Systematic Literature Review of the Prevalence and Prognostic Value of Delta-Like Ligand 3 Protein Expression in Small Cell Lung Cancer

Background: Delta-like ligand 3 (DLL3), a member of the Notch pathway, has been identified as a potential therapeutic target as it is highly expressed in small cell lung cancer (SCLC), a subtype accounting for 15% of lung cancer cases. Objective: A systematic literature review (SLR) was conducted to understand the prevalence and prognostic impact of DLL3 expression on survival of patients with SCLC and treatment response. Patients and Methods: Systematic literature searches were conducted across multiple databases to capture studies of any SCLC population that evaluated DLL3 expression. Specific outcomes of interest included prevalence of DLL3 expression, method of expression analysis, and impact on outcome, including treatment response and survival (overall, progression-free, disease-free) according to varying levels of DLL3 expression/positivity. Standard risk of bias tools were used to evaluate study quality. Results: Among the 30 included studies, the most common DLL3 testing method was immunohistochemistry (N = 26, 86.7%). For comparability, results focused on the 13 (22.3%) studies that used the Ventana DLL3 (SP347) immunohistochemistry assay. The prevalence of DLL3 positivity ranged from 80.0–93.5% for studies using a threshold of ≥ 1% of tumor cells (N = 4) and 58.3–91.1% for studies with a ≥ 25% threshold (N = 4). DLL3 expression was generally categorized as high using cutoffs of ≥ 50% (prevalence range: 45.8–79.5%; N = 6) or ≥ 75% (prevalence range: 47.3–75.6%; N = 5) of cells with positivity. Two studies used an H-score of ≥ 150 to define high DLL3 expression with prevalence ranging from 33.3–53.1%. No consistent associations were seen between DLL3 expression level and patient age, sex, smoking history, or disease stage. Two studies reported change in DLL3 expression category (high versus low) before and after chemotherapy. No statistically significant differences were reported between DLL3 expression groups and survival (overall, progression-free, or disease-free) or treatment response. Conclusions: There is a high prevalence of DLL3 expression in SCLC. Further research and analytical methods may help to characterize different populations of patients with SCLC based on DLL3 expression. While no significant prognostic factor in the included studies was identified, additional cohort studies using standardized methodology, with longer follow-up, are needed to better characterize any potential differences in patient survival or response by DLL3 expression level in SCLC.</p

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-mediated cardiovascular, rheumatic, and renal toxicities from checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Although they are of variable occurrence, cardiovascular, rheumatic, and renal immune-mediated toxicities are among the most serious of these adverse events. We present MASCC recommendations with respect to the workup and management of cardiovascular, rheumatic, and renal immune-mediated toxicities with a focus on presentations that require treatment with immunomodulating agents.The Cancer Association of South Africa (CANSA), the National Research Foundation (NRF) of South Africa and the NIH/NCI (Cancer Center Support Grant P30 CA008748).http://link.springer.com/journal/5202021-08-20hj2020Immunolog

Fractures following hematopoietic stem cell transplantation: Risk prediction and evaluation of prevention and treatment stratergies

In the last couple of decades, the number of survivors following a hematopoietic stem cell transplantation (HSCT) has been steadily increasing. Bone loss and its clinical manifestations of osteopenia, osteoporosis and fragility fractures are rapidly occurring, long-lasting and common complications following HSCT. Bone remodeling in the context of HSCT is multifactorial and pre-, peri- and post- transplantation factors are involved in the dysregulation of bone homeostasis. Little research has been conducted to identify patients at high risk of bone complications following HSCT. The overall objectives of this study are to identify patients at high risk of bone complications that can potentially benefit from pharmacological intervention in a large cohort of patients that received a HSCT and to evaluate the most effective methods to prevent and treat bone loss and fractures following HSCT. This project was divide into three papers with the following aims: 1) To evaluate the predictive ability of the World Health Organization Fracture Risk Assessment model - FRAX in identifying osteoporotic fractures in patients following a HSCT; 2) To compare and contrast the rates of osteoporotic fractures and evaluate a comprehensive set of demographic and clinical characteristics in osteoporotic fracture risk prediction following HSCT in patients with and without multiple myeloma; 3) To evaluate the evidence and analyze the treatments currently available to treat or prevent bone loss following HSCT in a systematic review and meta-analysis. The first two aims utilize data from a 10-year cohort of adult patients that underwent a HSCT at The University of Texas MD Anderson Cancer Center. All patients were retrospectively followed for a minimum of 3 years for assessment of osteoporotic fractures. (Abstract shortened by ProQuest.

