AbstractSignal transduction pathways integrate a variety of microenvironmental cues to guide cell function by regulating gene transcription, cell cycle status, growth, and differentiation. It is well established that perturbation of these processes plays a key role in hematologic malignancies including lymphomas and chronic and acute lymphocytic leukemias. Altered intracellular signaling pathways have been proposed to mediate many biological properties of T cell large granular lymphocytic leukemia (T-LGL), a disorder characterized by a clonal proliferation of CD8 T cells resulting in immune-mediated cytopenias, most commonly neutropenia. Since T-LGL offers a unique opportunity to study signal transduction in the pathologic clonal cytotoxic T cell (CTL) compared to normal CTL, we have investigated a potential imbalance in T-LGL pro-survival signaling to define the mechanisms underlying the semi-autonomous proliferation leading to leukemia. Increased activity of the PI3K-AKT signaling axis in T-LGL cells appears to operate in conjunction with or parallel to increased STAT3 activation in these cells to inhibit the apoptotic program. This contrasts with recently reported findings in which STAT3 was shown to induce apoptosis in mammary gland epithelial cells via inhibition of the PI3K-AKT pathway, highlighting how signaling pathways interact to direct effector function in a cell-specific manner. Furthermore, the ability to define pathophysiology at the molecular level opens new avenues for targeted therapeutics.
PURPOSE Soon after the Russian invasion of Ukraine in February 2022, an initiative was organized to evacuate Ukrainian children with cancer, most initially to Poland. This study assessed the impact of this rapid increase in clinical need on the Polish system of pediatric cancer care. METHODS This multicenter longitudinal approach was performed among all 19 Polish Pediatric Oncology Centers (PPOCs). We compared PPOC capacity before the invasion with that during the first 11 weeks after the invasion, using three ratios: patients to physicians (PtP), patients to nurses (PtN), and patients to beds (PtB). In addition, we used national data from an ongoing leukemia clinical trial to assess differences between the two study periods in the time required to comply with protocol-indicated medical procedures requiring general anesthesia. RESULTS During the study period, 237 Ukrainian refugee children with cancer were treated in PPOCs; 60% of them arrived during the first 21 days of the war. The relative increase in patients varied significantly among the PPOCs, ranging from 42% to 460%. The average PtP, PtN, and PtB ratios increased significantly by 85%, 131%, and 105%, respectively. The portion of patients experiencing a delay in obtaining medical procedures requiring general anesthesia increased from 15% before the war to 18.2% ( P = .043). CONCLUSION Because of the large number of Ukrainian children with cancer were evacuated to Poland, capacity of PPOCs was reduced, affecting cancer care for all patients. Maintaining standards of pediatric oncology care in Poland would not be possible without further patient referral to medical facilities around the world by international humanitarian collaborative action.
