Understanding inequities in precision oncology diagnostics.

Advances in molecular diagnostics have enabled the identification of targetable driver pathogenic variants, forming the basis of precision oncology care. However, the adoption of new technologies, such as next-generation sequencing (NGS) panels, can exacerbate healthcare disparities. Here, we summarize data on use patterns of advanced biomarker testing, highlight the disparities in both accessing NGS testing and using this data to match patients to appropriate personalized therapies and propose multidisciplinary strategies to address inequities looking forward.

Resident-Reported Impact of a Novel Oncology Curriculum for Internal Medicine Residents.

The Accreditation Council of Graduate Medical Education mandates that all internal medicine residents gain exposure to internal medicine subspecialties including hematology and oncology. While many residents meet this criterion through inpatient oncology rotations, the current structure of many inpatient oncology rotations leaves little opportunity for formal education. We therefore designed a novel oncology curriculum consisting of one-page oncology teaching sheets to increase the number, breadth, and quality of formal teaching sessions on our resident inpatient oncology services. In order to evaluate the curriculum, we conducted pre- and post-intervention surveys of residents. From these surveys, we found that 72.2% of residents used the teaching sheets on their inpatient oncology rotation and that the teaching sheets led to an increase in the number of formal oncology teaching sessions (mean 3.4 ± 2.1 post-implementation vs 2.6 ± 2.0 pre-implementation, p = 0.008), the breadth of oncology topics taught (% reporting ≥ 5 topics; 26.1% vs 16.3%, p = 0.035), the proportion of residents reporting improvement in overall oncology knowledge (80.2% vs 62.4%, p = 0.012), and the proportion of residents reporting improvement in their ability to care for patients (70.8% vs 48.9%, p = 0.013). These results demonstrate that formal oncology teaching can be improved on inpatient oncology rotations through a simple and easily replicable oncology curriculum.

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML.

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2-mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 (Tet2) mutations and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.

Effects of Interleukin-1ß Inhibition on Incident Anemia: Exploratory Analyses From a Randomized Trial.

Background: Inflammatory cytokines, such as interleukin (IL)-1ß, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1ß can reverse these effects is unclear. Objective: To determine whether IL-1ß inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia. Design: Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846). Setting: Many clinical sites in 39 countries. Participants: 8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry. Intervention: Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Measurements: Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women). Results: Anemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1ß inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher. Limitation: CANTOS was not designed to assess the cause of anemia in individual trial participants. Conclusion: These exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1ß/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia. Primary Funding Source: Novartis Pharmaceuticals.

Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis.

Emapalumab is a fully human immunoglobulin G1 monoclonal antibody directed against interferon-γ (IFN-γ), which in November 2018 received the first global approval for the treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance to HLH therapy. This review will highlight the pathophysiology of primary HLH, the therapeutic rationale for use of IFN-γ-targeting therapy, and potential limitations to its broader use in the treatment of HLH.

Management of disseminated intravascular coagulation in a patient with hepatic angiosarcoma: A case report.

RATIONALE: Hepatic angiosarcoma is a rare endothelial cell tumor that may lead to concurrent consumptive coagulopathies including disseminated intravascular coagulation (DIC). This report details a multifaceted approach to managing DIC in a patient with advanced-stage hepatic angiosarcoma, which continued to progress after a brief response to taxane-based chemotherapy. PATIENT CONCERNS: A 55-year-old man with a recent history of hemorrhoids and hemarthroses presented with acute rectal bleeding. He was found to have concurrent hepatomegaly, abnormal liver function tests, anemia, thrombocytopenia, and coagulopathy. DIAGNOSES: DIC in the setting of hepatic angiosarcoma. INTERVENTIONS: The patient's acute bleeding in the setting of DIC was controlled with a combination of antifibrinolytic agents to prevent clot breakdown, heparin products to prevent deposition of new clot, and romiplostim to increase platelet production. His angiosarcoma was treated with various combinations of chemotherapy, including taxane-based chemotherapy, doxorubicin, and pazopanib. OUTCOMES: The patient's DIC and acute bleeding on initial presentation improved following treatment with unfractionated heparin and low-molecular weight heparin maintenance therapy. It is unclear if the chemotherapy to treat the hepatic angiosarcoma played a significant role in the improvement of DIC. LESSONS: Laboratory measurement of prothrombin fragment 1.2, a byproduct of prothrombin conversion to thrombin, proved to be a useful way to monitor this patient's DIC over time.

Functional, chemical genomic, and super-enhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma.

