)R activity. Melanoma cell viability studies were conducted to test if enhancing GABA(A)R mediated chloride transport using a benzodiazepine impaired viability. While a syngeneic melanoma mouse model was used to assay the effect of benzodiazepine on tumor volume and its ability to potentiate radiation and/or immunotherapy. Treated tumors were analyzed for changes in gene expression by RNA sequencing and presence of tumor infilitrating lymphocytes by flow cytometry. RESULTS: Genes coding for subunits of GABA(A)Rs express functional GABA(A)Rs in melanoma cells. By enhancing GABA(A)R mediated anion transport, benzodiazepines depolarize melanoma cells and impair their viability. In vivo, benzodiazepine alone reduces tumor growth and potentiates radiotherapy and α-PD-L1 anti-tumor activity. Combination of benzodiazepine, radiotherapy, and α-PD-L1 results in near complete regression of treated tumors and a potent abscopal effect, mediated by increased infiltration of polyfunctional CD8+ T cells. Treated tumors show expression of cytokine:cytokine receptor interactions and overrepresentation of p53 signaling. CONCLUSIONS: This study identifies an anti-tumor strategy combining radiation and/or immune checkpoint inhibitor with modulation of GABA(A)Rs in melanoma using a benzodiazepine.

664 Background: Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have showed a correlation between immune cell infiltration and poorly differentiated cancers. We evaluated the impact of poorly differentiated histology on survival in patients with advanced GI malignancies treated with immunotherapy. Methods: We performed a retrospective, single institution analysis of patients with poorly differentiated GI tumors treated with CPI between 2016 and 2021. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor/patient characteristics, progression free survival (PFS) and overall survival (OS). Results: A total of 123 patients were included. Median age was 66years. Majority had stage IV disease (88.2%), were White (65.5%) and male (64.5%). Most common diagnoses were HCC (28.5%), gastric (15.4%) and esophageal (14.6%) adenocarcinomas. About 32% were MSI-H, with 10% BRAF mutation rate. About 25% received CPI as initial treatment and 35.5% received 2 or more prior lines of therapy. Compared with well and moderately differentiated histology, poorly differentiated tumors had shorter mPFS (3.4 vs 2.5 vs. 2.2months; p = 0.29) and mOS (not reached [NR] vs. 20.9 vs. 14.2 months; p = 0.14) respectively. On UVA, the degree of tumor differentiation did not correlate with mPFS or mOS. Female patients (HR: 0.55, CI: 0.34-0.90, p = 0.018) and ECOG of 1 vs. ≥2 had significantly longer mPFS (HR: 0.58, CI: 0.35-0.97, p = 0.036). ECOG 1 correlated with better mOS (HR: 0.47, CI: 0.23-0.94, p = 0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, CI: 2.41-13.63, p < 0.001) and mOS (HR: 5.45, CI: 1.64-18.12, p = 0.006). Number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, CI: 1.03-1.39, p = 0.022) and mOS (HR: 1.23, CI: 1.01-1.50, p = 0.045). On MVA, ECOG status of 0/1 vs. ≥2 and MSI-H vs. MSS remained significantly associated with longer mPFS and mOS. There was no correlation with race or mutations such as BRAF or KRAS. Conclusions: Poorly differentiated histology did not predict for PFS or OS. Treatment naïve patients, female gender, ECOG 1 and MSI-H were most likely to benefit from CPI.

