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Importance: Findings from several high profile meta-analyses have raised concerns about an ongoing global decline in sperm concentration and male fertility. However, these studies exhibit considerable heterogeneity in key variables including study population, methodology, fertility status, and geographic region., Objective: To perform a systematic review and meta-analysis exploring temporal trends in sperm concentration among fertile men and men unselected for fertility status in the United States., Data Sources: A literature search performed in Scopus and PubMed databases for studies published between 1970 and 2023. Additional studies were included from citations of prior global meta-analyses and reviews evaluating temporal trends in sperm count., Study Selection and Synthesis: Studies were included if they presented original data on sperm concentration in US men without known infertility from 1970 to 2023. Aggregate data were assessed across all study populations, with additional subgroup analyses stratified by fertility status and US region., Main Outcomes: Weighted generalized linear models were generated to evaluate the association between mean sperm concentration and sample collection year., Results: A total of 874 articles were screened, with 58 meeting the inclusion criteria. These represented 75 unique study populations totaling 11,787 men in the United States. Across all study populations, no change in sperm concentration was observed between 1970 and 2018 in unadjusted models (β = 0.14 million/mL per year). When adjusting for US region, no statistically significant decline in sperm concentration was seen. When adjusting for both region and fertility status, a modest annual decline was observed to meet statistical significance (β = -0.35 million/mL per year). Of the 49 study populations reporting adequate data to determine mean total sperm count, there was a significant increase in total sperm count of 2.9 million per year between 1970 and 2018. Subgroup analysis found no statistically significant change in mean sperm concentration among any US census region or fertility status cohort., Conclusion and Relevance: In contrast to prior global studies, this analysis suggests no clinically significant decline in sperm concentration among confirmed fertile men and the general male US population without known infertility. Although these findings provide some reassurance against a widespread rapid decline, further studies are necessary to better understand this important topic., Competing Interests: Declaration of Interests K.L. has nothing to disclose. R.C. has nothing to disclose. F.L. has nothing to disclose. B.R. has nothing to disclose. L.B. has nothing to disclose. J.M. has nothing to disclose. S. Kuribayashi has nothing to disclose. S. Kuroda has nothing to disclose. D.A.P. has nothing to disclose. S.C.V. has nothing to disclose. J.C. has nothing to disclose. S.D.L. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Gastric cancer is one of the leading malignancies worldwide. B vitamins play important roles in DNA synthesis and methylation because they are considered co-enzymes in one-carbon metabolism. There is inconclusive evidence regarding the associations between dietary vitamins B 1 , B 2 , and B 6 with the risk of gastric cancer in different epidemiologic studies. We, therefore, investigated such associations in a hospital-based case-control study comprising 1182 incident cases of gastric cancer and 2995 controls in Vietnam., Methods: Dietary vitamins B 1 , B 2 , and B 6 were derived from a semi-quantitative validated food frequency questionnaire. An unconditional logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer in relation to dietary intake of vitamins B 1 , B 2 , and B 6 ., Results: Overall, dietary vitamins B 1 (OR per-SD increment = 0.83; 95% CI: 0.78-0.89; P trend < 0.001) and B 6 (OR per-SD increment = 0.88; 95% CI: 0.81-0.94; P trend < 0.001) were associated with a reduced risk of gastric cancer. Compared with the lowest quintile, the ORs (95% CIs) of gastric cancer for quintiles 2, 3, 4, and 5 of the vitamin B 1 intake were 0.64 (0.51-0.79), 0.54 (0.43-0.69), 0.57 (0.44-0.74), and 0.42 (0.31-0.55), respectively; for vitamin B 6 intake, quintiles 2, 3, 4, and 5 were 0.53 (0.42-0.66), 0.54 (0.42-0.70), 0.61 (0.46-0.81), and 0.46 (0.33-0.63), respectively. This inverse association was not different across sex, BMI, and smoking statuses. No association was found between dietary vitamin B 2 and gastric cancer risk., Conclusions: Dietary vitamins B 1 and B 6 were associated with a reduced risk of gastric cancer in the Vietnamese population. Future studies are warranted to replicate our findings, which also have great implications for gastric cancer prevention and control programs in low- and middle-income countries.

