Citations

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Abstract Aims Pericardiocentesis is usually completed under fluoroscopy. The electroanatomic mapping (EAM) system allows visualizing puncture needle tip (NT) while displaying the electrogram recorded from NT, making it possible to obtain epicardial access (EA) independent of fluoroscopy. This study was designed to establish and validate a technique by which EA is obtained under guidance of three-dimensional (3D) EAM combined with NT electrogram. Methods and results 3D shell of the heart was generated, and the NT was made trackable in the EAM system. Unipolar NT electrogram was continuously monitored. Penetration into pericardial sac was determined by an increase in NT potential amplitude and an injury current. A long guidewire of which the tip was also visible in the EAM system was advanced to confirm EA. Epicardial access was successfully obtained without complication in 13 pigs and 22 patients. In the animals, NT potential amplitude was 3.2 ± 1.0 mV when it was located in mediastinum, 5.2 ± 1.6 mV when in contact with fibrous pericardium, and 9.8 ± 2.8 mV after penetrating into pericardial sac (all P ≤ 0.001). In human subjects, it measured 1.54 ± 0.40 mV, 3.61 ± 1.08 mV, and 7.15 ± 2.88 mV, respectively (all P < 0.001). Fluoroscopy time decreased in every 4–5 cases (64 ± 15, 23 ± 17, and 0 s for animals 1–4, 5–8, 9–13, respectively, P = 0.01; 44 ± 23, 31 ± 18, 4±7 s for patients 1–7, 8–14, 15–22, respectively, P < 0.001). In five pigs and seven patients, EA was obtained without X-ray exposure. Conclusion By tracking NT in the 3D EAM system and continuously monitoring the NT electrogram, it is feasible and safe to obtain EA with minimum or no fluoroscopic guidance.

Abstract Background An increasing incidence of pediatric-onset inflammatory bowel disease (PIBD) has been reported in many countries. However, the global burden and distribution of this disease remain less understood. We aimed to examine the global epidemiology and trends of PIBD from 1990 to 2019. Methods Data from the 2019 Global Burden of Disease Study, covering 204 countries, were analyzed. We assessed key measures like incidence, prevalence, mortality, and disability-adjusted life years (DALYs) using linear regression to calculate annual percentage changes and assess trends. Results Between 1990 and 2019, the PIBD incidence rate increased and the DALY rate and mortality rate declined. The incidence rate was notably elevated in the high Socio-demographic Index (SDI) quintile, reaching 6.3 per 100 000 person-years, corresponding to 13 914 new cases in 2019. Incidence and prevalence of PIBD positively correlated with the SDI, while higher death and DALY burdens were observed in lower-SDI countries. In 2019, the top 5 countries with the highest PIBD incidence rates were Canada (19.9 per 100 000 population), Denmark (12.4 per 100 000 population), Hungary (8.5 per 100 000 population), Austria (8.1 per 100 000 population), and the United States (7.4 per 100 000 population). Several countries experienced significant increases in incidence rates from 1990 to 2019, led by Taiwan (annual percent change 4.2%), followed by China (2.8%), Japan (2.1%), Australia (1.8%), and Hungary (1.6%). Discussion PIBD incidence has significantly increased since 1990. High-SDI countries face higher incidence, while lower-SDI countries experience higher mortality and DALY burdens. The study underscores the need for ongoing monitoring and research to address this emerging public health issue.

Abstract Cytotoxic CD8+ T cells play a key role in response to anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) therapy. However, the exact effector molecules that are regulated by PD-1 signals in cytotoxic CD8+ T cells have not been completely defined. Lack of this knowledge is a crucial problem in addressing how to overcome the low clinical response rate to ICI therapy. When exploring why certain patients not responding to ICI therapy, we found non-responders did not have an elevated NKG7 expression in CD8+ T cells as responders to ICI therapy. The difference in NKG7 expression in CD8+ T cells between non-responders and responders to anti-PD-1 therapy prompted us to investigate the potential role of PD-1 signaling in regulating NKG7 expression. To that end, we generated a CD8+ T cell-specific Pdcd1 conditional knockout mice (CD8 E8ICre-Pdcd1fl/fl, also known as CD8-PD-1 cKO) where Pdcd1 is deleted after thymic selection of single positive CD8+ T cells. We observed a delayed tumor growth and prolonged survival in CD8-PD-1 cKO mice compared to control mice after B16-OVA melanoma tumor challenge. On Day 12, when the CD8-PD-1 cKO mice demonstrated their ability to control tumor growth, we conducted single cell RNA sequencing on isolated tumor infiltrating CD8+ T cells, revealing a significant increase of Nkg7 expression in effector CD8+ T cells in the Pdcd1 deficient CD8+ T cells compared to the control wild type T cells. Pdcd1-deficient effector CD8+ T cells also had increased expression of genes linked to NFAT/Calcineurin signaling pathway including Nfatc1, S100a4, Tbet and Tox, suggesting Nkg7 could be regulated by Pdcd1 via the NFAT pathway. To determine the impact of increased NKG7 expression in CD8+ T cells, we used OVA protein as a surrogate tumor antigen in vaccination. We found a complete B16-OVA tumor rejection in CD8-PD-1 cKO mice compared to control mice when tumor cells were injected on day 7 after vaccination with OVA protein and poly (I:C) (as an adjuvant), but only a partial rejection on day 21. The CD8-PD-1 cKO mice that were tumor-free for 30-40 days rejected 2nd tumor challenge with B16-OVA tumors. This long-term protection is tumor antigen (OVA) specific because these mice did not reject B16F10 tumor cells that do not express OVA antigen. We also found effector memory CD8+ T cells with high cytotoxicity increased in the spleen of CD8-PD-1 cKO mice after OVA antigen immunization compared to control. In conclusion, we found NKG7 is one of the effector molecules in cytotoxic CD8+ T cells, which can be regulated by PD-1 signals through NFAT signaling. Targeting the PD-1-NFAT pathway may be a new option to overcome low responses of T cells to ICI therapy in treatment of refractory cancer. Citation Format: Zhiming Mao, Joanina Gicobi, Jacob Hirdler, Xin Liu, Michelle Hsu, Emilia Dellacecca, Wenjing Zhang, Fabrice Lucien-Matteoni, Hai dong. PD-1 signals regulate NKG7 that is required for CD8+ T cells to sustain cytotoxicity and durable antitumor memory responses [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 3979.

