Dihydroartemisinin-induced ferroptosis in acute myeloid leukemia: links to iron metabolism and metallothionein.

Artemisinin is an anti-malarial drug that has shown anticancer properties. Recently, ferroptosis was reported to be induced by dihydroartemisinin (DHA) and linked to iron increase. In the current study, we determined the effect of DHA in leukemic cell lines on ferroptosis induction and iron metabolism and the cytoprotective effect triggered in leukemic cells. We found that treatment of DHA induces early ferroptosis by promoting ferritinophagy and subsequent iron increase. Furthermore, our study demonstrated that DHA activated zinc metabolism signaling, especially the upregulation of metallothionein (MT). Supportingly, we showed that inhibition MT2A and MT1M isoforms enhanced DHA-induced ferroptosis. Finally, we demonstrated that DHA-induced ferroptosis alters glutathione pool, which is highly dependent on MTs-driven antioxidant response. Taken together, our study indicated that DHA activates ferritinophagy and subsequent ferroptosis in AML and that MTs are involved in glutathione regenerating and antioxidant response.

A meropenem pharmacokinetics model in patients with haematological malignancies.

BACKGROUND: Optimal dosing of antibiotics is critical in immunocompromised patients suspected to have an infection. Data on pharmacokinetics (PK) of meropenem in patients with haematological malignancies are scarce. OBJECTIVES: To optimize dosing regimens, we aimed to develop a PK population model for meropenem in this population. METHODS: Patients aged ≥18 years, hospitalized in the haematology department of our 1500 bed university hospital for a malignant haematological disease and who had received at least one dose of meropenem were eligible. Meropenem was quantified by HPLC. PK were described using a non-linear mixed-effect model and external validation performed on a distinct database. Monte Carlo simulations estimated the PTA, depending on renal function, duration of infusion and MIC. Target for free trough concentration was set at >4× MIC. RESULTS: Overall, 88 patients (181 samples) were included, 66 patients (75%) were in aplasia and median Modification of Diet in Renal Disease (MDRD) CLCR was 117 mL/min/1.73 m2 (range: 35-359). Initial meropenem dosing regimen ranged from 1 g q8h to 2 g q8h over 30 to 60 min. A one-compartment model with first-order elimination adequately described the data. Only MDRD CLCR was found to be significantly associated with CL. Only continuous infusion achieved a PTA of 100% whatever the MIC and MDRD CLCR. Short duration of infusion (<60 min) failed to reach an acceptable PTA, except for bacteria with MIC < 0.25 mg/L in patients with MDRD CLCR below 90 mL/min/1.73 m2. CONCLUSIONS: In patients with malignant haematological diseases, meropenem should be administered at high dose (6 g/day) and on continuous infusion to reach acceptable trough concentrations.

Radiotherapy of relapse-refractory follicular lymphoma.

PURPOSE: To assess the efficacy of treatment and outcomes of patients with relapsed or refractory follicular lymphoma treated with external beam irradiation. PATIENTS AND METHODS: Fifteen patients who received external beam radiotherapy for relapsed or refractory follicular lymphoma were studied. The median age was 68.3 years (range: 37.9-87.08 years) with four men and 11 women. Seven patients had early stage (I or II); eight advanced stage (III or IV). Median FLIPI score was 2. Two patients had high tumour bulk disease. Six patients had extranodal invasion, with five patients having bone marrow invasion. RESULTS: The median time of follow-up after relapse or first-line treatment in case of refractory disease was 61.9 months (range: 9.1-119.7 months). Complete response after external beam radiotherapy was seen in 11 cases (73%) and partial response in two (13%), with a median dose of 30Gy (range: 2-40Gy) and median number of fractions of 15 (range: 2-20). Eight patients (53%) relapsed after external beam radiation therapy in a median of 20.2 months, mostly out of irradiated volumes. Most patients (66%) had a disease control after one or two courses of external beam radiation therapy. At last follow-up, 86% of patients were in remission including those with salvage chemotherapy. The toxicity profile was favourable with toxicity higher than grade 1. In univariate analysis, a Follicular Lymphoma International Prognostic Index (FLIPI) score above 2 was the only predicting factor for non-control disease. CONCLUSION: For relapsed and refractory follicular lymphoma, external beam radiotherapy should be considered as an effective modality when integrated in a multimodality approach. Randomised studies are warranted to validate this strategy.

[Autoimmune and inflammatory disorders associated with lymphoid hematological malignancies]. / Manifestations auto-immunes et inflammatoires des hémopathies lymphoïdes.

In this literature review, we reported autoimmune and inflammatory disorders associated with lymphoid hematological malignancies, including non-Hodgkin's lymphoma, Hodgkin's lymphoma and chronic lymphocytic leukemia. The different types of systemic involvement are classified by affected organ. We listed in this review the joint diseases, skin, neurologic, hematologic, renal, and vasculitis. We tried to determine whether there is a correlation between each autoimmune manifestation and a specific type of lymphoma or a particular feature that may support a paraneoplastic origin, if there is an impact on the prognosis of the hematological malignancy, and finally, we identified the different therapeutic strategies used in the literature.