Polyunsaturated fatty acids (PUFAs) are fatty acids, containing more than one double bond and have both anti-inflammatory properties and inhibit tumor progression effects as well as carcinogenic properties. There is inconclusive evidence regarding the effect of PUFA intake on gastric cancer in diverse populations. We, therefore, aimed to determine the association between PUFA intake and risk of gastric cancer in a hospital-based case-control study comprising 1182 incident cases of gastric cancer and 2965 controls in Vietnam. A semiquantitative validated food frequency questionnaire was used to derive PUFA intake. Unconditional logistic regression model was applied to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer in relation to PUFA intake. Overall, there was a dose-response inverse association between PUFA intake and gastric cancer risk (ORper-SD increment = 0.72, 95% CI: 0.65-0.79; Ptrend < 0.001). Compared with quintile 1 (the lowest quintile), the ORs and respective 95% CIs of gastric cancer for quintiles 2, 3, 4, and 5 of the PUFA intake were 0.65 (0.52-0.80), 0.51 (0.41-0.64), 0.47 (0.37-0.59), and 0.37 (0.28-0.48), respectively. A similar pattern was observed in both sexes and individuals aged <60 years and those aged 60 years or older. In summary, we found a risk reduction of gastric cancer in individuals with a higher intake of PUFA in the Vietnamese population, regardless of sex or age. Our findings have great implications for the prevention and control programs against gastric cancer in low-middle-income countries and similar limited-resource settings., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The deceased donor shortage in the United States has led to increased utilization extended criteria donor (ECD) liver grafts. Centers often utilize ECD grafts in patients with low Model for End-Stage Liver Disease (MELD) scores, like patients with hepatocellular carcinoma (HCC). However, few studies have directly examined the outcomes of using ECD grafts in patients with HCC., Methods: Adults receiving liver transplantation (LT) for HCC between 2010 and 2020 were identified in the Organ Procurement and Transplantation Network database. Recipients were categorized according to donor type: standard criteria donor (SCD), extended criteria donor, donation after brain death (ECD-DBD), and donation after circulatory death (DCD). Multivariable Cox regression analysis identified variables associated with overall or graft survival at 3 years post-LT., Results: Most patients received ECD-DBD grafts (51.4%); only 8.3% received DCD grafts. The time on the waitlist was similar for ECD and SCD recipients (P = .79). SCD recipients had higher 5-year overall survival post-LT than ECD-DBD or DCD recipients (79.1%, 77.1%, and 76.8%, respectively, P < .001). Similarly, 5-year graft survival was also highest in SCD recipients (SCD = 77.8%, ECD-DBD = 75.7%, and DCD = 72.2%, P < .001). In multivariable analysis, DCD grafts increased mortality risk (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 1.12-1.57, P = .001), but ECD-DBD grafts did not (HR = 1.10, 95% CI = 1.00-1.22, P = .052)., Conclusions: DCD and ECD-DBD recipients had significantly lower overall and graft survival. However, the survival benefit of LT for patients with HCC greatly outweighs the small differences in patient and graft survival from using ECD grafts. Further research should investigate whether treatment of ECD grafts with machine perfusion may ameliorate this discrepancy., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare for this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Breast cancer predominantly affects women and poses challenges in the treatment of both local and advanced diseases. In a previous study, we reported the effectiveness of ER121, a structurally resolved small compound specifically designed to target human cancers expressing or overexpressing mutant EGFR and HER2., Purpose: The objective of this study is to assess the efficacy and toxicity of ER121 in metastatic and triple negative breast cancer (TNBC, HER2+) cells and tumor models. The Herceptin-resistant breast cancer cell line JIMT-1 was used in an in vivo tumor model, and MMTV-erbB2 (Fo5) transgenic mice models were used to evaluate the efficacy and safety of ER121 as neoadjuvant., Methods: ER121 treatment focusing on experimental brain metastasis in TNBC, HER2+ model, was quantified by total flux employing the In Vivo Imaging System (IVIS). We also compared the brain tissue from the treated and the controls