Background: Although clinical trial data exist describing the adverse effects of Bruton's tyrosine kinase inhibitors (BTKi)s, the patient experience outside clinical trials, including differences among agents is less well-described. We evaluated the selection criteria, efficacy and toxicities related to the use of BTKi at our site. Methods: A retrospective patient chart review was used to collect data from patients treated with one or more BTKi. Demographics, prior therapies, duration of treatment, response to treatment, and incidence and severity of pre-determined toxicities of interest were collected for each patient. Descriptive statistics for each variable were reported. Association between variables of interest and the study cohort were examined using ANOVA for categorical variables and Pearson correlation coefficient for continuous variables. Survival and duration of treatment were estimated using the Kaplan-Meier method according to first novel agent. Survival analysis for each novel agent was conducted using Cox proportional hazards models and log-rank tests. Results: One hundred forty patients were included in this study, including 94 patients with CLL, 24 with MCL, and 22 with other NHL subtypes. One hundred thirteen patients received ibrutinib, while 17 patients received acalabrutinib (n=16) or zanubrutinib (n=1), which were combined in the statistical analysis. Of patients receiving ibrutinib, 69% reported at least one toxicity event during the duration of their treatment. Across all patients who received ibrutinib, 35 individuals did not report a toxicity, 48 individuals reported one toxicity, and 30 individuals reported two or more toxicities. Among the 78 patients who experienced at least one toxicity, 41 (52.5%) discontinued the medication due to these adverse effects, most commonly cytopenias (n=9), diarrhea (n=8), and fatigue (n=9). 57% of patients who reported diarrhea, 36% of patients who reported cytopenias, and 33% of patients who reported fatigue discontinued therapy due to that reported AE. In total, 60/113 patients receiving ibrutinib discontinued therapy, including 40 (66%) due to toxicity and 14 (23.3%) due to disease progression. The remaining patients discontinued therapy due to voluntary choice of new therapy or due to personal decision to stop treatment. Patients remained on ibrutinib therapy for a median duration of 40 months. 53% of patients taking zanabrutinib or acalabrutinib reported at least 1 toxicity, but only 11.7% of patients discontinued therapy for any reason. All patients who discontinued zanubrutinib/acalabrutinib therapy did so due to toxicity, with no patients ceasing therapy due to disease progression. Because only 2 of 17 patients discontinued zanubrutinib/acalabrutinib treatment, a raw median duration of treatment was calculated to be 5 months. 12.4% of patients taking ibrutinib experienced a gastrointestinal toxicity, whereas 5.9% of patients taking acalabrutinib/zanubrutinib experienced a gastrointestinal toxicity (Table 1). Additionally, 8% of individuals taking ibrutinib reported a musculoskeletal toxicity, while no acalabrutinib/zanubrutinib patients reported a musculoskeletal toxicity. There were no statistically significant differences in frequency of toxicities encountered, possibly due to study size. Other toxicities common to all analyzed BTK inhibitors included hematological, cardiovascular, and constitutional adverse effects with no significant difference between agents. Conclusions: We identified that >1/3 of individuals taking BTK inhibitors are stopping therapy prematurely due to toxicity related outcomes rather than due to disease progression. Our findings suggest that proactive identification and management of adverse effects could prolong therapy duration and provide better outcomes for patients. Strategies to personalize therapy selection to limit therapy discontinuation due to toxicity are needed as additional targeted agents are developed. Figure 1 Figure 1. Disclosures Valla: BeiGene: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy; Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.

10588 Background: Testing for mutations in BRCA1 and BRCA2 is recommended for all women with ovarian cancer (OC), given important implications for treatment and prognosis. Despite this recommendation, studies show that only a small percentage of OC patients (pts) undergo genetic testing (GT). In this study, we evaluated rates of genetics referral, counseling and testing among OC pts at an academic medical center. Our goal was to identify factors associated with lower rates of GT. Given the large Black population at our center, we specifically wanted to evaluate the association between race and GT given limited existing data on this issue. Methods: Retrospective chart review was performed evaluating rates of referral and uptake for GT, and percentages of BRCA mutation carriers among pts with OC diagnosed and treated at Emory’s Winship Cancer Institute between 2008 and 2018. Associations between age, race, histology, family history (FH), performance status, provider characteristics and genetics referral and testing were evaluated using logistic regression models. Results: Of the 171 pts who met inclusion criteria, the majority were age 55 or older (62%) with high grade serous carcinoma (60.8%). Pts were predominantly Caucasian (59.4%), followed by Black (29.1%), Asian (10.3%) and Hispanic (1.2%). Overall, GT rates were low with 44.7% of pts referred for genetic counseling and 39.8% receiving testing. Among pts who did receive GT, the percentage of deleterious BRCA1 and BRCA2 mutations identified was 11% and 8.8% respectively. Variables correlating with higher likelihood of genetics discussion, referral and testing included serous histology (50% vs 23.9% non-serous, p < 0.001), Caucasian or Asian race (87.5% Asian, 58.8% Caucasian vs 42.2% Black, p = 0.003) and seeing a medical oncologist (67.5% vs 44.7% seeing gynecologic oncologist alone, p = 0.004). Notably, while fewer Black women were referred for GT (25.9% vs 74.1% Caucasian), those that did undergo GT were found to have higher rates of BRCA1 and BRCA2 mutations when compared to Caucasian pts (22.2% vs 8.2% BRCA1; 11.1% vs 6.0% BRCA2). Pts with a FH of OC were more likely to undergo GT (69.2% vs 37.9%, p = 0.027), and pts with a FH of breast cancer were more likely be referred for testing (57.1% vs 39.6%, p = 0.042), suggesting that FH impacted referral patterns. Conclusions: The rates of GT among OC pts at our institution were lower than expected despite the broad recommendation for GT in this population. It is imperative to improve access to GT for all OC pts regardless of FH, and in particular among Black pts given the higher rates of BRCA mutations in this population. Pts and providers must work together to overcome barriers to genetics referral and testing in order to improve GT rates and clinical outcomes. Further research is needed to design interventions that may help improve adherence to this important recommendation in the future.