Dynamic evolution of bone marrow adipocyte in B cell acute lymphoblastic leukemia: insights from diagnosis to post-chemotherapy.

Adipocyte is a unique and versatile component of bone marrow microenvironment (BMM). However, the dynamic evolution of Bone Marrow (BM) adipocytes from the diagnosis of B cell Acute Lymphoblastic Leukemia (B-ALL) to the post-treatment state, and how they affect the progression of leukemia, remains inadequately explicated. Primary patient-derived xenograft models (PDXs) and stromal cell co-culture system are employed in this study. We show that the dynamic evolution of BM adipocytes from initial diagnosis of B-ALL to the post-chemotherapy phase, transitioning from cellular depletion in the initial leukemia niche to a fully restored state upon remission. Increased BM adipocytes retards engraftment of B-ALL cells in PDX models and inhibits cells growth of B-ALL in vitro. Mechanistically, the proliferation arrest of B-ALL cells in the context of adipocytes-enrichment niche, might attribute to the presence of adiponectin secreted by adipocytes themselves and the absence of cytokines secreted by mesenchymal stem cell (MSCs). In summary, our findings offer a novel perspective for further in-depth understanding of the dynamic balance between BMM and B-ALL.

Impact of measurable residual disease in combination with CD19 on postremission therapy choices for adult t(8;21) acute myeloid leukemia in first complete remission.

BACKGROUND: The post-remission therapy (PRT) choices for adult t(8;21) acute myeloid leukemia (AML) in first complete remission (CR1) need to be further explored. AIMS: We aimed to investigate the impact of measurable residual disease (MRD) combined with CD19 on PRT choices for adult t(8;21) AML in CR1. METHODS: A total of 150 t(8;21) AML patients were enrolled, including 67 underwent chemotherapy (CMT) and 83 allogeneic hematopoietic stem cell transplantation (allo-SCT) as PRT in CR1. Subgroup analyses were performed according to MRD level after three cycles of chemotherapy combined with CD19 expression. RESULTS: Multivariate analysis indicated MRDhigh after three courses of treatment (HR, 0.14 [95% CI, 0.03-0.66]; p = 0.013) and CD19 negativity (HR, 0.14 [95% CI, 0.02-0.96]; p = 0.045) were risk factors for relapse, while allo-SCT was protective factor for relapse (HR, 0.34 [95% CI, 0.15-0.75]; p = 0.008). Grouped by MRD after three courses of chemotherapy, allo-SCT had lower CIR (p < 0.001) and better OS (p = 0.003) than CMT for MRDhigh patients, CMT showed a higher CIR (35.99% vs. 15.34%, p = 0.100) but comparable OS (p = 0.588) than allo-SCT for MRDlow patients. Grouped by CD19 expression, allo-SCT demonstrated lower CIR (p < 0.001) and better OS (p = 0.002) than CMT for CD19- patients. CMT had a higher CIR (41.37% vs. 10.48%, p = 0.007) but comparable OS (p = 0.147) than allo-SCT for CD19+ patients. Grouped by MRD combined with CD19, MRDhigh /CD19+ subsets were identified out of CD19+ patients benefiting from allo-SCT with lower CIR (p = 0.002) and superior OS (p = 0.020) than CMT. CMT preserved comparable CIR (p = 0.939) and OS (p = 0.658) with allo-SCT for MRDlow /CD19+ patients. MRDlow /CD19- subsets were also identified from MRDlow patients requiring allo-SCT with lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT. Allo-SCT maintained lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT for MRDhigh /CD19- patients. CONCLUSIONS: MRD combined with CD19 might optimize PRT choices for adult t(8;21) AML patients in CR1.

Automatic origin prediction of liver metastases via hierarchical artificial-intelligence system trained on multiphasic CT data: a retrospective, multicentre study.