groups. Additionally, ER121 was evaluated in JIMT-1, a Herceptin-resistant breast cancer cell line, both in vitro and in vivo tumor model. We also administered ER121 orally in neoadjuvant model with the MMTV-erbB2 (Fo5) transgenic mice, the survival rates were compared with the control group. Tumor-free survival of multiple treated groups were analyzed by Kaplan-Meier analysis employing the log-rank test with the Bonferroni correction using R Statistical Software., Results: In this study, we present findings indicating that ER121 treatment significantly attenuated breast tumor growth using a TNBC, HER2+ model, focusing on experimental brain metastasis, as quantified by total flux employing IVIS. These observations were further corroborated by analysis of brain tissue from the treatment group compared to controls. Data is presented as Mean ± S.D. statistical significance was calculated using Student t test (* p  < 0.05). Additionally, ER121 significantly inhibited JIMT-1, a Herceptin-resistant breast cancer cell line was used in vivo xenograft model. Additionally, we used a neoadjuvant model with the MMTV-erbB2 (Fo5) transgenics and the tumor-free survival rates exhibited a remarkable difference between the control and treated groups when ER121 was administered orally. We found statistically significant p values of 0.048 employing log-rank test with Bonferroni Correction for comparing ER121 high, ER121 Low, Herceptin and PBS groups. All analyses were performed using R Statistical Software., Conclusion: ER121 is a non-toxic small-molecule erbB kinase inhibitor and holds promise as an oral and systemic therapeutic agent for treating progressive erbB-driven tumors in therapeutic settings. Moreover, ER121 shows potential as a preventive therapy in neoadjuvant settings for erbB2-associated tumors and when administered systemically can dramatically limit erbB2 brain metastases in animal models., Competing Interests: Professor Mark Greene reports grants from NIH, grants from BCRF, during the conduct of the study; In addition, ER121 is described in US11708335B2 ; and Dr. Greene is a director at Martell Diagnostic Laboratories, Inc., a private biotechnology company. He is also a paid consultant to 101 therapeutics, a private biotechnology company. The authors report no other conflicts of interest in this work., (© 2024 Goel et al.)

Background: Despite being the second leading cause of death in the United States, cancer disproportionately affects underserved communities due to multiple social factors like economic instability and limited healthcare access, leading to worse survival outcomes. This cross-sectional database study involves real-world data to explore the relationship between the Social Vulnerability Index (SVI), a measure of community resilience to disasters, and disparities in screening, incidence, and mortality rates of breast, colorectal, and lung cancer. The SVI encompasses four themes: socioeconomic status, household composition & disability, minority status & language, and housing type & transportation., Materials and Methods: Using county-level data, this study compared cancer metrics in U.S. counties and the impact of high and low SVI. Two-sided statistical analysis was performed to compare SVI tertiles and cancer screening, incidence, and mortality rates. The outcomes were analyzed with logistic regression to determine the odds ratio of SVI counties having cancer metrics at or above the median., Results: Our study encompassed 3,132 United States counties. From publicly available SVI data, we demonstrated that high SVI scores correlate with low breast and colorectal cancer screening rates, along with high incidence and mortality rates for all three types of cancers. County level SVI has impact on incidence rates of cancers; breast cancer rates were lowest in high SVI counties, while colorectal and lung cancer rates were highest in the same counties. Age-adjusted mortality rates for all three cancers increased across SVI tertiles. After risk adjustment, a 10-point SVI increase correlated with lower screening and higher mortality rates., Conclusion: In conclusion, our study establishes a significant correlation between SVI and cancer metrics, highlighting the potential to identify marginalized communities with health disparities for targeted healthcare initiatives. It underscores the need for further longitudinal studies on bridging the gap in overall cancer care in the United States., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mehta, Jeon and Nagaraj.)

