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Background: Children with relapsed/refractory cancer have a myriad of palliative care needs. While pediatric oncology clinicians meet many of these needs, studies suggest that these children often have distressing symptoms and that families feel unprepared for their child's end-of-life (EOL). Oncology clinicians cite barriers to pediatric palliative care (PPC) consultation, including concerns that PPC teams will upset families with EOL discussions. This study evaluated topics addressed by PPC teams over the course of their relationship with children who died from cancer. Methods: Retrospective chart review of children who were diagnosed with relapsed/refractory cancer, received PPC consultation at an academic children's hospital, and died between January 2008 and January 2017. Information was extracted regarding the child's treatment, EOL care, and the content of PPC consultation over the course of the team's relationship with the child/family. Results: Fifty-six children were included in the analysis. The most frequent reasons for the initial consult were pain ( n = 31, 55%) and non-pain symptom management ( n = 18, 32%). At the initial consult, the PPC team most often discussed symptom management and psychosocial support. Prognosis was not discussed in any initial consult. Over subsequent visits, the PPC team expanded their scope of discussion to include goals of care, advance care planning, and hospice. Discussion: Concerns from oncology clinicians that PPC teams will extend beyond the reasons for initial consult into prognostic/EOL discussions at the first visit may be unfounded. Greater familiarity with PPC team practices may facilitate more timely consultation of PPC and its complementary set of services.

PURPOSE Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19– relapses and explore treatment variables associated with inferior survival. METHODS We conducted a retrospective multi-institutional study of 80 children and young adults with B-cell acute lymphoblastic leukemia experiencing nonresponse (n = 23) or relapse (n = 57) after tisagenlecleucel. We analyze associations between baseline characteristics and these outcomes and establish survival rates and salvage approaches. RESULTS The overall survival (OS) at 12 months was 19% across nonresponders (n = 23; 95% CI, 7 to 50). Ninety-five percent of patients with nonresponse had high preinfusion disease burden. Among 156 morphologic responders, the cumulative incidence of relapse was 37% (95% CI, 30 to 47) at 12 months (CD19+; 21% [15 to 29], CD19–; 16% [11 to 24], median follow-up; 380 days). Across 57 patients experiencing relapse, the OS was 52% (95% CI, 38 to 71) at 12 months after time of relapse. Notably, CD19– relapse was associated with significantly decreased OS as compared with patients who relapsed with conserved CD19 expression (CD19– 12-month OS; 30% [14 to 66], CD19+ 12-month OS; 68% [49 to 92], P = .0068). Inotuzumab, CAR reinfusion, and chemotherapy were used as postrelapse salvage therapy with greatest frequency, yet high variability in treatment sequencing and responses limits efficacy analysis across salvage approaches. CONCLUSION We describe poor survival across patients experiencing nonresponse to tisagenlecleucel. In the post-tisagenlecleucel relapse setting, patients can be salvaged; however, CD19– relapse is distinctly associated with decreased survival outcomes.

In response to the COVID-19 pandemic, we developed and implemented a theory-informed process to adapt a comprehensive pre-clerkship medical school curriculum to run in the virtual learning environment utilizing sociocultural learning theory and cognitive load theory. Of 124 student respondents, 45% rated virtual learning as very or extremely effective, and 49% as moderately effective. Positive aspects of virtual learning included effectiveness of chat moderators, displaying pronouns on Zoom, active learning technology, and captioning and transcription. Negative aspects included access to technology and feeling isolated from community. Overall course ratings, examination performance, and work hours did not differ pre- and post-implementation.

Background Consultation of specialty palliative care remains uncommon in pediatric stem cell transplant (SCT) despite growing evidence that early integration of palliative care improves outcomes in patients with advanced cancers or undergoing SCT. Little is known about how multidisciplinary pediatric SCT teams perceive palliative care and its role in SCT. Procedure We conducted semi-structured interviews of members of a multi-disciplinary SCT team to understand their perceptions of palliative care, how specialty palliative care is integrated into SCT, and to identify barriers to increased integration. Eligible participants included physicians, nurses, nurse practitioners, social workers, and child life specialists. Data was analyzed using thematic analysis. Results Four major themes were identified. First, SCT team members held a favorable perception of the palliative care team. Second, participants desired increased palliative care integration in SCT. Third, participants believed that the palliative care team had insufficient resources to care for the large number of SCT patients which led to the SCT team limiting palliative care consultation. And, finally, the lack of a standardized palliative care consultation process prevented greater integration of palliative care in SCT. Conclusions SCT team members held a favorable perception of palliative care and saw a role for greater palliative care integration throughout the SCT course. We identified modifiable barriers to greater palliative care integration. SCT teams who desire greater palliative care integration may adapt and implement an existing model of palliative care integration in order to improve standardization and increase integration of specialty palliative care in SCT.

