Citations

Abstract Although immune checkpoint blockade that targets the PD-L1 has revolutionized the treatment of human cancers, only a small proportion of patients positively respond to this form of treatment. A limitation of these therapies is that they only target and inhibit PD-L1’s extracellular function, which is to bind its receptor on PD-1 on T cells and inhibit T cell cytotoxicity. Recent discoveries have shown that PD-L1 expressed on tumor cells can signal intrinsically and independently of PD-1 ligation to promote tumor cell survival. Besides tumor cells, host myeloid cells have been shown to have high expression of PD-L1, therefore contributing to the immunosuppressive nature of the tumor. However, PD-L1 intrinsic signaling in human myeloid cells has not been studied. Therefore, the purpose of our work is to determine the intrinsic functions of PD-L1 in myeloid cells and how this impacts anti-tumor immunity. To study this, we used a novel PD-L1 antibody (H1A) that does not block PD-L1’s binding with PD-1, but directs PD-L1 for degradation, thereby decreasing total PD-L1 expression. Additionally, we developed a chimeric mouse model in which the murine PD-1/PD-L1 has been replaced with the human version. This allows us to evaluate PD-L1’s intrinsic function in vivo. In our preliminary studies, the degradation of PD-L1 in human monocytes led to increased chemokine release as well as increased conversion of effector T cells. Additionally, H1A treatment of tumor-bearing mice led to lower tumor burden in a CD8 T cell dependent manner. Based on these results, PD-L1 intrinsic signaling has the potential to regulate the immune-stimulatory response of monocytes, thereby limiting effector T cell responses against cancer. Supported by grants from NIH (R0192389) and Mayo Clinic graduate school of biomedical sciences

Abstract Though anti-PD-1/PD-L1 immune checkpoint blockade therapy has demonstrated robust anti-tumor immunity in human patients with advanced cancers such as melanoma, only a fraction of patients achieved such durable anti-tumor responses. Among all the non-responders, some patients responded initially but developed resistance to the therapy in the later treatments. This reflects an urgent need to understand the role of PD-1 signals in CD8+ T cells at priming and at effector stages during tumor development for the benefit of immunotherapy. The controversy of rapid tumor progression in PD-1 conditional knockout in regulatory T cells and tumor regression in PD-1 targeted deletion in regulatory T cells indicated germline PD-1 knockout mice might not be sophisticated enough to study the role of PD-1 in CD8+ T cells during tumor development. Thus, we produced a CD8 T cell-specific PD-1 knockout mouse model (CD8 E8ICre-PD-1fl/fl, also called CD8-PD-1 cKO mice) in which PD-1 is deleted in CD8+ T cells in the peripheral tissues. When CD8-PD-1 cKO mice were challenged with B16-OVA mouse melanoma cells, we found a delayed tumor growth and prolonged survival of CD8-PD-1 cKO compared to control mice. However, after 20 days of tumor challenge, the delayed tumor growth rebound in CD8-PD-1 cKO mice. In an OVA antigen immunization model, we found increased effector cells and tissue resident cells in the spleen of CD8-PD-1 cKO mice compared with control mice on day 7 after immunization. Taken together, our results suggest that PD-1 may restrain the expansion of effector T cells that contribute to the early phase of tumor control, but the augmented effector T cell response may cause an attrition of memory T cell pool that will be needed for long term protection. R01CA256927

The NCCN Guidelines for Survivorship are intended to help healthcare professionals address the complex and varied needs of cancer survivors. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for psychosocial and physical problems resulting from adult-onset cancer and its treatment; recommendations to help promote healthy behaviors and immunizations in survivors; and a framework for care coordination. These NCCN Guidelines Insights summarize recent guideline updates and panel discussions pertaining to sleep disorders, fatigue, and cognitive function in cancer survivors.