Primary cardiac lymphomas (PCLs) are a rare clinical entity, in which treatment guidelines remain to be established. Rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) has been proposed, given that it involves a continuous infusion of anthracycline, reducing the risk of a cardiotoxicity and therefore the theoretical risk of perforation. However, the literature on this method of treatment is scarce. Herein, we present a unique case of a 75-year-old male, diagnosed with primary cardiac diffuse large B-cell lymphoma (DLBCL) with relatively unusual involvement of the coronary sinus, treated first with one cycle of R-EPOCH, followed by three cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) to reduce said risk. To our knowledge, this is one of two cases, in which a patient with PCL was treated this way., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: A phase 2 study of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy in metastatic non-small cell lung cancer (mNSCLC) followed by pembrolizumab (STOMP) was designed to explore the dual approach in enhancing single pembrolizumab with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mNSCLC., Methods and Materials: STOMP is a single-arm, open-label phase 2 study. Patients with mNSCLC received intratumoral injections of ADV/HSV-tk (5 × 10 11 vp) and SBRT (30 Gy in 5 fractions) followed by pembrolizumab 200 mg IV every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR) (complete response [CR] and partial response [PR]). Secondary endpoints included clinical benefit rate (CBR) (CR, PR and stable disease [SD]), progression-free survival (PFS), overall survival (OS), and safety., Results: 28 patients were enrolled, of whom 27 were evaluated for response. The ORR was 33.3%, including 2 CR (7.4%) and 7 PR (25.9%). CBR was 70.4%. Six of eight (75.0%) patients who were immune checkpoint inhibitor (ICI) refractory derived clinical benefits. Responders had durable responses with median PFS, and OS not reached. The entire cohort had a median PFS of 7.4 months (95% CI, 5.1-9.6 months), and median OS of 18.1 months (95% CI, 15.4-20.9 months). The combination was well tolerated, with grade 3 or higher toxicity in 6 (21.4%) patients., Conclusions: The dual approach of in situ ADV/HSV-tk plus valacyclovir gene therapy and SBRT as a chemotherapy-sparing strategy to enhance the antitumor effect of pembrolizumab is a well-tolerated encouraging treatment in patients with mNSCLC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The human epidermal growth factor receptor (HER) family consists of four members, activated by two families of ligands. They are known for mediating cell-cell interactions in organogenesis, and their deregulation has been associated with various cancers, including breast and esophageal cancers. In particular, aberrant epidermal growth factor receptor (EGFR) and HER2 signaling drive disease progression and result in poorer patient outcomes. Nitric oxide (NO) has been proposed as an alternative activator of the HER family and may play a role in this aberrant activation due to its ability to induce s-nitrosation and phosphorylation of the EGFR. This review discusses the potential impact of NO on HER family activation and downstream signaling, along with its role in the efficacy of therapeutics targeting the family., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 O’Neill, Sun, Sundararaman, Chang and Glynn.)

Trastuzumab deruxtecan (T-DXd) has been approved by the US Food and Drug Administration (FDA) to treat patients with metastatic HER2-positive and HER2-low breast cancer, and clinical trials are examining its efficacy against early-stage breast cancer. Current HER2 immunohistochemical (IHC) assays are suboptimal in evaluating HER2-low breast cancers and identifying which patients would benefit from T-DXd. HER2 expression in 526 breast cancer tissue microarray (TMA) cores was measured using the FDA-approved PATHWAY and HercepTest IHC assays, and the corresponding RNA levels were evaluated by RNAscope. HER2 protein levels by regression analysis using a quantitative immunofluorescence score against cell line arrays with known HER2 protein levels determined by mass spectrometry were available in 48 of the cores. RNAscope was also performed in 32 metastatic biopsies from 23 patients who were subsequently treated with T-DXd, and the results were correlated with response rate. HER2 RNA levels by RNAscope strongly correlated with HER2 protein levels (P < .0001) and with HER2 IHC H-scores from the PATHWAY and HercepTest assays (P < .0001). However, neither protein levels nor RNA levels significantly differed between cases scored 0, ultralow, and 1+ by PATHWAY and HercepTest. The RNA levels were significantly higher (P = .030) in responders (6.4 ± 8.2 dots/cell, n = 12) than those in nonresponders (2.6 ± 2.2, n = 20) to T-DXd. RNAscope is a simple assay that can be objectively quantified and is a promising alternative to current IHC assays in evaluating HER2 expression in breast cancers, especially HER2-low cases, and may identify patients who would benefit from T-DXd., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Multiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER-breast cancers.