Abstract Background: Although targeting myeloid cells has become one of the next generation targets for cancer immunotherapy, there is a lack of therapeutic tools to specifically target these cells. Our group has developed a novel humanized PD-L1-targeting antibody, H1A, that induces PD-L1 degradation via blockade of PD-L1 and CMTM6, therefore limiting PD-L1 intrinsic signaling while also preventing interactions with PD-1. In the immune cell compartment, CMTM6 expression is restricted to myeloid cells, making these cells the primary target of H1A. Recently, we unexpectedly found that targeting intrinsic PD-L1 in myeloid cells via H1A resulted in increased release of CCL2 from myeloid cells. In this study, we examined the role of CCL2/CCR2 signaling in CD8 T cell function using human peripheral blood-derived immune cells and evaluated the therapeutic potential of H1A antibody using our humanized PD-L1/PD-1 mouse model. Methods: Human PBMCs derived from healthy donors were treated with H1A or Atezolizumab, a blocking PD-L1 antibody, followed by mass cytometry and flow cytometry to evaluate immune cell phenotype and functional states. PD-L1 expressing myeloid cells isolated from human PBMCs were treated with H1A or Atezolizumab and assessed for CCL2 secretion using multiplex immunoassays. CCL2 production and transcription were confirmed by flow cytometry and single-cell RNA-sequencing. CCR2 blockade was used on human PBMCs to evaluate the effects of CCL2/CCR2 signaling on T cell function alongside H1A treatment. Finally, in vivo antitumor activity of H1A and Atezolizumab were compared in two humanized PD-L1 tumor models. Results: H1A reduced the frequency of regulatory T cells and increased effector T cells, in whole PBMCs upon global T cell activation with anti-CD3/CD28. H1A enhanced the secretion and production of CCL2 from myeloid cells, which was confirmed at a transcript level. CCR2 blockade diminished CD8 T cells’ ability to differentiate into effector cells in H1A treated PBMCs. H1A demonstrated comparable therapeutic effects with Atezolizumab in treatment of immunogenic and ICI-responsive mouse tumor MC38, which is CD8 T cell-dependent, but showed superior therapeutic effects in treatment of ICI-insensitive mouse tumor E0771 compared to Atezolizumab. Both treatments elicited durable memory specific immune responses upon E0771 tumor rechallenge. Conclusion: H1A demonstrated a superior antitumor activity compared to Atezolizumab in our preclinical models via a new mechanism by which H1A caused degradation of intrinsic PD-L1 in myeloid cells. This causes more release of CCL2 to improve T cell function via CCR2 upon T cell activation. Thus, H1A is emerging as a new immunotherapy tool to target PD-L1/CMTM6 in myeloid cells for treatment of cancers that are refractory to current immune checkpoint inhibitor therapy. Citation Format: Michelle Alexandria Hsu, Xin Liu, Ying Li, Whitney Barham, Kevin Pavelko, Jake Hirdler, Fabrice Lucien, Haidong Dong. Targeting PD-L1/CMTM6 in myeloid cells results in elevated release of CCL2 to improve CD8 T cell-mediated antitumor response [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 2664.

Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

Abstract Purpose: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. Experimental Design: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. Results: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. Conclusions: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. Significance: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

Abstract Accumulating evidence suggests that changes in the tumor microenvironment caused by radiotherapy are closely related to the recurrence of glioma. However, the mechanisms by which such radiation‐induced changes are involved in tumor regrowth have not yet been fully investigated. In the present study, how cranial irradiation‐induced senescence in non‐neoplastic brain cells contributes to glioma progression is explored. It is observed that senescent brain cells facilitated tumor regrowth by enhancing the peripheral recruitment of myeloid inflammatory cells in glioblastoma. Further, it is identified that astrocytes are one of the most susceptible senescent populations and that they promoted chemokine secretion in glioma cells via the senescence‐associated secretory phenotype. By using senolytic agents after radiotherapy to eliminate these senescent cells substantially prolonged survival time in preclinical models. The findings suggest the tumor‐promoting role of senescent astrocytes in the irradiated glioma microenvironment and emphasize the translational relevance of senolytic agents for enhancing the efficacy of radiotherapy in gliomas.