AbstractObjectiveTo evaluate the impact of a virtual registered nurse (ViRN) model on safety and care outcomes. ViRN is a telemedicine intervention that enables an experienced virtual nurse to assist the in‐person care team in providing care to patients.Data Sources and Study SettingElectronic health records data were utilized from the Mayo Clinic during the intervention (December 2020–November 2021) and historical periods (December 2018–November 2019). ViRN was implemented on general medical units at the Mayo Clinic Rochester. We used general medical units at the Mayo Clinic Arizona as the comparison group.Study DesignThis study used a difference‐in‐differences design to evaluate the impact of ViRN compared to usual care on transfer to the intensive care unit (ICU), inpatient mortality, and length of stay (LOS). We used logistic regression for transfer to the ICU and inpatient mortality and negative binomial regression for LOS. We controlled for demographics, patient interaction with the health system, clinical characteristics, and admission characteristics. We clustered standard errors to account for patients who have multiple admissions during the study period.Principal FindingsThere were no significant differences for transfer to the ICU (average marginal effect (AME) −0.08 percentage point [95% confidence interval (CI): −1.34, 1.18]), inpatient mortality (AME 0.43 percentage point [95% CI: −0.33, 1.18]), or LOS (AME −0.20 days [95% CI: −0.57, 0.17]). The findings were mostly consistent across the sensitivity analyses.ConclusionsOur results suggest that ViRN led to similar outcomes as usual care in general medical units. These findings support the potential to develop more advanced models of ViRN at the Mayo Clinic and the dissemination of the ViRN model to other systems. In the context of staffing shortages and other disruptions to the delivery of nursing care, it is critical to understand whether new models like ViRN provide nurse staffing alternatives without negatively affecting outcomes.

Background Although online self-triage is easily accessible, little is known about the patients who use self-triage or their subsequent diagnoses. We compared ear/hearing self-triage subsequent diagnoses to ear/hearing visit diagnoses in emergency departments (ED) and ambulatory clinics across the United States. Methods We compared International Classification of Diseases version 10 (ICD10) coded diagnoses following online self-triage for ear/hearing concerns with those from national ED and ambulatory clinic samples. We used data from the Centers for Disease Control (CDC) National Hospital Ambulatory Medical Care Survey (NHAMCS) and National Ambulatory Medical Care Survey (NAMCS) for comparison. Using matched ear/hearing diagnostic categories for those aged 1 and over, we compared self-triage diagnosis frequencies with national ED and ambulatory diagnosis frequencies. Results Following ear/hearing self-triage, there were 1092 subsequent office visits with a primary diagnosis code. For five frequently diagnosed ear/hearing conditions (i.e., suppurative and nonsuppurative otitis media [OM], otalgia, otitis externa, and cerumen impaction), there was a strong correlation between diagnosis counts made following self-triage and estimated counts of national ED visit diagnoses (r = 0.94; CI 95% [0.37 to 0.99]; p = .016, adjusted r2 = 0.85). Seven diagnoses were available to compare with the national ambulatory sample; correlation was r = 0.79; CI 95% [0.08 to 0.97]; p = .037, adjusted r2 = 0.54. For ages 1 and over, estimated hospital admissions from the national ED visits for ear/hearing were 0.76%, CI 95% [0.28-2.1%]; estimated total national ear/hearing ED visits were 7.5 million (for 4 years, 2016 through 2019). Conclusion The strong correlation of ear-related self-triage diagnoses with national ED diagnoses and the low hospitalization risk for these diagnoses suggests that there is an opportunity for self-triage of ear/hearing concerns to decrease ED visits for these symptoms.

To understand whether they found a two-step decision process helpful and why, adolescent-parent dyads participating in a study investigating return of genomic testing results were asked about their decision-making experience. Responses were qualitatively coded and analyzed using thematic analysis. Adolescents and parents found both joint and independent decision-making stages helpful. Regarding independent decision-making, adolescents appreciated exercising independence, while parents valued both adolescent and parental independence. Joint decision-making allowed each to hear the other's viewpoints. Some found joint decision-making irrelevant but recognized it might help others. Overall, adolescents and parents had similar reasons for finding the two-step decision-making process helpful. Our findings support using such a process for engaging parents and adolescents in challenging research and clinical decisions.