Estrogen receptor-negative (ER-) breast cancer is an aggressive breast cancer subtype with limited therapeutic options. Upregulated expression of both inducible nitric oxide synthase (NOS2) and cyclo-oxygenase (COX2) in breast tumors predicts poor clinical outcomes. Signaling molecules released by these enzymes activate oncogenic pathways, driving cancer stemness, metastasis, and immune suppression. The influence of tumor NOS2/COX2 expression on the landscape of immune markers using multiplex fluorescence imaging of 21 ER- breast tumors were stratified for survival. A powerful relationship between tumor NOS2/COX2 expression and distinct CD8+ T cell phenotypes was observed at 5 years post-diagnosis. These results were confirmed in a validation cohort using gene expression data showing that ratios of NOS2 to CD8 and COX2 to CD8 are strongly associated with poor outcomes in high NOS2/COX2-expressing tumors. Importantly, multiplex imaging identified distinct CD8+ T cell phenotypes relative to tumor NOS2/COX2 expression in Deceased vs Alive patient tumors at 5-year survival. CD8+NOS2-COX2- phenotypes defined fully inflamed tumors with significantly elevated CD8+ T cell infiltration in Alive tumors expressing low NOS2/COX2. In contrast, two distinct phenotypes including inflamed CD8+NOS2+COX2+ regions with stroma-restricted CD8+ T cells and CD8-NOS2-COX2+ immune desert regions with abated CD8+ T cell penetration, were significantly elevated in Deceased tumors with high NOS2/COX2 expression. These results were supported by applying an unsupervised nonlinear dimensionality-reduction technique, UMAP, correlating specific spatial CD8/NOS2/COX2 expression patterns with patient survival. Moreover, spatial analysis of the CD44v6 and EpCAM cancer stem cell (CSC) markers within the CD8/NOS2/COX2 expression landscape revealed positive correlations between EpCAM and inflamed stroma-restricted CD8+NOS2+COX2+ phenotypes at the tumor/stroma interface in deceased patients. Also, positive correlations between CD44v6 and COX2 were identified in immune desert regions in deceased patients. Furthermore, migrating tumor cells were shown to occur only in the CD8-NOS2+COX2+ regions, identifying a metastatic hot spot. Taken together, this study shows the strength of spatial localization analyses of the CD8/NOS2/COX2 landscape, how it shapes the tumor immune microenvironment and the selection of aggressive tumor phenotypes in distinct regions that lead to poor clinical outcomes. This technique could be beneficial for describing tumor niches with increased aggressiveness that may respond to clinically available NOS2/COX2 inhibitors or immune-modulatory agents.

The herb Prunella vulgaris has shown significant immune-stimulatory and anti-inflammatory effects in mouse models. Here, the effects of a novel Prunella vulgaris -containing herbal mixture, PV-1, were examined in several mouse models for cancer, including chemically induced models of lung and oral cancers as well as syngraft models for lung cancer and melanoma. PV-1, consisting of extracts from Prunella vulgaris , Polygonum bistorta , Sonchus brachyotus and Dictamnus dasycarpus , exhibited no toxicity in a dose escalation study in A/J mice. PV-1 significantly inhibited mouse lung tumor development induced by the lung carcinogens vinyl carbamate and benzo[a]pyrene. PV-1 also hindered the induction of oral squamous cell carcinomas in C57BL/6 mice caused by 4-nitroquinoline-1-oxide. Flow cytometry analysis showed that PV-1 increased the numbers of CD8+ tumor-infiltrating lymphocytes (TILs) and increased the production of granzyme B, TNF-α, and IFN-γ by CD8+ TILs. PV-1 also suppressed granulocytic myeloid-derived suppressor cell numbers (g-MDSCs) and improved the anti-cancer activity of anti-PD-1 immunotherapy. These results indicate that PV-1 remodels the tumor immune microenvironment by selectively inhibiting g-MDSCs and increasing CD8+ TILs within tumors, resulting in decreased immune suppression and enhanced cancer chemopreventive efficacy., Competing Interests: MH is a co-founder of Sanarentero LLC Houston, Texas, USA, but Sanarentero was not involved in the research conducted for this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Chen, Palen, Johnson, Bui, Xiong, Pan, Hu, Wang and You.)