Ewing sarcoma is an aggressive bone and soft tissue tumor in children and adolescents, with treatment remaining a clinical challenge. This disease is mediated by somatic chromosomal translocations of the EWS gene and a gene encoding an ETS transcription factor, most commonly, FLI1. While direct targeting of aberrant transcription factors remains a pharmacological challenge, identification of dependencies incurred by EWS/FLI1 expression would offer a new therapeutic avenue. We used a combination of super-enhancer profiling, near-whole genome shRNA-based and small-molecule screening to identify cyclin D1 and CDK4 as Ewing sarcoma-selective dependencies. We revealed that super-enhancers mark Ewing sarcoma specific expression signatures and EWS/FLI1 target genes in human Ewing sarcoma cell lines. Particularly, a super-enhancer regulates cyclin D1 and promotes its expression in Ewing sarcoma. We demonstrated that Ewing sarcoma cells require CDK4 and cyclin D1 for survival and anchorage-independent growth. Additionally, pharmacologic inhibition of CDK4 with selective CDK4/6 inhibitors led to cytostasis and cell death of Ewing sarcoma cell lines in vitro and growth delay in an in vivo Ewing sarcoma xenograft model. These results demonstrated a dependency in Ewing sarcoma on CDK4 and cyclin D1 and support exploration of CDK4/6 inhibitors as a therapeutic approach for patients with this disease.

The role of spirituality and religious coping in the quality of life of patients with advanced cancer receiving palliative radiation therapy.

OBJECTIVES: National palliative care guidelines outline spiritual care as a domain of palliative care, yet patients' religiousness and/or spirituality (R/S) are underappreciated in the palliative oncology setting. Among patients with advanced cancer receiving palliative radiation therapy (RT), this study aims to characterize patient spirituality, religiousness, and religious coping; examine the relationships of these variables to quality of life (QOL); and assess patients' perceptions of spiritual care in the cancer care setting. METHODS: This is a multisite, cross-sectional survey of 69 patients with advanced cancer (response rate = 73%) receiving palliative RT. Scripted interviews assessed patient spirituality, religiousness, religious coping, QOL (McGill QOL Questionnaire), and perceptions of the importance of attention to spiritual needs by health providers. Multivariable models assessed the relationships of patient spirituality and R/S coping to patient QOL, controlling for other significant predictors of QOL. RESULTS: Most participants (84%) indicated reliance on R/S beliefs to cope with cancer. Patient spirituality and religious coping were associated with improved QOL in multivariable analyses (ß = 10.57, P < .001 and ß = 1.28, P = .01, respectively). Most patients considered attention to spiritual concerns an important part of cancer care by physicians (87%) and nurses (85%). LIMITATIONS: Limitations include a small sample size, a cross-sectional study design, and a limited proportion of nonwhite participants (15%) from one US region. CONCLUSION: Patients receiving palliative RT rely on R/S beliefs to cope with advanced cancer. Furthermore, spirituality and religious coping are contributors to better QOL. These findings highlight the importance of spiritual care in advanced cancer care.

Autoantibodies to recombinant human CTL2 in autoimmune hearing loss.

OBJECTIVES/HYPOTHESIS: Choline transporter-like protein 2 (CTL2), a 68-72 kDa inner-ear membrane glycoprotein, is a candidate target antigen in autoimmune hearing loss (AIHL). The objective of this study was to test recombinant human CTL2 as a potential target for the detection of human autoantibodies in patients with AIHL. STUDY DESIGN: In vitro assay development. METHODS: Human inner ear CTL2 mRNA was cloned into baculovirus and used to infect insect cells. Immunofluorescence and western blotting were used to determine optimal expression of recombinant human CTL2 (rHuCTL2) in insect cells. AIHL patient sera of known reactivity with guinea pig inner ear were tested for antibodies to purified rHuCTL2 on western blots. Sera from normal hearing donors were used as controls. RESULTS: The rHuCTL2 protein migrated as three bands: a core protein of 62 kDa and two N-glycosylated bands at 66 and 70 kDa. Sera from 6/12 (50%) of AIHL patients with antibody to the 68-72 kDa inner-ear protein or to supporting cells also have antibody to rHuCTL2. Four of the four patients with antibody to rHuCTL2 responded to corticosteroids, whereas 4/8 that lacked antibody to rHuCTL2 did not. Among normal human sera, 80% were negative; binding was barely detectable in 3/15 (20%). CONCLUSIONS: The rHuCTL2 protein can be produced efficiently and used as a substrate for testing human sera. Antibodies to rHuCTL2 were detected in 50% of inner-ear-reactive AIHL sera. Additionally, circulating antibody to rHuCTL2 is with associated response to corticosteroids in some AIHL patients.