Patients and families affected by sarcomas often ask, "What is cancer?" Answers frequently portray cancer as mutant cells gone rogue with rapid, uncontrolled, and even zombie-like growth. This analogy may be helpful for encouraging compliance during chemotherapy, when cure requires enduring significant toxicity. However, this "zombie" paradigm understates cancer's most lethal and sophisticated property-its ability to evolve. [1][2][3][4] In contrast, viewing cancer as an invasive and evolving species may provide a more accurate and accessible analogy. This model "normalizes" cancer cells by emphasizing their obedience to the same laws of ecology and evolution that govern all living systems. Within this framework, the Darwinian dynamics of evolution can be leveraged to improve understanding of tumor growth and resistance.Normal mammalian cells do not evolve because their fates are determined by collective tissue controls, making their fitness (for a Glossary of Terms, see Table 1) identical to that of the host organism. Fundamentally, cancer is a shift in the order of natural selection from the host level to that of an individual cancer cell. This new, "self-defined" fitness function of the cancer cell can be considered a speciation event. 3 In becoming a singular unit of natural selection, a cancer cell must respond to external influences from the host environment. To understand malignancy as a complex, adapting system of cancer cells, we introduce key terms and emerging theories from evolutionary biology that may translate into novel clinical trials. Although evolutionary principles are applicable to many cancer types across adult and pediatric oncology, here, we apply these concepts to pediatric sarcoma, using an evolution-inspired clinical trial in metastatic fusion-positive rhabdomyosarcoma (FPRMS) as an illustration. PEDIATRIC SARCOMASSarcomas, such as osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma, collectively make up 10% of malignancies in children and young adults. Even when disease is clinically localized at presentation, surgery and/or radiation alone is usually insufficient for cure, as a majority of patients will relapse, frequently through development of distant metastases. Because there are no current ways to identify patients who can be cured by local control alone, chemotherapy is recommended for all patients. Cure rates increase up to 65% to 80% for localized disease with the addition of combination chemotherapy. [5][6][7][8][9] Although there is a growing understanding of the genetic features distinguishing sarcoma cells from somatic cells, the most successful treatments target pathways common to tumor and normal cells alike, so-called "never mutated pathways," such as DNA synthesis and replication, topoisomerase-mediated DNA repair, and microtubule function. 2,10-15 Unfortunately, outcomes for metastatic pediatric sarcomas have changed little over the past 2 decades, and the prognosis for metastatic pediatric sarcomas remains dismal. [16][17][18] The application of evolutionary concepts to ...
BackgroundPrimary immunodeficiency is common among patients with autoimmune cytopenia.ObjectiveThe purpose of this study is to retrospectively identify key clinical features and biomarkers of primary immunodeficiency (PID) in pediatric patients with autoimmune cytopenias (AIC) so as to facilitate early diagnosis and targeted therapy.MethodsElectronic medical records at a pediatric tertiary care center were reviewed. We selected 154 patients with both AIC and PID (n=17), or AIC alone (n=137) for inclusion in two cohorts. Immunoglobulin levels, vaccine titers, lymphocyte subsets (T, B and NK cells), autoantibodies, clinical characteristics, and response to treatment were recorded.ResultsClinical features associated with AIC-PID included splenomegaly, short stature, and recurrent or chronic infections. PID patients were more likely to have autoimmune hemolytic anemia (AIHA) or Evans syndrome than AIC-only patients. The AIC-PID group was also distinguished by low T cells (CD3 and CD8), low immunoglobulins (IgG and IgA), and higher prevalence of autoantibodies to red blood cells, platelets or neutrophils. AIC diagnosis preceded PID diagnosis by 3 years on average, except among those with partial DiGeorge syndrome. AIC-PID patients were more likely to fail first-line treatment.ConclusionsAIC patients, especially those with Evans syndrome or AIHA, should be evaluated for PID. Lymphocyte subsets and immune globulins serve as a rapid screen for underlying PID. Early detection of patients with comorbid PID and AIC may improve treatment outcomes. Prospective studies are needed to confirm the diagnostic clues identified and to guide targeted therapy.
Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200–300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75–150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML.
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