Background: Currently, the diagnostic testing for the primary origin of liver metastases (LMs) can be laborious, complicating clinical decision-making. Directly classifying the primary origin of LMs at computed tomography (CT) images has proven to be challenging, despite its potential to streamline the entire diagnostic workflow. Methods: We developed ALMSS, an artificial intelligence (AI)-based LMs screening system, to provide automated liver contrast-enhanced CT analysis for distinguishing LMs from hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), as well as subtyping primary origin of LMs as six organ systems. We processed a CECT dataset between January 1, 2013 and June 30, 2022 (n = 3105: 840 HCC, 354 ICC, and 1911 LMs) for training and internally testing ALMSS, and two additional cohorts (n = 622) for external validation of its diagnostic performance. The performance of radiologists with and without the assistance of ALMSS in diagnosing and subtyping LMs was assessed. Findings: ALMSS achieved average area under the curve (AUC) of 0.917 (95% confidence interval [CI]: 0.899-0.931) and 0.923 (95% [CI]: 0.905-0.937) for differentiating LMs, HCC and ICC on both the internal testing set and external testing set, outperformed that of two radiologists. Moreover, ALMSS yielded average AUC of 0.815 (95% [CI]: 0.794-0.836) and 0.818 (95% [CI]: 0.790-0.842) for predicting six primary origins on both two testing sets. Interestingly, ALMSS assigned origin diagnoses for LMs with pathological phenotypes beyond the training categories with average AUC of 0.761 (95% [CI]: 0.657-0.842), which verify the model's diagnostic expandability. Interpretation: Our study established an AI-based diagnostic system that effectively identifies and characterizes LMs directly from multiphasic CT images. Funding: National Natural Science Foundation of China, Guangdong Provincial Key Laboratory of Medical Image Processing.

Low-Dose Triptolide Enhanced Activity of Idarubicin Against Acute Myeloid Leukemia Stem-like Cells Via Inhibiting DNA Damage Repair Response.

Leukemia stem cells (LSCs) are considered to be the root of relapse for acute myeloid leukemia (AML). Conventional chemotherapeutic drugs fail to eliminate LSCs. Therefore, new therapeutic strategies eliminating LSCs are urgently needed. Our results showed that low-dose Triptolide (TPL) enhanced the anti-AML activity of Idarubicin (IDA) in vitro against LSC-like cells (CD34 + CD38- KG1αand CD34 + CD38- kasumi-1 cells) and CD34+ primary AML cells, while sparing normal cells. Inspiringly, the combination treatment with low-dose TPL and IDA was also effective against CD34 + blasts from AML patients with FLT3-ITD mutation, which is an unfavorable risk factor for AML patients. Moreover, the combination of TPL and IDA induced a remarkable suppression of human leukemia growth in a xenograft mouse model. Mechanistically, the enhanced effect of low dose TPL on IDA against LSCs was attributed to inhibiting DNA damage repair response. Thus, our study may provide a theoretical basis to facilitate the development of a novel LSCs-targeting strategy for AML.Graphical abstract.

Graft-vs-Host Disease-Induced Hyperthyroidism in a Recipient of Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report.

BACKGROUND: Hyperthyroidism after hematopoietic stem cell transplantation (HSCT) is rare, and only a few cases have been reported. What is more important, the fundamental mechanisms of hyperthyroidism after HSCT remained unclear. CASE: A 28-year-old man received an HLA haploidentical related-donor HSCT for acute myeloid leukemia and developed hyperthyroidism 31 months after HSCT. He presented with periodic paralysis as the initial symptom, his serum levels of free triiodothyronine (fT3), free thyroxine (fT4), and anti-thyroid autoantibodies increased, and thyroid-stimulating hormone level decreased. As a result, he was diagnosed with hyperthyroidism. Although systemic symptoms, signs, and laboratory findings of graft-vs-host disease (GVHD) were absent, thyroid histopathologic examination revealed thyroid follicular destruction and infiltrations of lymphocytes, which mainly consisted of CD20+ B lymphocytes and CD4+ and CD3+ T lymphocytes by immunohistochemistry. These were in accordance with the pathologic features of GVHD. The symptom of periodic paralysis resolved after treatment with prednisolone and methimazole for 1 month. The treatments lasted for 4 months, and the plasma levels of fT3, fT4, TSH, and anti-thyroid peroxidase normalized. He did not relapse after drug withdrawal with observation for 24 months to date. CONCLUSIONS: To the best of our knowledge, the present case was the first to be confirmed with thyroid-specific GVHD-induced hyperthyroidism after allogeneic HSCT.