BackgroundIsolated myeloid sarcoma (MS) is a rare extramedullary tumor mass composed of malignant myeloid precursor cells without any evidence of leukemia in the peripheral blood and bone marrow. We describe the clinical characteristics and outcomes of patients diagnosed with isolated MS at our institution.MethodsWe retrospectively reviewed 9 of 497 acute myeloid leukemia (AML) patients (1.8%) with isolated MS. Isolated MS patients were divided into 2 groups according to the first-line treatment strategy: systemic treatment only (S) or local treatment with or without systemic treatment (LS).ResultsThe most common site of MS occurrence was the head and neck area (N=4, 44.4%), followed by the anterior mediastinum (N=2, 22.2%) and the gastrointestinal tract (N=2, 22.2%). The tumors of 4 patients (44.4%) eventually evolved to AML, in a median time of 13.4 months (range, 2.4–20.1 mo). The number of patients achieving complete remission after first-line treatment was higher in the LS group (N=5, 83.3%) than in the S group (N=1, 33.3%) (P =0.226). All patients in the LS group survived, but those in the S group died (P=0.012).ConclusionAccurate and rapid diagnosis using various modalities and the early initiation of intensive combined treatment may be the optimal strategies to reduce the risk of isolated MS subsequently evolving to AML. To fully understand the characteristics of isolated MS, a larger number of patients from a multinational study is necessary.

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Background: The histone methyltransferase G9a has recently been identified as a potential target for epigenetic therapy of acute myeloid leukemia (AML). However, the effect of G9a inhibition on leukemia stem cells (LSCs), which are responsible for AML drug resistance and recurrence, is unclear. In this study, we investigated the underlying mechanisms of the LSC resistance to G9a inhibition. Methods:We evaluated the effects of G9a inhibition on the unfolded protein response and autophagy in AML and LSC-like cell lines and in primary CD34 + CD38 − leukemic blasts from patients with AML and investigated the underlying mechanisms. The effects of treatment on cells were evaluated by flow cytometry, western blotting, confocal microscopy, reactive oxygen species (ROS) production assay. Results: The G9a inhibitor BIX-01294 effectively induced apoptosis in AML cell lines; however, the effect was limited in KG1 LSC-like cells. BIX-01294 treatment or siRNA-mediated G9a knockdown led to the activation of the PERK/ NRF2 pathway and HO-1 upregulation in KG1 cells. Phosphorylation of p38 and intracellular generation of reactive oxygen species (ROS) were suppressed. Pharmacological or siRNA-mediated inhibition of the PERK/NRF2 pathway synergistically enhanced BIX-01294-induced apoptosis, with suppressed HO-1 expression, increased p38 phosphorylation, and elevated ROS generation, indicating that activated PERK/NRF2 signaling suppressed ROS-induced apoptosis in KG1 cells. By contrast, cotreatment of normal hematopoietic stem cells with BIX-01294 and a PERK inhibitor had no significant proapoptotic effect. Additionally, G9a inhibition induced autophagy flux in KG1 cells, while autophagy inhibitors significantly increased the BIX-01294-induced apoptosis. This prosurvival autophagy was not abrogated by PERK/NRF2 inhibition.Conclusions: PERK/NRF2 signaling plays a key role in protecting LSCs against ROS-induced apoptosis, thus conferring resistance to G9a inhibitors. Treatment with PERK/NRF2 or autophagy inhibitors could overcome resistance to G9a inhibition and eliminate LSCs, suggesting the potential clinical utility of these unique targeted therapies against AML.

Background. The Trastuzumab for Gastric Cancer phase III trial demonstrated that combining trastuzumab with chemotherapy significantly improved overall survival compared with chemotherapy alone in HER2‐positive advanced gastric or gastroesophageal junction cancer. We report health‐related quality of life (HRQoL) and quality‐adjusted time without symptoms of disease or toxicity (Q‐TWiST) results from this trial. Patients and Methods. Patients were randomized to receive six cycles of chemotherapy given every 3 weeks (capecitabine or fluorouracil, plus cisplatin) either alone or combined with administration of trastuzumab every 3 weeks until disease progression. At each clinical visit, HRQoL was assessed using two European Organization for Research and Treatment of Cancer quality of life questionnaires, QLQ‐C30 and QLQ‐STO22. Q‐TWiST methodology was applied retrospectively using the clinical data and utility coefficients. Results. Trastuzumab plus chemotherapy prolonged time to 10% definitive deterioration in all QLQ‐C30 and QLQ‐STO22 scores, including QLQ‐C30 global health status versus chemotherapy alone, from 6.4 months to 10.2 months. In addition, trastuzumab plus chemotherapy extended Q‐TWiST by 2.42 months compared with chemotherapy alone. Conclusion. Compared with chemotherapy alone, trastuzumab plus chemotherapy prolongs time to deterioration of HRQoL and increases quality‐adjusted survival in patients with HER2‐positive gastric or gastroesophageal junction cancer.

Background: In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with a dismal outcome. Although uncoordinated 51-like kinase 1 (ULK1), which plays a central role in the autophagy pathway, has emerged as a novel therapeutic target for various cancers, its role in FLT3-ITD AML remains elusive. In this study, we evaluated the effects of ULK1 inhibition on leukemia cell death in FLT3-ITD AML. Method: We evaluated ULK1 expression and the levels of apoptosis and autophagy following ULK1 inhibition in FLT3-ITD AML cell lines and investigated the mechanism underlying apoptosis induced by ULK1 inhibition. Statistical analysis was performed using GraphPad Prism 4.0 (GraphPad Software Inc). Results: FLT3-ITD AML cells showed significantly higher ULK1 expression than FLT3-wild-type (WT) AML cells. Two ULK1 inhibitors, MRT 68921 and SBI-0206965, induced apoptosis in FLT3-ITD AML cells, with relatively minimal effects on FLT3-WT AML cells and normal CD34-positive cells. Apoptosis induction by ULK1 inhibition was associated with caspase pathway activation. Interestingly, ULK1 inhibition paradoxically also induced autophagy, showing synergistic interaction with autophagy inhibitors. Hence, autophagy may act as a prosurvival mechanism in FLT3-ITD AML cells. FLT3-ITD protein degradation and inhibition of the ERK, AKT, and STAT5 pathways were also observed in FLT3-ITD AML cells following treatment with ULK1 inhibitors. Conclusion: ULK1 is a viable drug target and ULK1 inhibition may represent a promising therapeutic strategy against FLT3-ITD AML.