Background: The first-in-class approved BCMA CAR-T therapy was idecabtagene vicleucel (ide-cel), approved in March 2021, for RRMM patients who progressed after 4 or more lines of therapy. Despite the promising outcomes, there were limited apheresis/production slots for ide-cel. We report outcomes of patients at our institution who were on the "waitlist" to receive ide-cel in 2021 and who could not secure a slot., Methods: We conducted a retrospective review of RRMM patients evaluated at the University of Kansas Cancer Center for ide-cel from 3/2021-7/2021. A retrospective chart review was performed to determine patient and disease characteristics. Descriptive statistics were reported using medians for continuous variables. Survival analysis from initial consult was performed using Kaplan-Meier Survival estimator., Results: Forty patients were eligible and were on the "waitlist" for CAR-T. The median follow-up was 14 months (2-25mo). Twenty-four patients (60%) secured a production slot and 16 (40%) did not. The median time from consult to collection was 38 days (8-703). The median time from collection to infusion was 42 days (34-132 days). The median overall survival was higher in the CAR-T group (NR vs 9 mo, p<0.001)., Conclusions: Many patients who were eligible for ide-cel were not able to secure a timely slot in 2021. Mortality was higher in this group, due to a lack of comparable alternatives. Increasing alternate options as well as improvement in manufacturing and access is an area of high importance to improve RRMM outcomes., Competing Interests: Author NA: Advisory Board BMS, consultancy and institutional research funding from Kite. Author JM reports honoraria from Kite/Gilead, Juno Therapeutics, Allovir, Magenta Therapeutics, EcoR1 Capital, Janssen and BMS/Celgene. He receives research funding from Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, Pluristem Therapeutics, Kite/Gilead and Allovir. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ahmed, Wesson, Mushtaq, Bansal, AbdelHakim, Bromert, Appenfeller, Ghazal, Singh, Abhyankar, Ganguly, McGuirk, Abdallah and Shune.)

A strong correlation between NOS2 and COX2 tumor expression and poor clinical outcomes in ER breast cancer has been established. However, the mechanisms of tumor induction of these enzymes are unclear. Analysis of The Cancer Genome Atlas (TCGA) revealed correlations between NOS2 and COX2 expression and Th1 cytokines. Herein, single-cell RNAseq analysis of TNBC cells shows potent NOS2 and COX2 induction by IFNγ combined with IL1β or TNFα. Given that IFNγ is secreted by cytolytic lymphocytes, which improve clinical outcomes, this role of IFNγ presents a dichotomy. To explore this conundrum, tumor NOS2, COX2, and CD8 + T cells were spatially analyzed in aggressive ER-, TNBC, and HER2 + breast tumors. High expression and clustering of NOS2-expressing tumor cells occurred at the tumor/stroma interface in the presence of stroma-restricted CD8 + T cells. High expression and clustering of COX2-expressing tumor cells extended into immune desert regions in the tumor core where CD8 + T cell penetration was limited or absent. Moreover, high NOS2-expressing tumor cells were proximal to areas with increased satellitosis, suggestive of cell clusters with a higher metastatic potential. Further in vitro experiments revealed that IFNγ + IL1β/TNFα increased the elongation and migration of treated tumor cells. This spatial analysis of the tumor microenvironment provides important insight into distinct neighborhoods where stroma-restricted CD8 + T cells exist proximal to NOS2-expressing tumor niches that could have increased metastatic potential., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Antitumor immune polarization is a key predictor of clinical outcomes to cancer therapy. An emerging concept influencing clinical outcome involves the spatial location of CD8 + T cells, within the tumor. Our earlier work demonstrated immunosuppressive effects of NOS2 and COX2 tumor