Pediatric and adult patients with recurrent/refractory Burkitt lymphoma (BL) continue to have poor outcomes, emphasizing the need for newer therapeutic agents. Bruton’s tyrosine kinase (BTK) is activated following B-cell receptor stimulation and in part regulates normal B-cell development. Ibrutinib, a selective and irreversible BTK inhibitor, has been efficacious in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström’s macroglobulinemia, and marginal zone lymphoma. In this study, we investigated the efficacy of ibrutinib alone and in selective adjuvant combinations against BL in-vitro and in a human BL xenografted immune-deficient NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mouse model. Our data demonstrated that phospho-BTK level was significantly reduced in BL cells treated with ibrutinib (p

The stochastic and heterogeneous nature of Systemic Lupus Erythematosus (SLE) supports a model whereby multiple genetic and/or environmental hits culminate in loss of tolerance and autoantibody production. Consistent with this model, the phenotype of CD45E613R mice that contain a single point mutation in the juxtamembrane wedge of CD45 depends on genetic context. Despite similar dysregulated phosphatase activity in all immune cells, CD45E613R mice on a C57Bl/6 (B6) background have no overt phenotype while BALB/c (BA) mice develop anti-double stranded (ds) DNA antibodies. An unbiased genome-wide screen for modifiers of autoantibody production between CD45E613R B6 and BA mice identified two candidate loci: Wedge Associated Modifier (Wam) 1 on Chromosome (Chr) 9 encompassing tlr9 and Wam2 on Chr 17 encompassing MHC H2. Previous work has shown that the hyporesponsive BA TLR9 allele permits anti-ds DNA antibodies while the B6 TLR9 allele is resistant. Here, we analyze the contribution of the MHC to this phenotype. CD45E613R BALB/c mice congenic for the B6 H2 locus develop anti-Sm antibodies while B6 mice congenic for the BALB/c H2 locus develop anti-Sm and anti-dsDNA antibodies. H2 congenic CD45E613R BALB/c mice have increased transitional B cells and a trend in increased B1 cells compared to congenic B6 mice. Thus, we hypothesize that MHC influences autoantibody specificity.

The mechanisms regulating the transition from autoreactivity to autoimmunity are poorly understood. CD45E613R mice express a point mutation in the juxtamembrane wedge that results in dysregulated phosphatase activity. Despite similar hyperactive ITAM-mediated signaling in multiple cell lineages, the phenotypic consequences of this mutation vary with genetic context. While both BALB/c and C57Bl/6-129 F1 CD45E613R mice develop similar high titer anti-nuclear antibodies (ANA) and immune complex deposition in the glomeruli, only F1 mice develop glomerulonephritis (GN). Here, we leverage these distinct phenotypes in the context of a common point mutation to define mechanisms leading to GN. BALB/c ANA are primarily anti-dsDNA while F1 ANA are anti-dsDNA, -H3 and -Sm/RNP. Consistent with this profile, F1 B cells have increased TLR7/9 signaling. Treatment of RAW264.7 cells with aged F1 but not BALB/c CD45E613R sera induces an inflammatory phenotype. Additionally, IL-10, IL-12, MCP-1 and RANTES are elevated in aged F1 CD45E613R mice. Analysis of young, autoantibody-free mice shows increased CD11b+ CD11c+ F4/80+ renal mononuclear cells surrounding F1 but not BALB/c CD45E613R glomeruli. Upon stimulation, only F1 CD45E613R renal mononuclear cells produce TNFα and IFNγ. Together, these data support a model in which an expanded antibody repertoire combined with altered kidney immune cell subsets and altered cytokines mediate the transition from autoreactivity to autoimmunity.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder with a range of presentations. Lupus nephritis is a particularly severe feature of SLE that predicts a poor outcome. Currently, it is unclear why some patients develop severe end organ disease while others have a relatively benign course. The CD45E613R mouse is a tractable model of SLE to study the transition from autoreactivity to autoimmunity. These mice express a single amino acid substitution (E613R) in the juxtamembrane wedge of CD45 that results in dysregulated phosphatase activity in all hematopoietic cells. Mirroring the variable presentation of human SLE, the phenotype of CD45E613R mice varies with genetic background. CD45E613R mice backcrossed to C57BL/6 (B6) or 129/Sv backgrounds fail to develop autoantibodies or end organ damage while F1 B6-129 CD45E613R mice develop high titer auto-antibodies and severe nephritis. Interestingly, BALB/c CD45E613R mice develop auto-antibodies but no nephritis. Using cytokine arrays and flow cytometry, we identified dysregulated cytokines and immune cell subsets in F1 B6-129 CD45E613R mice relative to the parental strains and wild-type controls. Classical inflammatory cytokines IL-1a and TNF-a were elevated in B6-129 F1 wedge mice. In contrast, MIP-1a and GM-CSF were most elevated in BALB/c wedge mice, implicating a protective effect. Uncovering new biomarkers and understanding disease pathogenesis should provide new insights into therapies for lupus nephritis.