Rheumatic and Musculoskeletal Adverse Events with Immune Checkpoint Inhibitors: Data from the United States Food and Drug Administration Adverse Event Reporting System

Background: Despite their efficacy, immune checkpoint inhibitors (ICIs) can cause significant immune-related adverse events (irAEs). Rheumatic and musculoskeletal irAEs can be serious and adversely affect the quality of life. The full spectrum of irAEs is still emerging, and to represent and better understand their scope, we evaluated the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: We used AERSMine, an open-access web application to mine FAERS data across 11,919,342 patients from 2011 (first quarter) to 2018 (fourth quarter). Measures of disproportionality were calculated using well-established pharmacovigilance metrics, proportional reporting ratios, and safety signals (information component), in patients receiving ICI. Results: We analyzed 63,979 cancer patients for reports of ICI-associated AEs. Eighty-two percent of these reports were in relation with anti-PD-1 inhibitors. Rates of rheumatic and musculoskeletal AEs were higher in men and in patients >65 years of age. Several statistically significant AEs were identified, most in relation with PD-1 inhibitors. AEs with the highest number of reports included arthralgia (n = 1062), followed by myalgia (n = 532), myositis (n = 438), arthritis (n = 403), and rhabdomyolysis (n = 230). Novel AEs affecting the skeleton included compression fractures, fractures at various skeletal sites (rib, thoracic vertebral, and humerus), osteonecrosis of the jaw, osteitis, and osteomyelitis. Conclusion: A wide spectrum of rheumatic and musculoskeletal AE signals were detected within the FAERS data which may signify the emerging trends of irAEs post approval of ICI. Additional research to explore mechanisms and identify optimal management strategies of these AEs is warranted

Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors

Objective To estimate the incidence of immune checkpoint inhibitor-related myositis (ICI-myositis) in cancer patients receiving ICIs, and to report associated clinical manifestations, patterns of care, and outcomes. Methods We identified a retrospective cohort of patients receiving ICIs between 2016 and 2019 seen at the University of Texas MD Anderson Cancer Center. Cases of ICI-myositis were identified using International Classification of Disease codes and confirmed by reviewing medical records and pathology, as available. Results A total of 9,088 patients received an ICI. Thirty-six patients (0.40%) were identified as having ICI-myositis: 17 patients (47%) with ICI-myositis alone and 19 (53%) with overlap manifestations (5 patients with myocarditis, 5 with myasthenia gravis, and 9 with both). The incidence of ICI-myositis was 0.31% in those receiving ICI monotherapy and 0.94% in those receiving combination ICI therapy (relative risk 3.1 [95% confidence interval 1.5-6.1]). Twenty-five patients (69%) received >= 1 treatment in addition to glucocorticoids: plasmapheresis in 17 patients (47%), intravenous immunoglobulin in 12 (33%), and biologics in 11 (31%). Patients with overlap conditions had worse outcomes than those with myositis alone, and 79% of them developed respiratory failure. Eight patients died as a result of ICI-myositis, and all had overlap syndrome with myasthenia gravis or myocarditis (P < 0.05); 75% of these patients had a concomitant infection. Conclusion ICI-myositis is a rare but severe adverse event. More than half of the patients presented with overlap manifestations and had deleterious outcomes, including respiratory failure and death. None of the patients with ICI-myositis alone died as a result of adverse events. Optimal treatment strategies have yet to be determined