expression. Here, we show that NOS2/COX2 levels influence both the polarization and spatial location of lymphoid cells including CD8 + T cells. Importantly, elevated tumor NOS2/COX2 correlated with exclusion of CD8 + T cells from the tumor epithelium. In contrast, tumors expressing low NOS2/COX2 had increased CD8 + T cell penetration into the tumor epithelium. Consistent with a causative relationship between these observations, pharmacological inhibition of COX2 with indomethacin dramatically reduced tumor growth of the 4T1 model of TNBC in both WT and Nos2 - mice. This regimen led to complete tumor regression in ∼20-25% of tumor-bearing Nos2 - mice, and these animals were resistant to tumor rechallenge. Th1 cytokines were elevated in the blood of treated mice and intratumoral CD4 + and CD8 + T cells were higher in mice that received indomethacin when compared to control untreated mice. Multiplex immunofluorescence imaging confirmed our phenotyping results and demonstrated that targeted Nos2/Cox2 blockade improved CD8 + T cell penetration into the 4T1 tumor core. These findings are consistent with our observations in low NOS2/COX2 expressing breast tumors proving that COX2 activity is responsible for limiting the spatial distribution of effector T cells in TNBC. Together these results suggest that clinically available NSAID's may provide a cost-effective, novel immunotherapeutic approach for treatment of aggressive tumors including triple negative breast cancer., Competing Interests: Declaration of competing interest The authors have no conflict of interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The aim of this study was to demonstrate that uveal melanoma (UM) treated with eye plaque brachytherapy (EPB) with intra-operative ultrasound (IOUS) guidance results in increased local control., Material and Methods: A retrospective study was conducted among 212 patients with 214 UM tumors treated by iodine-125 EPB with IOUS guidance from 2013 to 2019. 85 Gy was prescribed to tumor apical height or 5 mm from inner sclera, whichever was greater. Lesions were treated to 95% of 85 Gy at 2 mm margin from tumor edge. Local failure (LF), distant metastasis (DM), and radiation-related toxicity were recorded., Results: Median tumor apical height was 3.3 mm. COMS stage was 90 small (42.1%), 81 medium (37.9%), and 43 large (20.1%). Most patients had gene expression profile (GEP) class available, with 119 (55.6%), 30 (14.0%), 55 (25.7%) cases classified as 1A, 1B, and 2, respectively. Median dose at apex for tumor height > 5 mm and ≤ 5 mm was 85.0 Gy and 120.6 Gy, respectively. Outcomes data for 180 patients with over 12 months follow-up were reported. Mean follow-up was 37.3 months. Rates of LF and DM were 0.0% and 12.2%, respectively. Actuarial estimates of 5-year DM for class 1A, 1B, and 2 tumors were 2.5%, 0.0%, and 57.8%, respectively. 87 patients (48.3%) developed radiation-related toxicities., Conclusions: The excellent local control rate amongst lesions ranging across all sizes and GEP classes emphasizes the importance of image-guided brachytherapy with IOUS. We report favorable 5-year DM rates compared to established rates. Acceptable rate and severity of radiation-related toxicities were observed., Competing Interests: Andrew J. Wong, Bin S. Teh, Brandon T. Nguyen, Ramiro Pino, Maria E. Bretana, and E. Brian Butler report no conflict of interest. Eric H. Bernicker report grants or contracts from any entity, past 36 months: Merck; Participation on a Data Safety Monitoring Board or Advisory Board: DSMB MD Anderson. Patricia Chevez-Barrios report grants or contracts from any entity, past 36 months: Adopt-A-Scientist (retinoblastoma), NASA (space flight effect on eyes). Amy C. Schefler report consulting fees, past 36 months: Genentech, Regeneron, Aura Biosciences, Castle Biosciences; Payment of honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events, past 36 months: Genentech, Regeneron, Aura Biosciences, Castle Biosciences., (Copyright © 2022 Termedia.)