Anti-nuclear autoantibody (ANA) production by autoreactive B cells is a hallmark symptom of the autoimmune disease Systemic Lupus Erythematosus (SLE), which has a complex genetic etiology with environmental influences. In the CD45E613R knock-in mouse model of SLE, mice homozygous for an activating point mutation in CD45 develop high titer anti-dsDNA autoantibodies on the BALB/c (BA) and not the C57BL6/J (B6) or 129/Sv genetic backgrounds despite hyper-responsive ITAM signaling in several immune lineages in each genetic background. A screen for genetic modifiers of autoantibody production identified the candidate gene Tlr9. Sequence analysis of B6 and BA alleles of Tlr9 indicate several point mutations, resulting in five amino acid substitutions in TLR9. Splenic CD11b+ myeloid cells from BA express lower levels of TLR9 and BA-derived BMDCs are less responsive to synthetic TLR9 ligand CpG DNA. BA B cells are also less responsive to TLR9-mediated signaling than B6 B cells despite similar levels of TLR9 protein, indicating the BA TLR9 allele is hypo-responsive. Genetic ablation of TLR9 in CD45E613R mice on the non-autoreactive B6 genetic background augments disease, with mice developing splenomegaly and increased frequencies of memory T cells by 3 months of age. Some aged animals also developed ANAs, supporting the hypothesis that reduced TLR9 responsiveness permits increased autoreactivity in the context of hyper-responsive ITAM signaling.

Pep and CD45 are tyrosine phosphatases whose targets include the Src-family kinases, critical mediators of antigen receptor signaling. A polymorphism in PTPN22, the gene that encodes the human Pep ortholog Lyp, confers susceptibility to multiple human autoimmune diseases. However, the significance of the R620W risk allele is not clear. We report that misexpression of wild type or R620W Lyp/Pep in Jurkat cells, in the context of their binding partner Csk, unmasks the risk allele as a hypomorph. Although Pep deficient mice on the B6 background have hyper-responsive memory T cells, they fail to develop autoimmune disease. Mice containing a point mutation in CD45 (E613R) develop a B cell-driven lupus-like disease on the mixed 129/B6, but not on the B6 background. To model in mice how human susceptibility loci such as PTPN22 cooperate to provoke autoimmune disease, we studied the ability of Pep deficiency to act as a genetic modifier of the CD45 E613R mutation on the non-autoimmune B6 background. Double mutant mice develop a lupus-like disease as well as a lymphoproliferative syndrome. Following antigen receptor stimulation, peripheral B cells in the double mutant mice phenocopy hyper-responsive CD45 E613R B cells, whereas peripheral T cells respond like Pep-/- T cells. These studies suggest that Pep-/- T cells in the context of a susceptible microenvironment can drive hyper-responsive CD45 E613R B cells to break tolerance.